miRNAs involvement in the etiology and targeted therapy of bladder cancer: Interaction between signaling pathway

Bladder cancer (BC) accounts for roughly 3% of all cancer diagnoses in developed countries. The prognosis could be improved significantly if the cancer is detected and classified as either muscle‐invasive bladder cancer (MIBC) or non‐muscle‐invasive bladder cancer (NMIBC) as promptly as possible. A potential ray of hope for the treatment of BC has emerged with the rapid development of nanomedicine and microRNAs (miRNAs), which promise to have fewer adverse effects, more tumor‐inhibitory effects, and decreased drug resistance. The complex interplay between hereditary and environmental variables is the root cause of this malignancy. Gene expression can be regulated by miRNAs, which are small, non‐coding RNAs that can either prevent the translation of protein‐coding genes or cleave RNA transcripts at certain locations. Elevated genomics has enabled a more extensive investigation of miRNAs whose expression is considerably different in BC patients compared to healthy volunteers or between BC tumor tissues and peripheral tissues. miRNAs have recently been discovered to be important regulators of BC cell carcinogenicity. Inaccurate diagnoses and prolonged treatment delays are more likely to occur due to the current diagnostic process such as lack of sensitivity and specificity and poor image quality. Patients now have access to a plethora of treatment options, including but not limited to surgery, chemotherapy, immunotherapy, gene therapy, and other innovative medicines, and in some cases, combination therapies. BC is one of the deadliest and most disabling malignancies affecting the urinary tract. Cancer of the urinary bladder has a terrible propensity for being fatal. BC is an intricate illness whose development can be affected by multiple parameters. Standard treatments for BC increase prognosis and survival, although recurrence is a major concern for patients. miRNAs are naturally occurring, small RNA molecules that have been linked to cancer through their expression being dysregulated. miRNAs modulate many cellular activities including proliferation, migration, differentiation, and apoptosis. MiRNA dysregulation is recognized in BC, and miRNAs are used as diagnostic and prognostic indicators. However, this manuscript discusses the recent progress made in nanomedicine and the function of miRNAs in the pathogenesis and targeted therapy of BC.

recently been discovered to be important regulators of BC cell carcinogenicity.Inaccurate diagnoses and prolonged treatment delays are more likely to occur due to the current diagnostic process such as lack of sensitivity and specificity and poor image quality.Patients now have access to a plethora of treatment options, including but not limited to surgery, chemotherapy, immunotherapy, gene therapy, and other innovative medicines, and in some cases, combination therapies.BC is one of the deadliest and most disabling malignancies affecting the urinary tract.Cancer of the urinary bladder has a terrible propensity for being fatal.BC is an intricate illness whose development can be affected by multiple parameters.Standard treatments for BC increase prognosis and survival, although recurrence is a major concern for patients.miRNAs are naturally occurring, small RNA molecules that have been linked to cancer through their expression being dysregulated.miRNAs modulate many cellular activities including proliferation, migration, differentiation, and apoptosis.MiRNA dysregulation is recognized in BC, and miRNAs are used as diagnostic and prognostic indicators.However, this manuscript discusses the recent progress made in nanomedicine and the function of miRNAs in the pathogenesis and targeted therapy of BC. bladder cancer, miRNA; cellular signaling; chemotherapy; diagnosis; Immunotherapy; nanomedicine

