The Expanding Roles of Long Non‐Coding RNAs in Pancreatic Cancer

Pancreatic cancer is a clinically challenging disease with a poor survival rate and is one of the leading causes of cancer‐related morbidity. It is highly resistant to treatment and effective diagnostic tools during the early stages of the disease are lacking. Long non‐coding RNAs (lncRNAs) participate extensively in the physiological processes of various diseases, especially multiple types of cancers. lncRNAs have been shown to perform essential functions and are gaining increasing attention in pancreatic cancer research. This review summarizes the roles of lncRNAs in the occurrence, development, and therapeutic resistance of pancreatic cancer by categorizing their regulation of epigenetic inheritance, transcription, post‐transcription, and related signaling pathways. Potential clinical implications, including diagnostic and prognostic biomarkers, as well as the therapeutic prospects of these lncRNAs in pancreatic cancer, are also discussed. Novel insights into the role of lncRNAs in the pathogenesis of pancreatic cancer may help researchers develop novel therapeutic strategies.


Introduction
Pancreatic cancer is a serious global threat to human health, with a high degree of malignancy due to late diagnosis, rapid progression, therapeutic resistance, and a five-year survival rate of only stimulate diverse biological processes and play regulatory roles in epigenetics, transcription, post-transcription, translation, and post-translational processes.Several lncRNAs affect tumor proliferation, metastatic infiltration, and drug resistance and may serve as potential biomarkers to improve diagnosis and therapeutic response. [8]LncRNAs, such as MALAT1 and HOTAIR, have been identified as prognostic indicators of breast cancer. [9]Apart from their role in the occurrence and development of cancer, lncRNAs play a role in various diseases.Dysregulated lncRNAs have been associated with Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. [10]LncRNA BACE1-AS promotes the stability of BACE1 mRNA, leading to increased levels of neurotoxic amyloid protein platelets in patients with Alzheimer's disease.Furthermore, BACE1-AS can be detected in the plasma of these individuals and can serve as a potential biomarker. [11]Liu et al. found that MHRT levels were significantly increased in the peripheral blood of patients with acute myocardial infarction.In a myocardial injury model constructed by hydrogen peroxide treatment, MHRT expression in myocardial cells was significantly upregulated after hydrogen peroxide treatment, whereas the apoptosis rate of myocardial cells with MHRT gene knockout increased.These results indicate that MHRT affects and protects myocardial cells and can be used as a diagnostic biomarker. [12]In addition, lncRNAs can lead to atherosclerosis by causing the dysfunction of vascular endothelial cells, invasion and activation of monocytes, activation and migration of vascular smooth muscle cells, and abnormal lipid metabolism. [13]urrently, gene editing technology has been employed to modulate lncRNA levels, leading to the successful establishment of relevant mouse models to investigate their effects on biological processes and disease progression.For example, Ma et al. successfully constructed a HOTAIR mouse model, elucidating the essential role of sustained HOTAIR expression in facilitating breast cancer cell metastasis and offering novel prospects for breast cancer treatment. [14]In a pioneering study, Sun et al. generated an lnc-CTHCC gene-knockout mouse model, providing compelling evidence for its significant involvement in hepatic carcinoma pathogenesis and progression. [15]This review summarizes the functions of lncRNAs in pancreatic cancer occurrence, development, and therapeutic resistance.

Oncogenic lncRNAs
A growing body of research has explored the roles of lncRNAs in cell proliferation, invasion, migration, and expansion. [9]The specific mechanisms by which lncRNAs promote pancreatic cancer occurrence and development are shown in Figure 1.

LncRNAs Promote Cell Migration and Invasion
LncRNA-associated migration and invasion are typical characteristics of malignant tumors.Specifically, lncRNA LINP1 strengthens pancreatic cancer cell metastasis by modulating miRNA-491-3p, thus increasing the incidence of lymph node or distant metastasis. [36]27] Mechanistically, UCA1 mainly functions as a competitive endogenous miRNA sponge, including miR-135a, miR-107, and miR-590-3p. [37]Therefore, abrogating the inhibitory effects of miRNAs on target genes can facilitate the invasion and migration of pancreatic cancer cells.Moreover, hypoxic exosomal UCA1 regulates the miR-96-5p-mediated AMOTL2/ERK1/2 axis to promote angiogenesis and tumor growth. [38]LncRNA UCA1 also promotes the migration and invasion of pancreatic cancer cells via the Hippo-YAP pathway. [39]Furthermore, lncRNA NEAT1 expression is upregulated in pancreatic cancer tissues and cell lines, with a high level of NEAT1 associated with tumor size, tumornode-metastasis stages, lymph node and distant metastasis, and poor prognosis. [18]The upregulation of lncRNA DANCR combined with miR-33b inhibits its expression, thus increasing the expression of the miR-33b-targeted gene MMP16 as well as cancer cell migration and invasion. [40]Additionally, DANCR promotes pancreatic cancer cell growth and metastasis by sponging as a ceRNA of miR-214-5p and by upregulating E2F2 expression in pancreatic cancer cells. [41]Similarly, silencing of the lncRNA HOTAIR restrains the Wnt/-catenin signaling pathway to mitigate EMT. [42]Additionally, lncRNA ZFAS1 sponges miR-3924 to regulate the RHOA/ROCK2 signaling pathway and targets the miR-497-5p/HMGA2 axis to promote pancreatic adenocarcinoma metastasis. [32,43]An increased level of SNHG15 accelerates pancreatic cancer cell invasion and migration. [33]Further, lncRNA LINC00941 accelerates the development of pancreatic cancer by promoting tumor invasion and metastasis. [34,35]evels of lncRNAs are associated with tumor cell migration and invasion.Valuable information can be obtained by detecting and analyzing lncRNAs in various diseases.We propose that these lncRNAs may serve as potential therapeutic targets to inhibit the migration and invasion of pancreatic cancer cells and improve the survival rate of these patients.

Tumor Suppressor LncRNAs
Glycolysis-associated lncRNA DICER1-AS1 inhibits glycolysis and proliferation of pancreatic cancer cells by regulating the m6A reader YTHDF3. [44]Another lncRNA, CF129, inhibits pancreatic cell proliferation by suppressing FOXC2 transcription, which depends on MKRN1-mediated ubiquitin-dependent p53 degradation. [45]Moreover, lncRNA FAM66C interacts with miR-574-3p and inhibits its expression in vitro and in vivo, thereby inhibiting proliferation and promoting apoptosis in pancreatic cancer cells. [46]LncRNA FLVCR1-AS1 acts as a ceRNA to isolate miR-5c-514p or miR-5b-10p from spongy KLF513 mRNA, thereby decreasing the KLF10-mediated inhibitory effect.A direct transcriptional target of KLF10 can inhibit pancreatic cancer cell proliferation, cell cycle progression, and cell migration. [47]Overexpression of lncRNA PWAR6 induces G1/G0 phase arrest and promotes cell apoptosis, inhibiting cell proliferation and migration. [48]WAR6 binds to EZH2, facilitating the EZH2/PRC2-mediated epigenetic modification of the YAP1 promoter to exert tumorinhibitory activity in human pancreatic cancer cells. [48]iu et al. found that the expression of lncRNA A2M-AS1 in pancreatic cancer cells was much lower than that in controls.A2M-AS1 not only interacted with poly (rC) binding protein 3 (pancreatic cancer BP3) directly but also promoted p38 activation to restrain the phosphorylation of the AKT-mTOR signaling pathway, inducing pancreatic cancer iron death. [49]Similarly, decreased lncRNA DGCR5 upregulated the expression of the tumor suppressor BNIP 3 and p38 MAPK by sponging miR-27a-3p, thereby promoting pancreatic cancer cell apoptosis and inhibiting pancreatic cancer development. [50]In addition, lncRNA CTD-3252C9.4 motivated pancreatic cancer cell apoptosis and inhibited tumor growth by binding to interferon regulatory factor 1 and suppressing interferon alpha-inducible protein 6 transcription. [51]Gong et al. [52] found that lncRNA LINC00673 inhibits the proliferation and metastasis of pancreatic cancer cells by inhibiting miR-504 through the targeting of HNF1A, a novel oncogene that regulates the properties of human pancreatic cancer stem cells.The repression or upregulation of these lncRNAs may provide novel directions for pancreatic cancer therapy.
During the early tumor stages, tumor suppressor lncRNAs play a role in regulating cellular proliferation and apoptosis, thereby inhibiting abnormal tumor cell growth and impeding tumor formation.During the disease stages of tumor progression and metastasis, tumor suppressor lncRNAs can modulate the signaling pathways involved in cellular migration, invasion, and metastasis, suppress the migratory and invasive abilities of tumor cells, and reduce the risk of metastasis.Functional mechanisms provide a theoretical basis for the application and therapeutic potential of tumor-suppressor lncRNAs in cancer research.