| INTRODUCTION
Bladder cancer (BC) stands as the tenth most prevalent kind of cancer globally. 1There will be approximately 17 200 fatalities and 83 730 new instances of BC in the United States in 2021, according to estimates. 2BC is expected to have a 27.1% incidence rate and an 8.9% fatality rate in Europe. 3Smoking is one of the most common risk factors for BC, which is a difficult condition with numerous possible risk factors.Radiation therapy (particularly external radiation therapy for gynecological malignancies), malnutrition, metabolic issues, bladder schistosomiasis, and persistent urinary tract infections are all major risk factors. 4,5Investigation into the contribution of genetics in the etiology of BC has recently become highly competitive due to the potential therapeutic applications of integrating molecular subtypes and genetic disorders. 6The most prominent symptoms are the need to urinate often and the presence of painless hematuria. 7Comprehensive testing for BC 8 encompassing urine cytology, cystoscopic biopsy, and imaging is administered whenever symptoms of hematuria, painful urination, and signs of metastatic disease present themselves (back or pelvic pain).The United States ranks BC as the sixth most prevalent form of the disease.In 2019, there will be approximately 80 470 newly diagnosed cases of urinary BC in the United States 9,10 ; 61 700 will be detected in males and 18 770 will be diagnosed in women.
Roughly 17 670 individuals will lose their lives to the disease.Cancer of the bladder can be broken down into two broad categories based on tumor size: muscle-confined (MIBC) and muscle-invasive (NMIBC). 11Seventy percent of patients are diagnosed with NMIBC, whereas the remaining individuals have either MIBC or an advanced stage of BC. 12 Patients in the United States face a significant financial burden due to BC 13,14 because the average cost per patient ranges from 40 000 USD to more than 170 000 USD.The bladder is a crucial component of the urinary system, performing crucial functions such as the temporary storage of urine via enormous folded interior linings and the outflow of urine via contractions and relaxations of the bladder musculature. 15,16The bladder is differentiated into an apex at its top, a substantial body, a posterior fundus that seems to be triangular, and a neck where the fundus converges. 17Cancer of the urinary bladder (BC) ranks as the most prevalent malignancy worldwide.This phase started in the urothelial cells which line the bladder. 18Uroepithelial cells are the connecting tissue between the urinary tract and the kidney. 19Muscle-invasive and non-muscle-invasive BCs are the two primary forms of this malignancy.Non-muscle invasive BC comprises approximately 70%-80% of all incidences, and despite having local therapy, certain patients have a high possibility of recurrence and a fluctuating risk of progression. 20Around 25% of patients with MIBC have major surgery or radiotherapy, both of which are associated with poor outcomes despite being part of standard treatment. 20wever, minimal research indicates that second-line medicines significantly improve survival for patients with advanced BC or who refuse first-line chemotherapy. 20There is an immediate need to discover new tumor indicators that might predict recurrence or survival, as well as to clarify novel molecular pathways of BC advancement.
The specificity of urine cytology for the diagnosis of BC is high (90%-95%), making up for its low sensitivity (30%-40%).The low sensitivity of urine cytology implies a painful cystoscopic therapy for people who have undergone transurethral excision of bladder tumors to verify the initial diagnosis and screen for recurrence during follow-up examinations.Selected Works Diagnostics for BC in urine has also been recognized for use in diagnostics.The in situ fluorescent hybridization techniques, as well as the monitoring of bladder tumor antigen and nuclear matrix protein 22 (NMP22, Sysmex Corp., Kobe, Japan), are an example of these techniques.Though more sensitive than urine cytology (50%-70%), 21 these novel urinary indicators have not been widely used since their specificities are lower (60%-80%).Conventional urine cytology is a good example of how specificity can be at the expense of sensitivity.As a result, there is an immediate need for improved diagnostic biomarkers for people with BC.MicroRNAs (miR-NAs) inhibit the protein manufacturing process by targeting specific regions of the genome. 22miRNAs are found naturally, as small (19-22   base pairs), noncoding RNA molecules.Unlike some other RNA molecules, miRNAs are capable of regulating the production of several mRNAs, or protein-coding RNAs.In living beings, bioinformatics indicates that miRNAs regulate anywhere from 30% to 60% of proteincoding genes. 23,24Several analyses have demonstrated that overproduced miRNAs can function either as oncogenes or tumor suppressors in a variety of malignancies. 25These miRNAs have the possibility of interfering with the complex RNA regulatory networks necessary for the maintenance of cancer cells. 26Extensive studies into miRNAs and the genes they target in clinical BC have already been going on since 2006.The identification of miRNAs having abnormal expression in BC seems to have the capability to elucidate unappreciated molecular pathways that contribute to the development and spread of this disease.miRNAs are a group of small, noncoding RNA species that have been found to play an important role in controlling a broad range of molecular pathways, including carcinogenesis. 26Recent investigations have shown that miRNAs are present in a wide range of bodily fluids, both free and enclosed in circulatory microvesicles, revealing that they are not isolated to a specific tissue.miRNAs have been hypothesized to play a role in cell communication between physiological as well as pathological processes, although this hypothesis is still not confirmed.
Today, cystoscopy, biopsies, and CT scans are the gold standard for diagnosis.Cystoscopy has a hard time picking out the round shapes of abnormal tissue and tumors at an early stage.Thus, it is the examiner's level of expertise that ultimately determines the efficacy of cystoscopy.When a tumor is substantial, CT can be used to assess its location and the extent to which it has invaded surrounding tissue.8][29][30] BC treatment and management are primarily informed by the tumor stage and metastatic spread (Figure 1).Total transurethral resection of the bladder tumor (TURBT) to eliminate as much of the malignancy as feasible is the recommended therapy for patients with NMIBC, and may be combined with intravesical immunotherapy to avoid the occurrence or slow the disease's progression to a more advanced stage. 31oblems in administering standard drugs for treating BC are prominent at present.BC most typically develops in the urothelium, where the tissue protects the urinary bladder.Hematuria, urinary pain, and increased frequency and urgency are some of the vague symptoms associated with it.The only way to be sure what's causing these symptoms all of which could be caused by fairly common urinary tract infections is to perform a cystoscopy and examine the bladder's lining under a microscope.As a biopsy is often part of this process, it can be somewhat intrusive, and, in certain cases, anesthesia will be required.
Another noninvasive technique involves looking at cells that have been accidentally excreted into the urine, but this isn't always appropriate because the amount of cells varies on the stage of the disease, compared to the fewer cells seen in the early stages. 32To minimize potential delays in diagnosis and treatment caused by the inability of conventional imaging techniques to recognize bladder tumors before they grow to a specific size, further study of imaging techniques is recommended.Patients have now a broad range of treatment options, comprising surgeries, chemotherapy, immunotherapy, gene therapy, novel therapies, as well as combination therapies.After transurethral excision of BCs, adjuvant therapy with intravenous chemotherapy is commonly used. 33The bladder permeability barrier (BPB), which is generally localized on the uroepithelial surface and decreases drug penetration while also interfering with the typical discharge and dilution of the medication, 34 rendering current intravesical chemotherapy ineffective.Elevated expression of therapeutic nucleic acid expression in the patient's targeted sites is the technique through which gene therapy helps to reduce diseases caused by abnormal gene expression. 35Yet, the lack of safe and effective delivery vectors is the most significant barrier to the advancement of gene therapy technologies at present.While viral vectors are the most often used, non-viral vectors are quickly gaining popularity.Immunotherapy employs pharmaceuticals engineered to stimulate the body's immune system to fight cancer cells. 36Current challenges usually involve: Immunotherapy is not without its possible side effects.There are three main problems with cancer immunotherapy: Intravenous medication administration entails the accompanying potential for short-term inhibition of the malignancy response and substantial immune-related detrimental impact. 37,38Moreover, injecting large numbers of immune cells can disrupt the delicate equilibrium of the immune response, resulting in excessive production of cytokines and the onset of cytokine storms.
Effective cancer treatment options include dynamic therapy, which targets sick cells and tissues while sparing healthy ones. 39Physicians frequently use photodynamic treatment, which includes the manipulation of light as photosensitizers (PSs) require external stimulation to become active, during which stage they generate reactive oxygen species (ROS) and lead to abnormal cell death. 40Whenever nanosystems are used in healthcare, this is considered to as nanomedicine.Nanosystems have unique chemical and physical characteristics, such as a tiny size effect, a big specific surface area, a high reactivity, and a quantum effect, that set them apart from more traditional biological materials. 41In addition to nanotechnology's many promising medical applications, nanocarrier-assisted drug delivery systems have attracted a lot of attention from researchers.Cancer imaging, diagnosis (increased permeability and retention), and treatment are all made possible by the capacity of well-designed nanoparticles to target and transport agents or medications to distinct types of cells within targeted organs (Figure 2). 42,43Several different nano-drugs have been approved by the FDA to be tested in clinical studies for BC.In this study, the author examines the benefits and drawbacks of a diversity of nanocarriers employed for detecting and treating BC.

| MICRO-RNA IN BLADDER CANCER, BOTH CLINICALLY AND PATHOLOGICALLY
miRNAs are short RNA molecules (between 18 and 22 nucleotides in length) which partially supplement the 3' untranslated region of target messenger RNAs, and actively play roles in adversely regulating gene expression.These miRNAs not only show variant expression between various cancer types 44,45 but also show differential expression in malignant versus normal tissue.Several cellular processes, including apoptosis, development, proliferation, and differentiation, have been found to involve miRNAs.Due to their interaction in so many cellular processes, miRNAs have been identified as possible therapeutic targets as well as biological markers for the early detection or prognosis of a wide range of tumors. 46,47 encounter obstacles related to early diagnosis, recurrence, and development of the illness.Since current prognostic techniques do not explicitly display the clinical outcomes, 48 they are of limited use to doctors.The tumor's grade, stage, size, and number of foci comprise all of these characteristics.The framework for BC diagnosis and surveillance regimens has been established by combining data from cystoscopy and urine cytology. 49As a result, researchers have been on the search for improved biomarkers, with very much attention given to the role of miRNAs in BC development (Figure 3).