Diagnostic and Prognostic Roles of lncRNAs in Pancreatic Cancer
CA19-9-a unique serum biomarker approved by the United States Food and Drug Administration-is not recommended for early screening of pancreatic cancer because of its low sensitivity (80%) and specificity (75%). [53]LncRNAs are involved in neoplasm biogenesis [54] and various tumor phenotypes can be modified by regulating the expression of specific lncRNAs. [55]Numerous lncRNAs are positively or negatively correlated with the occurrence and development of pancreatic cancer.Therefore, they may be potential biomarkers for the early diagnosis and prognostic prediction of pancreatic cancer.
Plasma or serum lncRNAs elicit multiple biological effects and may be useful diagnostic and prognostic biomarkers for pancreatic cancer.For example, the serum levels of lncRNA HOTAIR and hexokinase 2 (HK2) are abnormally higher in patients with pancreatic cancer than in healthy humans.Serum HOTAIR and HK2 levels may predict pancreatic adenocarcinoma prognosis. [56]ie et al. found that the differential expression of salivary HO-TAIR and PVT1 might be closely associated with distal pancreatic cancer and could serve as novel non-invasive biomarkers with high sensitivity and specificity in the diagnosis and prognosis of pancreatic carcinoma. [57]In addition, the expression level of HOTTIP-005-a lncRNA HOTTIP splicing variant-in pancreatic cancer cell lines was much higher than that in normal cells.HOTTIP expression was positively correlated with patient survival, and high HOTTIP-005 expression may be a poor prognostic factor in patients with pancreatic cancer. [58]In a nude mouse model, a slow tumor growth rate and fewer lung metastatic nodule foci were observed in the lncRNA NEAT1 knockdown group than in the control group. [18]Reducing the migratory versus invasive nature of tumors may improve the prognosis of patients with tumors.LncRNA TSLNC8 has been reported to be upregulated in pancreatic cancer tissues, and its overexpression is strongly associated with poor prognosis in patients with pancreatic cancer.Furthermore, TSLNC8 promotes the binding of HUR to CTNNB1 mRNA and improves the stability of CTNNB1 mRNA.TSLNC8 promotes pancreatic cancer cell invasion and distant metastasis by activating the Wnt/-catenin signaling pathway. [59]n the other hand, plasma lncRNA GAS8-AS1 was reduced in pancreatic cancer patients compared to the control group.Patients with a low level of plasma GAS8-AS1 had a better overall five-year survival rate. [60]The levels of exosomal UCA1 in the serum of pancreatic cancer patients were dramatically higher than in healthy controls.The increased expression of UCA1 in serum exosomes was positively correlated with tumor size, lymphatic invasion and advanced TNM stage.Moreover, Kaplan-Meier survival analysis and ROC curves demonstrated that serum exosome UCA1 was negatively associated with patients' overall survival. [38]In addition, lncRNAs, including HULC, NT5E, and ANRIL, have been considered independent prognostic factors for the survival of pancreatic cancer patients. [61]The results of a meta-analysis and systematic review suggest that salivary noncoding RNA had high diagnostic accuracy for pancreatic cancer.The odds ratio for diagnosing pancreatic cancer in its early stages is much higher than in advanced cases, and the diagnostic value of salivary non-coding RNA increased in older patients. [62]he plasma level of lncRNA ABHD11-AS1 is reportedly a more precise biomarker for early pancreatic cancer diagnosis than the commonly used tumor markers, carcinoembryonic antigen (CEA), CA199, or carbohydrate antigen 125 (CA125).Moreover, the combination of ABHD11-AS1 and CA199 exhibited excellent performance in discriminating early pancreatic cancer patients from healthy controls.These findings suggest that ABHD11-AS1 may be a promising biomarker for early pancreatic cancer screening and monitoring alone or combined with traditional tumor markers like CA199. [63]Moreover, the combined detection of lncRNAs and CA199 can improve pancreatic cancer's diagnostic accuracy and prognostic ability.Although lncRNAs show many advantages as a biomarker for pancreatic cancer, they require further large-scale studies for effectiveness evaluation and clinical practice for personalized treatment and monitoring.The reported lncRNAs with potential diagnostic/prognostic values in pancreatic cancer are summarized in Table 1.

LncRNAs and Therapeutic Resistance in Pancreatic Cancer
The relationship between lncRNAs and therapeutic resistance in cancer is receiving increasing attention. [64]This section highlights the role of lncRNAs in the regulation of therapeutic resistance in pancreatic cancer.The specific mechanisms of action of lncRNAs in drug resistance in pancreatic cancer are shown in Table 2 and Figure 2.

LncRNAs and Chemo-Resistance in Pancreatic Cancer
Chemotherapy with gemcitabine, albumin-binding paclitaxel, and oxaliplatin significantly improves the survival rate of patients with pancreatic cancer.61b,65] To this end, LncRNAs are involved in the chemoresistance of pancreatic cancer cells. [66]

Micro-RNA Regulation
LncRNAs inhibit oncogenes by competitively binding to miRNAs and promoting tumor cell invasion and metastasis to cause drug resistance. [67]For example, lncRNA HOTTIP is highly upregulated in pancreatic cancer tissues and is associated with poor prognosis of pancreatic cancer. [68]LncRNA HOTTIP facilitates pancreatic cancer resistance to cisplatin by inhibiting miR-137 expression and is involved in gemcitabine resistance in pancreatic cancer via the promotion of HOXA13 expression.Silencing or deleting HOTTIP reversed cisplatin resistance and potentiated chemosensitivity to gemcitabine both in vitro and in vivo. [69]ncRNA PVT1 is correlated with a lower survival rate and poor prognosis in pancreatic cancer patients because it: 1) tar-gets miR-519d-3p to drive glycolysis; 2) inhibits p21 proliferation; 3) sponges miR-448 and increases SERBP1 for migration; and 4) enhances the TGF- and Smad pathway to induce EMT. [70]LncRNA PVT1 is a crucial factor in gemcitabine resistance through miR-619-5p sponging to enhance Pygopus2 and autophagy-associated protein 14 (ATG14) expression, regulate catenin signaling, and increase active autophagy. [71]Additionally, PVT1 directly sponges miR-143 to regulate HIF-1 expression.The miR-143 inhibitor reversed autophagy and gemcitabine sensitivity induced by PVT1 knockdown.Furthermore, PVT1 improved gemcitabine sensitivity by regulating the miR-143/HIF-1/VMP1 axis. [72]Therefore, lncRNA PVT1 may help predict the prognosis of gemcitabine-resistant pancreatic cancer as a biomarker. [73]Both lncRNA HCP5 and LINC00346 significantly increased the development of gemcitabine-resistant pancreatic cancer cells via miR-214-3p regulation and miR-188-3p sponging, respectively. [74]NHG14 sponges miR-101 to promote pancreatic ductal adenocarcinoma progression and enhances gemcitabine resistance by stimulating cell autophagy. [75]Down-regulation of NEAT1 by miR-506-3P sponging reduced ZEB2 expression, thereby reversing EMT in gemcitabine-resistant pancreatic cancer cells and increasing their sensitivity to the drug. [76]Adipose-derived mesenchymal stem cells secrete extracellular vesicles containing NEAT1 to promote pancreatic cancer cell proliferation, migration, and gemcitabine resistance.Furthermore, NEAT1 enhances tumor growth and progression by downregulating miR-491-5p and SOCS3 and upregulating Snail in vivo. [77]LncRNA SBF2-AS1 sponges miR-142-3p as a ceRNA to regulate the cytoskeletal gene twinfilin 1 and contributes to gemcitabine resistance. [78]he overexpression of lncRNA TUG1 has been observed in pancreatic cancer tissues and 5-FU-based chemotherapy samples.TUG1 antagonizes downstream miR-376b-3p and increases dihydropyrimidine dehydrogenase-regulated 5-FU catabolism, resulting in 5-FU resistance. [79]Conversely, another lncRNA, GAS5, overcame gemcitabine resistance in pancreatic cancer by targeting miR-221/SOCS3 to restrain EMT and antagonize multi-drug resistance by inhibiting the miR-181c-5p/Hippo axis. [80]High levels of lncRNA AB209630 improved gemcitabine sensitivity in pancreatic cancer by downregulating miR-373 while decreasing AB209630-facilitated gemcitabine resistance. [81]LncRNA ANRIL activates HMGB1-induced autophagy by targeting miR-181a and facilitates cell proliferation, invasion, and migration in pancreatic cancer cells, thereby enhancing resistance to gemcitabine. [82]Additionally, the lncRNA DBH-AS1 functions as a ceRNA for miR-3163 to increase USP44 expression, which participates in gemcitabine absorption. [83]Human pancreatic carcinoma is a typical chemotherapy drug-resistant cancer with a detrimental therapeutic efficacy associated with gemcitabine.Therefore, it is important to explore the underlying mechanisms and key targets here. [84]