| CELLULAR FUNCTIONS OF miRNAs
MiRNA functions are often uncovered using transgenic overexpression studies or animal knockout models. 50Individual miRNA deletion in C. elegans seldom resulted in obvious aberrant phenotypes.In contrast, at least one aberrant knockout phenotype has been linked to 77% of the human miRNA families that are preserved in fish. 51To see a phenotypic effect, it appears that many miRNA family members must be inhibited simultaneously. 52Disrupting numerous members of a miRNA family in mice is frequently necessary before abnormalities become apparent, but in Drosophila, the loss of just one member of a conserved miRNA family typically results in aberrant phenotypes.
Notable locations where the loss of a single copy results in haploinsufficient defects in both mice and humans include the miR-96 and miR-1792 loci.One study found that the deletion of the miR-17-92 cluster led to skeletal deformities, development problems, and learning difficulties, 51 while another found that the loss of a single copy of miR-96 led to deafness.In many cases, the phenotypic effects of miRNA knockouts are not immediately apparent.Although genetic inactivation of a miRNA may reduce its repression effects on its target mRNA, the majority of genes can survive this derepression in expression rather well. 52Extreme phenotypic impacts may be seen from even modest overexpression of numerous target mRNAs, especially if the targets are functionally connected.Overexpression of several mRNAs in the mitogen-activated protein kinase (MAPK) pathway, for instance, causes lethal epilepsy in mice lacking miR-128. 52However, overexpression artefacts are a potential problem in transgenic overexpression investigations, which are used to determine the cellular processes of particular miRNAs. 50In the nematode worm C. elegans, vulval development is defective when miR61 is overexpressed, but not when it is deleted.When miR-34 family members are overexpressed in mammals, it is thought that they function as a strong tumor suppressor downstream of p53.Although, despite deletions of all miR-34 members in mice, they display normal p53 responses to various cellular insults. 52

| TYPES OF NANOCARRIERS
The biomedical industry has seen an uptick in the usage of nanocarrier-assisted medication delivery systems in the past few years.Several types of nanocarriers have been developed to fill various roles in medical studies.Organic and inorganic nanoparticles are the two primary types employed in contemporary nanocarrier-assisted medication delivery systems.Liposomal and polymeric nanoparticles are examples of organic nanocarriers, while, gold nanoparticles and mesoporous silica nanoparticles (MSN) are examples of inorganic nanocarriers (Figure 4).

| ORGANIC MATERIAL NANOCARRIERS
Liposomes: Liposomes are a type of lipid delivery mechanism in the shape of a sphere. 53Liposomes are useful for clinical applications in drug administration because they are biodegradable, biocompatible, and have a high encapsulation rate while also being very simple to produce and durable. 54,55The term "trigger release" refers to a phenomenon that occurs during drug delivery in which the release of medication is triggered or controlled by dynamic changes in the microenvironment of liposomes within the target tissue. 56There are six major categories of liposomes, including those that are sensitive to heat, acidity, ultrasound, enzymes, magnetic fields, or ligands. 57 adriamycin hydrochloride.In the following years, most FDA registrations for nanocarrier-assisted pharmaceuticals were liposomes, demonstrating the safety and efficacy of a nanocarriers species. 59Despite the growing use of liposomal nanocarriers in cancer treatment, there are still difficulties to be addressed, such as not achieving the necessary delivery efficiency.
Polymeric nanoparticle: Polymeric drug delivery carriers are distinguished by their hydrophilic and hydrophobic selective release, regulated release kinetics, and biocompatibility. 37The goal of encapsulating chemotherapeutic medications in polymeric nanodelivery systems is to increase antitumor activity, decrease metastasis, and lessen side effects. 60Polymers can either incorporate the active chemicals or encapsulate them inside their molecular structure.Gels, chitosan, microemulsions, and micelles are examples of popular polymer-carriers utilized for nano-drug delivery.
Microemulsions: Microemulsions are a stable dispersion of droplets that are formed from a combination of oil, water, a ternary surfactant, and (optionally) a quaternary co-surfactant. 61Controlled drug release, improved drug stability, and the elimination of the issue of water insolubility common to hydrophobic medicines are all benefits of this method. 62Nanoemulsions offer several benefits over liposomal nanoparticles, including increased drug retention duration due to improved solubility and absorption of less bioavailable compounds. 63,64Co-surfactants enhance microemulsions because they decrease the tension of the surfactant film, rendering it a more flexible and dynamic layer, that improves the microemulsion's drug dispersion and allows for easier transdermal absorption. 37,65Chen et al. employed drug delivery vehicles using viscous microemulsions to promote the synergistic anticancer effects of gemcitabine and cisplatin by enhancing their efficacy of permeating bladder endothelial tissue.
Based on the findings, microemulsions show promise as a vehicle for the intravesical administration of drugs. 66Nanoemulsions have the potential to improve cancer drug delivery, but they still have some issues that need to be fixed.A major issue with targeted nanoemulsions is the fact that only 0.7% of the pharmaceutical dose is delivered to solid tumors. 67Second, the nanoemulsions which avoid being filtered out by the kidney's renal clearance biological barrier and the Mononuclear phagocytic system (MPS) could reach and connect with tumor tissue.

| INORGANIC MATERIAL NANOCARRIERS
Magnetic nanoparticles: The magnetic characteristics of magnetic nanoparticles (MNPs) make them useful in diagnostic imaging and other biomedical procedures.The separation, binding, and purification of biomolecules and cells are a few examples of the numerous ways MNPs have been placed use in biomedicine. 68They have additionally been utilized as contrast media in MRI scans, in magnetic thermotherapy, as targeted drug delivery, and in a variety of other health settings.
The following characteristics are necessary for MNPs to be used in biomedical settings: MNPs can be constructed sensitive to a static magnetic field due to various their (i) ability to generate a uniform magnetic field, that either prevents people from aggregating and leads to more uniform and precise properties; (ii) increases in saturation magnetization power and magnetization rate together with excellent chemical stability are all beneficial. 68Cell labeling, biomolecular separation, biological system detoxification, thermal therapy, treatment adherence, and magnetic resonance imaging (MRI) are just some of the numerous research fields that have profited from using nanocomposites with magnetic properties.Suo et al. designed a magnetic multi-walled carbon nanotube device containing epothilone for intravesical drug perfusion (EPI).The technique increased EPI's toxicity to BC cells and reduced BC cell growth, suggesting enhanced therapeutic efficacy of BC with diminished toxicity to normal cells.Although such types of MNPs have already been given the green light by the FDA, there is no questioning that they pose risks to human health. 69ld nanoparticles: Gold nanoparticles (AuNPs) have been found to effectively absorption of optical, UV, and near-infrared light with subsequent thermal emission making this nanotechnology applicable to photothermal and immunotherapy, radiation, and drug delivery.70 This is because they are relatively safe to use, stable, easy to synthesize, and may be conjugated into a wide variety of biomolecules.Paclitaxel (PTX) and 5-fluorouracil (5-FU) are two such examples of chemotherapeutic medications that have been conjugated with AuNPs to lessen the severity of treatment-related adverse effects.37,[71][72][73] Although several preclinical studies have demonstrated that AuNPs may have beneficial qualities, there have been no successful clinical applications of medicines containing AuNPs for the diagnosis or treatment of cancer.74 Biomarkers: Early recognition and diagnosis of BC are best accomplished with cystoscopy, but this invasive procedure is not without risks, including infection and bleeding.41,42 Certain forms of urological cancer can be detected with less effort and time spent when urine cytology (UCT) is done in conjunction with cystoscopy.While six biomarkers (NMP22 BC, NMP22 BladderChek, BTA Stat, BTA TRAK, UroVysion, UCYT+/immune cells) have been approved by the FDA for therapeutic application, their low sensitivity for detecting BCa severely restricts their effectiveness.72 Hence, the primary focus of recent research has been to increase the test's sensitivity.Nanotechnology is currently the primary focus of study because of its intriguing potential applications. Mothan 85% of cancerous tumor cells express telomerase, and this enzyme is highly active in these cells.75 This highlights the significance of sensitive detection of telomerase activity in tumor etiology and early diagnosis.Dynamic light scattering (DLS) is one approach used to evaluate telomerase activity, and its ability to detect a considerable increase in the hydrodynamic diameter of AuNP whenever transcriptase is activated has led to its widespread adoption.37,73 Patients with BC can be discriminated from healthy controls and patients with other cancers using the CHA-DLS biosensor.74 This indicates that the CHA-DLS biosensor might serve as a state-of-the-art and functional instrument for determining telomerase activity and identifying cases of BC.Therefore, the diagnostic utility values associated with this tool have not yet been determined, so substantial additional clinical research is required to complete the tool.
Cystoscopy: Recurrence rates after surgery are high because white light cystoscopy (WLC) is not sensitive enough to use in situ carcinogenesis detection (CIS) and extremely small tumors.However, compared to TURBT, which has a diagnosis asymmetric information rate of up to 50%, 76,77 WLC has a 30% misdiagnosis rate.This emphasizes the vital necessity of techniques that can improve the visibility of tumors during a cystoscopic screening since this would allow for performing a more precise diagnosis and treatment of BC.It is well known that narrow-band imaging and blue-light cystoscopy (BLC) significantly impact the detection rate of tumors.The surfactants 5-aminolevulinic acid (5-ALA) and hexamethyl levulinic acid are injected into the bladder before an endoscopic examination, causing tumor cells to emit red light when exposed to blue light.Because of the high contrast between blood arteries and other tissues, malignancies can be detected with relative ease using narrow-band imaging (NBI). 78The sensitivity of these two techniques is higher than that of WBL, although they are not as specific.There is a need for cuttingedge methods that can boost sensitivity and specificity in cystoscopic tumor visualization.Davis et al. 79 designed an intravesical surface-enhanced Raman scattering nanoparticle in anticipation of the difficulties of identifying BC using WLC.The nano endoscopic system misdiagnosed a normal sample on the WLC as a tumor, even though the histopathological analysis revealed hyperplasia and strong CA9 staining.Hence, using Raman endoscopy and intravesical SERS nanoparticles may improve tumor visibility during WLC.
Imaging: For cancer to be diagnosed by conventional imaging techniques, the tumor should grow to a specific size and radically affect the organ function; by this time, numbers of cells may have grown and might have metastasized, prolonging the diagnosis and, consequently, treatment of cancer. 80Thus, researcher requires more cutting-edge methods for enhanced imaging.Due to their importance in imaging, contrast compounds are increasingly being studied at the nanoscale.The use of MSN in imaging applications, notably for labeling and tracking cells, is a hotspot for investigation.Sweeney et al. 81 design a novel MSN technique for non-invasive longitudinal tracking of BC.The normal bladder epithelium of mice did not take up MSN, whereas tumor cells did.Specific peptide binding agents for BC cells can be added to MSN, improving its ability to improve the accuracy of MRI and fluoroscopic cystoscopy, which is promising for the early identification, diagnosis, and treatment of BC.At the nanotechnology, the Cyc6 peptide exhibits significant selectivity for BC cancer cells.

Sweeney et al. reported that in vitro studies indicate that functionaliz-
2 Positron emission tomography is a nuclear medicine imaging technique that is both sensitive and accurate.While nano tracers for other malignancies have been developed using PET technology, their use in detecting BC has yet to be widely recognized.
As the field of nanotechnology develops, researchers expect to develop even more potent nano tracers to utilize in the fight against BC.

| miRNAs AS BIOMARKER FOR BC
The microRNA category is a developing class of short, noncoding endogenous RNAs (18-25 nucleotides in length) which have been shown to the binding to the 3' Untranslated Region of target genes and thereby regulate their expression.Several intracellular processes are controlled by miRNAs, 45 including apoptosis, cell proliferation, invasion, and transformation.Since miRNAs were first identified in 1993 83 as a post-transcriptional gene regulatory mechanism, research on mammals has increased dramatically.Around 3000 human miRNAs have been found and sequenced using computational methods, and it is now known that miRNAs regulate roughly 30% of the transcriptome. 84Cancer is an incredibly diverse and complex disease that develops from abnormalities at many cellular levels, and miRNAs play a vital part in this.Hence, tumor genetic diversity and the finding of many miRNAs altered in a single tumor add complexity to investigations on miRNAs in cancer. 8Serum, plasma, and urine are just some of the bodily fluids where miRNAs can be found in their very stable cellfree form. 85

| DIAGNOSTICS AND BIOMARKERS
Although urine cytology is the non-invasive preferred approach for detecting and monitoring patients with BC, its inadequate sensitivity restricts its usefulness. 86,87Hence, it is essential to develop a patient identification and monitoring technique that is easy to implement without inflicting any harm to the patient. 87The diagnostic value of miRNA expression/profiling is hence the main focus of most recent research.
Urine: Recent investigations have shown that the miRNAs found in the urine sample are important because they signal the expression at the cellular level, in contrast to the cell-free and predominantly MV-derived miRNAs found in the supernatant. 88Multiple investigations have revealed that particular miRNAs can serve as excellent indicators of a BC diagnosis.The overexpression of miR-126, miR-182, and miR-199a in the urine of patients with the condition can be measured to obtain exceptional specificity and sensitivity in the diagnosis of BC. 89,90 Another study found that miRs-135b/15b/1224-3p were effective in detecting BC illness, 91 with a sensitivity of 94.1% and a specificity of 51.0%.Moreover, miR-106b levels in the urine have been demonstrated to exhibit a high diagnostic accuracy, 92 with a sensitivity of 76.8% and a specificity of 72.4% for discriminating between BCa patients and healthy persons.High diagnostic accuracy in diagnosing BC was connected to the expression of the miRNAs miR-143, miR-452, and miR-222 in urine, as found in the study by Puerta-Gil et al. 93 miRNAs highly expressed in urine, which relate well with tumor stage and grade, and which provide significant diagnostic accuracy for the identification of BC, have been discovered by investigators in a huge proportion. 94A recent investigation 95 revealed that miR-125b and miR-126 have a 100% sensitivity and specificity for the identification of patients with BC.Finally, studies on miR-187, miR-18a*, miR-25, miR-142-3p, miR-140-5p, and miR-204 showed that they may accurately identify and classify persons with BC based on their urine. 96rum: A prominent role for serum miRNAs exists in the diagnosis of BC, although reported results on miRNAs concentration in plasma and serum are still conflicting 97 (Figure 5).Investigators have determined that miR-505, miR-363, and miR-663b are more prominent in the plasma of patients with BC, while miR-99a, miR-194, miR-100, miR-497, and miR-1 have a lower prevalence. 98The same research showed that miRNAs' diagnostic performance varied among stages and grades; miR-497 and miR-663b, in particular, have the potential to serve as novel circulating biomarkers for clinically identifying BC 98 due to their high sensitivity and specificity.Although there is some variation in the reported data on the expression profile of miRNAs in circulation, the results on miRNA concentration in serum are inconsistent.Several miRNAs, including miR-378, miR-942, miR-106a-5p, miR-142-3p, and miR-374a, are elevated in serum; however, these findings require additional validation using larger series. 99