DNA Damage Repair and Cell Apoptosis
The cytotoxicity of chemotherapeutic drugs occurs directly or indirectly by triggering DNA damage in cancer cells.The ability of cancer cells to repair DNA damage can help them escape toxicity, resulting in drug resistance. [85]Several lncRNAs are involved in this process; for example, SRSF3 expression correlates with drug resistance and poor prognosis in pancreatic cancer.61a] LncRNA HOTAIR is involved in cisplatin resistance in pancreatic cancer, and a high level of HOTAIR accelerates resistance to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by modulating the expression of TRAIL death receptor 5. [86] Additionally, gemcitabine induces cell apoptosis by interfering with DNA replication in patients with pancreatic cancer. [87]LncRNA UPK1A-AS1 enhances the interaction between Ku70 and Ku80 to expedite nonhomologous end joining, thereby strengthening DNA double-strand break repair and causing oxaliplatin resistance. [88]

EMT and CSCs
EMT is a reversible programmed cellular process in which epithelial cells are transformed into stromal cells. [89]EMT progression is associated with acquiring cancer stem cell (CSC) characteristics. [90]CSCs were produced by the overexpression of EMT-induced transcription factors or activated EMT with TGF- in tumor tissues. [91]LncRNA DYNC2H1-4 knockdown inhibits EMT and acquires CSC properties in gemcitabine-resistant pancreatic cancer cells.Mechanistically, the overexpression of DYNC2H1-4 regulated EMT and CSCs by sponging miR-145. [92]he levels of another lncRNA, GSTM3TV2, were markedly increased in pancreatic tumor tissues.LncRNA GSTM3TV2 augments L-type amino acid transporter 2 and oxidized lowdensity lipoprotein receptor 1 by competitively sequestering let-7-an mRNA targeting cMyc, HMGA2, and Ras-leading to gemcitabine resistance in pancreatic cancer. [93]Xiong et al.
showed that GSTM3TV2 might be an oncogene that expedites chemoresistance in pancreatic cancer by regulating cellular proliferation, apoptosis, and EMT. [94]Gemcitabine could cause the expression of lncRNA HOTAIR in pancreatic CSCs, motivating proliferation and migration, maintaining self-renewal, attenuating apoptosis, and increasing chemotherapeutic resistance. [95]

Signaling Pathway Regulation
Multiple signaling pathways are involved in the efficacy of chemotherapeutic drugs by affecting the balance between cell survival and apoptosis.Reciprocal feedback (lncRNAs, HIF1A-AS1, and HIF1) promotes gemcitabine resistance in pancreatic cancer. [96]HIF1A-AS1 accelerates the interplay between the serine/threonine kinase AKT and Y-box-binding protein 1 (YB1), facilitating its phosphorylation (pYB1).HIF1A-AS1 recruits pYB1 to HIF1 mRNA, consequently accelerating HIF1 translation.Furthermore, HIF1 promotes HIF1A-AS1 transcription by directly binding to the HIF1 response element of the HIF1A-AS1 promoter to generate positive feedback. [96]ncRNA PVT1 induces gemcitabine resistance in pancreatic cancer by interacting with the enhancer of EZH2. [97]Histone acetyltransferase 1 facilitates the transcription of lncRNA PVT1 and enhances the stability of EZH2, resulting in gemcitabine resistance in pancreatic cancer cells.Inhibition of PVT1 suppresses O6methylguanine-DNA methyltransferase expression by inhibiting the SHH/GLI pathway. [98]Importantly, exosome UCA1-derived from hypoxia-induced pancreatic stellate cells-can recruit EZH2 and regulate histone methylation levels in the SOCS3 gene region, enhancing the resistance of pancreatic cancer cells to gemcitabine. [99]

Modification of the Drug Pump
In general, lncRNAs play essential roles in pancreatic cancer drug resistance.ATP-binding cassettes are necessary drug transporters that regulate drug absorption, distribution, and clearance. [100]In gemcitabine-resistant pancreatic cancer cells, catenin enters the nucleus to bind to Pygopus2 and the TCF/LEF binding element (TBEs) to form a ternary complex, which promotes lncRNA PVT1 expression by combining with its promoter region.Subsequently, PVT1 competitively targets miR-619-5p to increase Pygopus2 and ATG14 levels, forming phagocytic vesicles that wrap into cells with gemcitabine.Gemcitabine is excreted from cells under the influence of P-gp and promotes pancreatic cancer cell resistance. [71]Exploring the mechanisms of action of lncRNAs in drug resistance may provide new therapeutic targets and strategies for pancreatic cancer.Chemotherapy-resistant lncRNAs play important roles in cancer treatment and are involved in the regulation of chemotherapy resistance via multiple mechanisms.Some lncRNAs can promote multi-drug resistance by reducing the entry of drugs into cells or increasing the efflux of drugs through exosomes.Some lncRNAs regulate apoptosis and the cell cycle, affecting the sensitivity of cells to chemotherapy.In addition, lncRNAs participate in chemotherapy resistance by regulating tumor stem cell char-acteristics and altering transcriptional and epigenetic regulation.Further studies are needed to explore the molecular mechanisms of chemotherapy resistance and provide new therapeutic strategies to overcome drug resistance.