| NON-MUSCLE INVASIVE BLADDER CANCER
The standard treatment for non-muscle invasive illness is transurethral resection of the bladder tumor TURBT (Trans urethral resection of bladder tumor) is a diagnostic and therapeutic procedure for earlystage BC.The lesion is sliced into fragments and sent off to pathology during this procedure using a resectoscope.However, to its fragmented methodology, which could result in tumor cells implanting within healthy bladder mucosa, TURBT has come under heavy criticism.In primary, single-lesion NMIBC cases, a single post-TURBT chemotherapeutic instillation was found to reduce the chance of recurrence. 100 a result, en bloc radiation therapy (EBRT) for bladder tumors has been developed and is gaining popularity around the world.The goal of this procedure is to reduce the possibility of bladder perforation, contain leaking cells, and supply enough tissue for an accurate assessment of the margins. 101However, EBRT (External beam radiation therapy) has difficulties in addressing multifocal, flat tumors, particularly those on the bladder dome, and it has not been proven to significantly lessen the recurrence risk when compared with conventional resection. 102The eradication of tumors larger than 3 cm through the urethra can be challenging even after EBRT has been administered.BCG immunotherapy is the only non-invasive treatment that's been clinically proven to be effective for decades to prevent the course of high-risk NMIBC.
Although being effective, there has been an ongoing debate on the best timetable, timing, dose, stresses, and definition of failure.The ideal BCG dosage has been examined in the EORTC-GU study (EORTC 30962). 103

| MUSCLE-INVASIVE BLADDER CANCER
It is predicted that even without treatment, 90% of individuals with MIBC will die within two years. 104Surgery, especially a radical cystectomy and pelvic lymph node incision, has been the gold standard for treating muscle-invasive BC for a long time.Interestingly, lymph node removal's efficacy has recently been challenged, and researchers still waiting for the results of an ongoing randomized investigation. 105The majority of patients experience a recurrence of metastatic disease, and even among those who have received radical cystectomy, half will still die from BCa within 5 years.This has led to a rise in the popularity of perioperative chemotherapy that specifically targets micrometastases.Patients with muscle-invasive disease who are scheduled for radical cystectomy are now regularly given cis-platin-based, combination neoadjuvant chemotherapy (NAC) before surgery.Because of this, there is an urgent need for substitute drugs in patients who are ineligible for cis-platin-based therapy and markers that would suggest BCa susceptibility to NAC so that speedy surgery can be pursued. 106Those with clinical T2, T3, or even T4 BCa benefit from NAC's survival benefit despite the inherent delay.Nonetheless, histology of the surgical specimen confirms non-responding illness in a third of NAC patients. 107Their outlook is far poorer than that of their responding peers.As a result, there is an urgent need for alternate drugs in people who cannot undergo cis-platin-based therapy or have biomarkers reflecting susceptibility to neoadjuvant chemotherapy to undergo surgery right away.

| BLADDER CANCER DIAGNOSIS 11.1 | Current diagnosis approaches of bladder cancer
Cystoscopy, biopsies, urine cytology, and imaging techniques are just some of the current methods for detecting BC. 108 To perform a F I G U R E 5 The impact of miRNAs in bladder cancer and their applications as diagnostic and prognostic tools, as well as therapy markers.
cystoscopy, a thin, narrow tube (cystoscope) is inserted into the urethra and the bladder.The lens of the cystoscope is used to look for abnormalities in the urethra and bladder. 109Urine cytology is the practice of analyzing a urine sample of cancer cells under a microscope. 110Finally, imaging tests like CT scans, MRIs, PET scans, bone scans, and chest x-rays can aid in early diagnosis and inform treatment plans. 111The development and prognosis of BC must be evaluated comprehensively; hence a reliable diagnostic method is essential.Cystoscopy and imaging examination are the primary diagnostic tools for determining the quality, location, and stage of BC before therapy.In situations when painless hematuria is the predominant symptom, a diagnosis of BC is confirmed through endoscopic biopsy or biopsy plus histopathologic assessment (Figure 6).Furthermore, the clinical state before treatment can be established using whole-body CT analysis.MRI and PET/CT can be used as secondary references to CT scans in cases when liver metastasis, lymph node metastasis, or bone metastases are suspected.Clinicians also frequently use symptom evaluation, urine cytology, and biomarker detection.The most reliable methods for detecting and keeping tabs on recurrent BC are a cystoscopy and biopsy. 111Nonetheless, cystoscopy is an intrusive technique that is often performed regularly.Urinary tract infections, urethral strictures, and other consequences are also probable. 6The expertise levels of doctors are substantially connected with their ability to diagnose BC early.Intravesical injection of 5-aminolevulinic acid (ALA) or hexaminolevulinic acid through a cystoscope is a comparatively recent technique to identify BC (HLA).A fluorescence cystoscope has improved detection rates for malignancies, particularly carcinoma in situ.False positives are possible, but inflammation, a recent TURBT, or BCG injections can all throw off the results.Hence, new technological breakthroughs that aid and improve cystoscopy are desperately needed.Abdominal and pelvic CT scans are the gold standard for detecting BC on imaging scans. 112Effectiveness in recognizing and assessing BC using this technique was established.But still, the fact that the bladder is swollen affects the accuracy of scans of the bladder wall and tumor.Patients with renal insufficiency or an allergy to iodine contrast agents face significant obstacles whenever it comes to enhanced CT/MRI. 113Ultrasound imaging is very useful for screening for hematuria in patients with renal failure and iodine contrasts medium allergy.Although ultrasonography has a high rate of detection, its accuracy is low. 114

| Current therapies
At present, TURBT followed by a single round of intravesical chemotherapy is the standard of care for patients with NMIBC. 38The proliferation of tumor cells that have not been destroyed by treatment can potentially be inhibited using SI with gemcitabine and mitomycin. 115so, according to the stages, patients are advised to have intravesical chemotherapy and BCG.Among the most often utilized intravesical agents for NMIBC are epirubicin, mitomycin, and BCG.
The use of BCG for the treatment of NMIBC was only authorized by the FDA in later years, while it has been used to treat BC since 1976. 116Even with the progress and enhancement of several immunological treatments for NMIBC over the years, intravenous BCG instillation remains the gold-standard treatment.According to the National Comprehensive Cancer Network's 2020 BC clinical practice guidelines, patients at high risk should receive BCG intravesical instillation following TURBT, however, patients at medium risk ought to receive this treatment before receiving any other induction therapy.
For patients at medium to high risk, BCG is recommended as a maintenance therapy instead of chemotherapeutic medicines. 1175][126] It has been determined that BCG can trigger apoptosis [127][128][129] and cellular oxidative stress, [130][131][132] both mechanisms that can directly eliminate BC cells.Figure 7

| miRNAs IN BC: ROLE IN DIAGNOSIS, PROGNOSIS, AND TREATMENT
Screening: Information about the oncogenesis of BC can be gleaned from miRNAs in tissue samples.Since miRNAs are so vital in healthcare, screening approaches based on them will eventually become standard procedures in clinical diagnostics.Recent advances in technology have created opportunities for screening for biomarkers, such as the measurement of low-abundance miRNAs. 138agnosis: Diagnosing and monitoring patients with BC requires both urine cytology and cystoscopy.Urine cytology is an effective method for detecting BC, with a specificity of 90%-95%.Several investigations have shown the potential of miRNAs as diagnostic biomarkers for cancer, with an averaged degree of specificity and sensitivity of approximately 70% and 80%, respectively. 139ognosis: A small number of miRNAs might become potential biomarkers of BC prognosis.The miRNAs miR-200, miR-145, and miR-214 have been determined to be significant predictive indicators for BC. 140,141miRNAs have been proven to be effective prognostic markers in a variety of disorders.
Treatment: miRNAs have become an appealing targeted therapy in the administration of BC, as revealed by a substantial number of recent researches.miRNAs were reported to have a substantial impact on BC cell proliferation, migration, apoptosis, and invasion, encouraging the investigators to hypothesize that they might serve as novel therapeutic targets for the disease. 142It comprises the most comprehensive list to date of miRNAs and their target molecules in BC.The use of these chemicals as biomarkers for early BC detection and staging is encouraging.Merely four miRNAs (miR-143, miR-1, miR-99a, and miR-100) are inhibited in every type of tissue, fluid, and organ.There were only two miRNAs whose expression was elevated in all three samples, and those were miR-21 and miR-210.However, more activities examining both urine and blood samples from patients with BC are necessary before all these results can be generalized. 142,143

| NANOMEDICINE-BASED BC DIAGNOSIS
Nanotechnology has been used with traditional diagnostic approaches in numerous studies to improve the accuracy and precision of BC screening (Table 1).

| USING NANOMEDICINE FOR BLADDER CANCER THERAPY
Multiple investigations have demonstrated the promising potential of using nanotechnology in the treatment of BC, and as a result, scientists are increasingly combining nanotechnology with traditional therapeutic approaches to address the various obstacles currently encountered when dealing with this disease. 3emotherapy: Intravenous infusion chemotherapy constitutes the most effective technique for avoiding transurethral resection of BC and the prevention or postponement of disease progression 149 in patients whose malignancies cannot be eliminated or whose tumors possess great histopathological characteristics.Poor targeting ability, limited drug penetration, shorter recovery time, inconsistent action, and then the incapacity to slow down the release process are all issues that now plague intravesical chemotherapy because of the existence of the BPB (Figure 8).Drug delivery carriers for tumor therapy are now being built using nanomaterials.1][152] Hence, therapeutic efficacy is enhanced by well-designed nanoparticles due to increased penetration efficiency. 153Some research has also centered on the issue of drug resistance developing during chemotherapy for BC.Postoperative chemotherapy for BC, which is currently being studied at an increasing rate, is thought to dramatically lower the F I G U R E 7 Current bladder cancer therapies.BCG, bacillus Calmette-Guerin; CT, computer tomography; TURBT, bladder cancer transurethral resection.recurrence rate and enhance the survival rate following surgery thanks to the introduction of nanotechnology.
Gene therapy: Gene therapy has become an exciting therapeutic area in cancer treatment because of the ineffectiveness of conventional therapies to precisely target tumor cells. 154By injecting therapeutic nucleic acids, gene therapy aims to eliminate disease-causing cells or alter immune responses.A significant obstacle in cancer gene therapy is the implementation of small interfering RNAs (siRNAs) or miRNAs to address cancer cells. 155,156A potential approach that combines nanotechnology and gene therapy to combat BC is the use of nanoparticle intravenous administration.There are still two major issues with BC gene therapy that need to be resolved.Medications have a more difficult time reaching tumor cells when a BPB is present.This is because the medication exposure time and concentration of BC cells are reduced during normal urination and urine circulation.
The R11 peptide may enhance the targeting capacity of BCa and the membrane penetration of nucleic acid materials for bioimaging, according to a recent study. 157The biggest challenge of gene therapy is getting the microRNA or siRNA to the cancer cells.Because of its singular characteristics, nanotechnology, a relatively new technology, is capable of satisfying this need.Nanotechnology was used to deliver specific RNAs into BC cells, where they effectively stifled tumor growth with minimal collateral damage.More RNAs will be used in gene therapy for BC in future research and the impact of these RNAs will be amplified by nanotechnology.
Photodynamic therapy: Photodynamic treatment can be used to treat malignant tumors with minimal or no surgical intervention (PDT).
Light excites photosensitizers which then release ROS triggering necrosis and death in the targeted cells. 158Lipophilic photosensitizers used in PDT (such as Photofrin) are known to penetrate mitochondria, where they alter mitochondrial function, release cytochrome c, and activate the intrinsic pathway of apoptosis. 159Photosensitizers can be harmful since they are lipophilic and can infiltrate normal cells as well as malignant cells.Photosensitizers can cause severe reactions in the skin and the bladder.PDT's therapeutic applicability for BC has also not been completely realized because the treatment's efficacy is now low for several reasons.Combining nanotechnology with modern photodynamic therapy has shown promising outcomes in recent years.
BC tissue having a low oxygen concentration is thought to be a contributing factor, as it would reduce the amount of oxygen available for treatment during PDT. 160BC's hypoxic microenvironment generated by cancer malignancy (increased levels of H 2 O 2 and more acidic pH), for example, might well be augmented by in situ generation of O 2 . 161gh quantities of H 2 O 2 are produced by BC cells in their hypoxic environment, which in turn causes acidosis.Photodynamic therapy for BC is not very efficient since the damaged tissue has a low oxygen content.Several investigators are utilizing MnO 2 NPs to provide high levels of O 2 to BC cells, thereby enhancing the photodynamic effect.
The rate of MnO 2 's reaction with H 2 O 2 was identified as being greater at pH 6.5 when comparing the HSA-MnO 2 -Ce 6 nanoparticletriggered O 2 generation at those two different pH values.PDT's potency in treating BC cells was boosted by laser-induced HSA-MnO 2 -Ce 6 nanoparticles, which emitted twice as much oxygen as hydrogen peroxide. 161The survey promised that in the future, more nanoparticles are going to be employed to alleviate the adverse effects of the therapy by protecting BC cells from the hypoxic environment.However, studies on the feasibility of photodynamic therapy in the treatment of BC are minimal.
Immunotherapy: Immunotherapy was initially used in humans in the 1890s. 162The utilization of immunotherapy to treat cancer has become increasingly popular. 163Initiating an immunological response toward malignancy in a targeted manner, immunotherapy can be used as a curative anti-cancer treatment. 164Immunotherapy targets cancer cells, but it also has the potential to trigger an immune response against healthy cells at any moment during or after treatment.Hence, clinicians and researchers must work toward eliminating or at least mitigating immunotherapy's negative consequences.Activating thioredoxin, transplanting bacterial colonies, and causing iron sagging are only a few of the current immunotherapy innovations and side-effect mitigation strategies presented by researchers. 164For immunotherapy to succeed, researchers must find ways to lessen the likelihood of unwanted effects.Fortunately, nanocarriers have recently evolved to rise to the occasion.Immunological medicines' activity, specificity, side effects, and anticancer efficacy can all benefit from this.The use of live BCG in the bladder for immunotherapy of BC is promising, but it is not without serious hazards.Immunotherapy against tumors is aided by BCG-CWS, the most immunoreactive component of BCG, which is well considered a substantial immune adjuvant. 165,166This helps to mitigate the negative effects of BCG.Oncologists can now use immune checkpoint inhibitors (ICIs) as either a neoadjuvant or frontline therapy. 167Since ICIs have emerged as promising novel immunotherapy, attention has turned from activating B cells to stimulating T cells.Since ICIs prevent T cells from being suppressed by the immune system, the latter's anti-tumor response is strengthened. 1680][171] Tumor cells can be eliminated immunogenically by listeriolysin O (LLO), which triggers an immunological response that is both pro-inflammatory and anti-tumor.To boost the efficacy of ICIs, Ter'an-Navarro et al. 172 designed a nanoparticle vaccination called GNP-LLO91-99.In certain patients with MIBC, ICIs can be quite effective; nonetheless, their objective remission rate is only approximately 20%. 171The inhibition of immune effector cells by the tumor microenvironment (TME) 173 could be a cause.The use of ICIs in conjunction with other forms of immunotherapy may therefore prove beneficial for people with BC.Low survival rates among patients with solid tumors have been linked to impairments in the CD73-adenosine metabolic pathway. 168The nanoplatforms for co-immunotherapy of BC were created and validated by Zhou et al. 174 using exosome-mimetic nanovesicles (EMVs) produced from macrophages.Both a CD73 inhibitor (AB680) and a monoclonal antibody against programmed cell death ligand 1 (anti-PD-L1) were successfully delivered with this system (aPDL1).By blocking the formation of extracellular adenosine, the nanoparticles improved the therapeutic efficacy of aPDL1.This was accomplished by stimulating the creation of cytotoxic T cells.Hence, using these nanoplatforms for co-immunotherapy of BCs is an exciting prospect. 1759][180] MiRNA expression changes may have a role in BC at an earlier stage, influencing carcinogenesis and tumor behavior. 181First, Gottardo et al. 182 found 10 miRNAs that were upregulated in BC.Dyrskjot et al. found that the expression of several miRNAs was altered in their research. 183Epithelial-mesenchymal transition is associated with a few miRNAs. 184,185As a result, miRNA expression is critically important in the development of bladder tumors. 181More than half of miRNA genes are found in areas of the genome that have been linked to cancer or that are particularly vulnerable.Deficiencies in miRNA quality control have been linked to several cancer types.The formation of cancer and the maintenance of tumor growth is influenced by both the loss and increase of miRNA function.7][188] In addition, miRNAs are powerful indicators for cancer detection 189 because they may have distinct expression patterns across cancer types, stages, and differentiation grades.MiR-129 was the most often up-regulated miRNA in BC. 190,191 However, it has been noticed that miR-145 and miR-133a are both down-regulated in cancer tissues, 192 and that using these two markers, authors can identify cancer cells from non-cancer cells with a sensitivity of >70% and a Furthermore, p53 inhibits the mesenchymal differentiation-promoting transcription factors ZEB-1 and ZEB-2 by controlling the miR200 family. 193