LncRNAs and Radio-Resistance in Pancreatic Cancer
Radiation therapy is a standard treatment based on ionizing radiation, which induces cancer cell apoptosis through DNA damage.LncRNAs affect the radiation response of pancreatic cancer cells by regulating the expression of multiple genes and signaling pathways. [101]The expression of HOTAIR increased in pancreatic cancer cells, including PANC-1 and AsPC-1 cells, after radiation.Another study confirmed this finding by showing that HOTAIR knockdown heightened radiosensitivity and affected autophagy by increasing ATG7 expression.These results indicate that lncR-NAs have great potential in pancreatic cancer radiotherapy. [102]ncRNAs associated with radiotherapy resistance participate in the development of resistance through various mechanisms, including interfering with DNA repair, regulating the cell cycle and apoptosis, influencing the tumor microenvironment, modulating tumor stem cell characteristics, and regulating gene expression.Currently, studies on the mechanisms of action of lncRNAs in radiotherapy resistance are limited.

LncRNAs and Immunotherapy Resistance in Pancreatic Cancer
Pancreatic cancer is traditionally considered a nonimmunogenic or "cold" tumor that may not be well-suited for immunotherapy. [103]However, immune cells can be activated in the tumor microenvironment of pancreatic cancer.LncRNAs are closely associated with immune resistance in pancreatic cancer. [104]Overexpression of lncRNA MALAT1 in pancreatic cancer is associated with poor prognosis and is accompanied by increased PD-L1 expression. [105]LncRNA PSMB8-AS1 was upregulated in pancreatic cancer tissues and cell lines, with a significant negative correlation with patient survival rate.LncRNA PSMB8-AS1 promotes pancreatic cancer progression by regulating miR-382-3p to target STAT1, thereby transcriptionally regulating PD-L1 to inhibit CD8+ T cell activity. [106]argeting MALAT1 and PSMB8-AS1 may be a potential strategy to overcome resistance to immune checkpoint inhibitors and enhance antitumor immune responses in patients with pancreatic cancer.
The tumor immune microenvironment is a complex ecosystem involving tumor cells, immune cells, stromal cells, blood vessels, and cytokines.In pancreatic cancer, it is characterized by inadequate T-cell infiltration, antigen escape, and increased immunosuppressive cells, including regulatory T cells and MDSCs. [107]Additionally, tumor-associated non-myelinating Schwann cell (TASc) infiltration is much higher in pancreatic cancer than in the normal pancreas, and the abundance of TAScs is positively correlated with immunosuppressive cell infiltration and poor prognosis in pancreatic ductal adenocarcinoma.Depletion of TASc-expressing lncRNA PVT1 restored the immuneresistant tumor microenvironment and improved the antitumor effects of immune checkpoint inhibitors. [108]Decreased or increased lncRNA levels may lead to functional changes in immune cells.LncRNAs can regulate immune cell function by regulating the differentiation, proliferation, migration, and apoptosis of immune cells, thereby affecting their ability to kill tumor cells.Immunotherapy often relies on the activation and regulation of immune signaling pathways, and certain lncRNAs may interfere with the transmission and effects of immune signals by interacting with key molecules.Furthermore, lncRNAs can interact with genes or signaling pathways associated with tumor immune evasion mechanisms, promoting the evasion of immune surveillance and leading to the development of immunotherapy resistance.