| ROLE OF miRNA IN CLINICAL PRACTICE
Diagnosis: Patients with NMIBC can be discriminated from healthy controls as well as those who have cystitis with an 80% accuracy and an 84% specificity adopting urinary cell-free miR-155. 194The level of free miR-155 in the urine additionally serves as a predictor of NMIBC recurrence and transformation into an invasive disease. 194In a second group of BC patients, upregulated of all of these miRNAs was associated with a reduced PFS. 195 axis was discovered to be important in modulating chemoresistance in BC based on in vitro and in vivo studies. 197Recent research has shown that miRNA-193a-3p directly targets PSEN1, providing further evidence that this miRNA has a role in the multi-chemoresistance of BC cells via PSEN1's DNA damage response mechanism.Hence, the miRNA-193a-3p/PSEN1 axis is an alternative potential therapeutic target for optimizing the response to chemotherapy in BC. 198 The molecular mechanisms depicted in (Figure 9) mediate the effect of miR-193a-3p on BC chemoresistance.MicroRNA-218 (miR-218) reduces glucose absorption and glutathione (GSH) levels while increasing cisplatin sensitivity in bladder cancer (BC) cells.Experiments on the function of this miRNA revealed that it targets Glut1.As a result of miR-218's effect on Glut1, BC is more sensitive to cisplatin.
One way to overcome chemoresistance in BC is to overexpress miR-218, while another is to inhibit glut1. 199  complex network of processes is responsible for its down-regulation.
Targeting various oncogenes, miR-145 may impede the spread of tumor cells.Given its unique function in regulating gene expression, miR-145 may provide a promising new target for miRNA replacement therapy in the management of cancer metastasis. 201For example, the downregulation of miR-150-5p expression speeds up cell cycle progression and proliferative capacity of BC cells, 202 suggesting that miRNAs may modulate the cell cycle to influence chemoresistance.Targeting and downregulating p27, a downstream effector of p53, miR-196a-5p prevents cisplatin/ gemcitabine-induced apoptosis in UCA1 cells. 203These findings provide further evidence that miRNAs regulate the chemosensitivity of BC cells via a complex network structure and that any component of the target gene axis of miRNAs may serve as a target for cancer treatment.Recent progress in nanomedicine and the role of miRNAs in this field have yielded promising preliminary data for diagnostic and prognostic applications in BC.For these strategies to be used in clinical settings, the information must first be functionally validated.
Clinicians dealing with BC patients F I G U R E 1 Bladder cancer's progression and severity.F I G U R E 2 Schematic diagram of the use of nanomedicine in imaging, diagnosis, and therapy of BC.
Effective infusion treatment for BC constantly makes use of ligandtargeted liposomes.The first nanocarrier to gain FDA approval was Doxil, 58 a liposomal medicine encapsulating the anticancer agent's F I G U R E 3 The implications of the micro-RNA signature in the diagnosis and prognosis of BC.F I G U R E 4 Types of nanoparticles used in the treatment and diagnostics of BC.
This enhanced the sensitivity of T1-and T2-weighted MRI signals in vivo, allowing for more accurate detection of tumor margins.Whenever applied to human research trials, this nanomaterial might assist in the early detection and treatment of BC by facilitating tumor staging, treatment monitoring, and medication delivery.Due to the significant contribution compounds perform in tumor imaging, multiple novel nanoparticles have been developed, including MSN and MNPs, which have resulted in enhanced performance in imaging for BC and guiding biopsies of lymph nodes.
depicts the current BC therapy approach.In cases of muscle-invasive or metastatic BC, radical cystectomy, and neoadjuvant chemotherapy are incredibly successful treatments.Platinum-based combination therapy seems to be more effective against later-stage BC.Methotrexate, vinblastine, doxorubicin, cisplatin, and gemcitabine cisplatin/carboplatin are some of the most often used combinations of chemotherapy drugs (GC regimens).Patients who aren't good candidates for cystectomy can improve their chances of local tumor management and live longer with the use of adjuvant and palliative radiotherapy. 133-135It has been massive improvements in immunotherapy and targeted therapy recently.In patients with advanced BC, the average survival rate has increased dramatically thanks to PD-1/L1 mAb-based immunotherapy compared to conventional treatment.In advanced BC, FGFR inhibitors and HER2 inhibitors have been approved, giving patients hope despite the failure of chemotherapy. 136,137F I G U R E 6 Strategies presently used in bladder cancer diagnosis.