LncRNA's Epigenetic Inheritance, Transcription, Post-Transcription and Related Signaling Pathways
The aberrant expression of lncRNAs and related regulatory mechanisms may provide a new approach to pancreatic cancer therapy and resistance.H19 was the first lncRNA to be used in pancreatic cancer therapy.Plasmid BC-819 promotes the expression of the diphtheria toxin A chain in cancer cells through the H19 regulatory sequence.BC-819 combined with gemcitabine or other chemotherapies has shown synergistic efficacy in the treatment of pancreatic cancer. [109]Inhibition of UCA1 significantly inhibits cell proliferation in vitro and tumor growth in vivo increases drug sensitivity, and improves chemotherapeutic efficacy in multiple types of cancer, particularly pancreatic cancer. [110]addington first conceptualized epigenetics as a type of inheritance that alters cellular phenotypes without changing DNA nucleotide sequences. [111]Epigenetic mechanisms including DNA methylation, histone post-translational modifications, chromatin remodeling, and post-transcriptional gene regulation by lncR-NAs are complicated.The DNA helix of genetic material is wrapped in the nucleus in the form of chromatin, and epigenetic mechanisms play a crucial role in the regulation of chromatin structures. [112]Alteration in epigenetic mechanisms can promote the escape of tumorigenesis from immune surveillance or drug resistance. [113]Epigenetic modifications can lead to changes in cellular phenotypes by inducing or suppressing gene expression.Whether epigenetic events occur at the right time, place, or regulatory level significantly affects an organism, potentially leading to tumorigenesis. [114]Fine-tuned epigenetic regulation is crucial for gene expression and biological behavior of tumors, providing new directions for targeted tumor therapy.
GLS-AS mediates the feedback loop between Myc and glutaminase (GLS).Overexpression of GLS-AS inhibits pancreatic cancer cell proliferation and invasion by repressing the Myc/GLS pathway, thus providing a potential therapeutic target for metabolic reprogramming in pancreatic cancer. [115]Mutant p53 drives LINC00857 as a protein scaffold to enhance the binding between FOXM1 and de-ubiquitinase OTUB1, thereby inhibiting FOXM1 degradation via the ubiquitin-proteasome pathway to promote cancer metastasis. [116]The oncogenic function of lncRNA SNHG15 has been detected in pancreatic cancer by epigenetically repressing P15 and Kruppel-like factor 2, competitively combining the enhancer of EZH2, and inducing histone H3 lysine 27 trimethylation. [117]egarding epigenetic modifications, lncRNA expression levels are closely related to DNA methylation levels.Liu et al. demonstrated that LINC00261 exhibits a high methylation level at the cg12179011 locus in pancreatic cancer and is associated with poor survival. [118]Methylation-mediated LINC00261 suppressed pancreatic cancer progression by epigenetically repressing c-Myc expression.Furthermore, STXBP5-AS1 epigenetically inhibited neighboring androglobin expression by efficiently recruiting EZH2 to the androglobin promoter and promoting DNA methylation.Androglobin dramatically restored drug resistance and colony formation in STXBP5-AS1-luxuriant GR cells, resulting in the inactivation of apoptosis. [119]n addition, lncRNAs can affect gene expression by regulating the histone modification status.For example, 45 lncR-NAs are involved in MAPK activity, with the consistent promotion of LINC00941 expression by MAPKs in pancreatic cancer cell lines. [120]KRAS/BRAF mutations and DUSP6 epigenetic aberrations are synergistically conducive to MAPK activation, an essential pancreatic cancer characteristic. [121]Therefore, epigenetic modifications of pancreatic cancer-associated lncR-NAs are crucial factors that affect the occurrence and development of pancreatic cancer.Investigating the functions of these lncRNAs and their relationships with epigenetic modifications may provide novel insights for targeted therapy and prognostic evaluation.