T A B L E 1 81 F
Current applications of nanotechnology in diagnosing BC.I G U R E 8 Properties of the bladder permeability barrier and bladder.
specificity of >75%.The scientists discovered a decrease in miR-141, miR-155, and miR-429 in urine sediment from individuals with BC, all of which are members of the miR-200 family.In the postoperative period, there was a notable rise in the concentrations of several miR-NAs.These results highlight the potential of miRNAs belonging to the miR-200 family (miRs-141, -429, -192, -146a, -141, and others) as non-invasive, diagnostic, and prognostic indicators.Most current miR studies in BC employ profiling to characterize time-dependent shifts in miR expression between stages and grades.In low-grade, non-muscle invasive bladder cancer (NMIBC), down-regulation of miRs was detected.This included down-regulation of miRs that target the fibroblast growth factor 3 (FGFR3) pathway, such as miR-145, miR-101, miR-100, and miR-99a.In contrast, high-grade muscleinvasive bladder cancer (MIBC) shows an overall higher expression of miRs compared to neighboring normal bladder urothelium.This includes miRs anticipated to target p53, such as miR-21 and miR-373.
Jiang et al. designed a miRNA panel with a diagnosing power of 0.899 when testing for BC.The panel contains six distinct miRNAs.The sensitivity of this miRNA panel was 90% for Ta tumors, 84.66% for T1 malignancies, and 89.54% for T2-T4 tumors.These results show that compared to urine cytology, this panel is quite effective.Overexpression of miR-210, miR-10b, and miR-29c was noticed in urine samples from people with BC, according to the investigation by Eissa et al.These miRNAs managed to show high sensitivity and specificity in distinguishing between BC patients and controls.The responsiveness was raised to 95.2% only when the overexpression of these miRNAs was combined with urine cytology. 195Prognosis: Highly expressed miRNAs comparing normal bladder tissue and BC samples were reported by Yin et al. using the TCGA-BCLA dataset; these miRNAs have the potential to be exploited as prognostic indicators for BC.The investigators were capable of discovering a hallmark of 21 miRNAs that significantly correlated with OS in individuals with BC.Furthermore, the BC diagnostic type and stage were found to correlate with the expression of this miRNA panel. 196,197Jiang et al. found that patients with NMIBC whose miR-152/miR-3187-3p expression levels were high had a significantly lower median survival time.Tumor recurrence in these patients has also been associated with increased levels of miR-152. 140Therapy: Moreover, miRNAs contribute to the control of how cancer cells react to chemotherapy.Investigators determined that miR-193a-3p plays a contribution to the development of BC cell multi-chemoresistance by comparing the expression levels of chemosensitive and chemoresistant cell lines.The lysyl oxidase-like 4 (LOXL4) gene appeared to be a target for this miRNA.The oxidative stress response is controlled by the miR-193a-3p/LOXL4 axis.This vival and modulating response to cisplatin remain little understood.To address this, the researcher utilized real-time quantitative polymerase chain reaction to analyze miR-203 expression in 108 tissues from BC patients undergoing cisplatin-based adjuvant chemotherapy and performed in vitro studies to investigate chemotherapeutic sensitivity to cisplatin in miR-203 overexpressing BC cells. 200Cancer cell lines from both solid tumors and blood malignancies have been found to have decreased expression of the tumor suppressor miR-145.However, a F I G U R E 9 MiR-193a regulates cell survival and multichemoresistance in bladder cancer via its targets (PSEN1, ING5, SRSF2, and LoxL4), the oxidative stress pathway, and the DNA damage response.T A B L E 2 Significance of miRNAs on BC chemoresistance.resistance miR-196a-5p, miR-294 203,207

18 |
FUTURE PERSPECTIVESBladder cancer (BC) is an aggressive and often fatal disease.The two primary types of bladder cancer are muscle-invasive and non-muscleinvasive.Although TURBT is the recommended treatment for NMIBC, recurrence rates of up to 65% after surgery are not atypical, as well as the disease often progresses to more advanced stages.Controlling postoperative recurrence of bladder cancer requires more stringent monitoring and more intensive therapy to enhance patients' survival rates.Unfortunately, conventional diagnostic and treatment methods fall short in actual patient care.Hence novel diagnostic tools that are both more precise and more sensitive are desperately needed.Bladder tumor cells behave aggressively, leading to their rapid proliferation and the ability to metastasize and enter blood vessels, from which they can spread to other organs.Hence, the progression of proliferation and invasion presents an enormous challenge for bladder cancer treatment.Epigenetic factors, which are master regulators of genes, should be the focus of new therapeutic modalities for bladder cancer, despite the importance of targeting abnormally expressed genes.As a result, this review focused on how miRNAs can control the growth of bladder cancer cells.Evidence is mounting that miRNAs and nanomedicine could be useful as novel clinical diagnostic biomarkers.The use of nanomedicine and miRNAs in diagnosing disease and developing targeted treatments is a novel strategy.Nanocarrier-assisted drug delivery systems, among the various medical applications of nanotechnology, have gained substantial research focus because of having high significant utility.Numerous scientists have tried to improve the treatment efficacy, however existing bladder cancer treatments by integrating nanotechnology into these methods, but all of them have their own set of limitations and difficulties in clinical implementation.Researchers can use human serum albumin nanoparticles and bladder cancer cells with overexpressed receptors to increase the specificity of chemotherapeutic drugs targeting tumor tissues.This approach has the added benefit of conferring novel properties on the newly constructed nanoparticles, which can further enhance the chemotherapeutic effect.Together, nanomedicine and miRNAs offer great potential as diagnostic indicators and treatment strategies in the treatment of BC.Extensive research has not yet led to agreement on a set of universally useful miRNA diagnostic panels.Consequently, further research needs to be done in these areas.19| CONCLUSIONBC is a malignant disease of the urogenital tract, and its treatment is complicated by factors such as the lack of creativity in bringing innovative treatments, the involvement of nanomedicine and miRNAs in the etiology and targeted therapy, and the lack of innovation in these areas.miRNAs have been focused on significant examination over the past decade because of their potential role in early diagnosis, prognosis, and prediction of treatment effectiveness, all of which are critical to the development and persistence of the malignant phenotype.However, only a subset of these trials specifically targets bladder cancer using nanomedicine or miRNAs.Many miRNA signaling investigations have been conducted in bladder cancer in recent years.This research indicates a potential function for miRNAs as both oncogenes and tumor suppressors, as these have been discovered to affect the expression of their targets in multiple research.The expression of these genes is significant for the initiation, categorization, and development of bladder cancer.The use of nanomedicine and miRNAs has the potential to significantly advance the development of biomarkers and therapeutic targets for the prevention and treatment of BC.Despite many studies, there is still no agreement on which diagnostic panels should include miRNA and nanomedicine.Therefore, more research is needed in these areas.In conclusion, in the interest of developing targeted therapy strategies for BC, miRNA-mRNA functional interactions should be designed.
| HOW TO USE miRNA DATABASES IN BC