Conclusion and Perspectives
LncRNAs are non-coding RNA with a length greater than 200 nt and high tissue specificity.They play a vital role in the occurrence, development, and prognosis of pancreatic cancer through epigenetic, cell cycle, and differentiation regulations. [122]Additionally, drug resistance in pancreatic cancer is closely associated with lncRNAs.This study provides a molecular rationale for exploring new therapeutics and evaluation methods for pancreatic cancer.Numerous lncRNAs, including HOTAIR, HK2, TSLNC8, GAS8-AS1, UCA1C, HULC, NEAT1, NT5E, and ANRIL, are potentially useful for diagnosing pancreatic cancer, and combining multiple lncRNAs may improve diagnostic efficiency.The expression of lncRNAs may also predict pancreatic cancer behavior.For instance, the expression of HOXA-AS3, HOTTIP, NEAT1, FGD5-AS1, CERS6-AS1, PSMB8-AS1, STAT1, LINC00857, and CRNDE is associated with survival in patients with pancreatic cancer.
The cell lines mentioned in this review-including SW1990, AsPC-1, PANC-1, and BxPC-3-are frequently used in human pancreatic cancer research.Pancreatic cancer cell lines exhibit different phenotypes, gene expression patterns, and physiological characteristics.Thus, selecting different pancreatic cancer cell for subsequent studies may lead to inaccuracies and irreproducibility of the research results, thereby affecting the understanding of biological questions and the development of solutions.Therefore, choosing the appropriate cell lines that best reflect the research question and maintaining consistency throughout all experiments is crucial.The extraordinarily complex TME of pancreatic cancer poses enormous challenges for the delivery and application of lncRNAs.First, the high fibrotic content makes it difficult for lncRNAs to cross the cell membrane and enter target cells.Second, multiple digestive enzymes and metabolic pathways in the gland can cause lncRNA degradation.Finally, because various cell types secrete similar lncRNA molecules, targeting specificity and selectivity should aim to avoid adverse effects when developing lncRNA application strategies.Due to the complex microenvironment of pancreatic cancer, alterations in the properties of cell membranes and surface molecules cause off-target effects during lncRNA transfection.Moreover, RNA enzyme degradation within tumors and other cells can cause lncRNA instability and degradation, resulting in short half-lives and low transfection efficiency.To overcome these issues, researchers have explored novel therapeutic strategies for the treatment of pancreatic cancer.The most common approach is drug intervention, which involves the design of specific small molecules that interfere with lncRNA transcription, stability, or regulatory factor binding.Another method utilizes RNA interference technology, in which specific small interfering RNAs or short hairpin RNAs are introduced to specifically bind to lncRNA subtypes, induce their degradation, or inhibit translation.Liu et al. constructed a bioscaffold carrying shPVT1-CM-D nanoparticles and oxaliplatin, which, when implanted after surgery, significantly suppressed postoperative recurrence and distant metastasis of colorectal cancer. [123]The CRISPR-Cas9 technology can also be employed to induce double-stranded DNA breaks in specific regions of lncRNAs. [124]Another method for targeting lncR-NAs involves the use of antisense oligonucleotides (ASOs) to regulate lncRNA expression and function.ASOs are short synthetic oligonucleotide sequences that bind to complementary sequences of target lncRNAs.ASOs can achieve precise targeting by inducing mRNA degradation, blocking transcription, and interfering with regulatory molecules. [125]Moreover, the efficiency, stability, and specificity of delivery in vivo are crucial issues that require further development.In the future, artificial intelligence and big data analysis can be used to analyze large-scale biological information and provide novel insights into the prediction and optimization of therapeutic strategies.This approach can be combined with genome-editing technologies to directly modify and manipulate lncRNA genes, thereby achieving the precise control and site-specific regulation of lncRNA expression.Moreover, modulation of epigenetic modifications, such as interference with DNA methylation, histone modifications, and chromatin structure, can alter the expression patterns of lncR-NAs and thereby have an impact on diseases.This study provides a new therapeutic strategy for the development of lncRNA regulators targeting specific diseases.However, specific therapeutic applications require further in-depth research and experimental validation to determine efficacy, safety, and applicability.Recently, a plethora of novel techniques have emerged to propel lncRNAs.Notably, high-resolution single-cell sequencing technology has enabled the sequencing of the transcriptome of individual cells, mapping them from a single-cell RNA sequencing atlas to spatial expression profiles. [126]In parallel, highthroughput screening technology evaluates a large number of lncRNAs, facilitating the identification of targets associated with tumor development and potential therapeutic targets. [127]RNA subcellular localization technology determines the distribution of lncRNAs within cells and provides valuable insights into their functions. [128]RNA interactome technology identifies the binding sites between lncRNAs and specific proteins, revealing their regulatory roles in tumor-related signaling pathways and cellular processes. [129]These cutting-edge technologies may serve as powerful tools for understanding the intricate relationship between lncRNAs and tumors.
Given the regulatory role of lncRNAs in pancreatic cancer, lncRNA-targeted therapies represent a new therapeutic approach.The adverse effects of gene therapies targeting lncRNAs remain a significant challenge.These risks include difficulty in discovering druggable lncRNAs and the lack of security due to insufficient basic research.Unexpected risks and inappropriate effects may be uncontrollable in clinical applications owing to the complex regulatory mechanisms of lncRNAs and other factors.Three points require further attention: 1) Optimum delivery systems to guarantee the precise efficacy of targeted lncRNAs, 2) safe approaches to ensure minimal adverse reactions, and 3) sufficient data for clinical trials.

Figure 2 .
Figure 2. A summary diagram on lncRNAs that participated in pancreatic cancer drug resistance.LncRNA PVT1, HCP5, LINC00346, SNHG14, SBF2-AS1, DYNC2H1-4, ANRIL, UCA1, GSTM3TV2, HIF1A-AS1, AB209630, and DBH-AS1 cause resistance to gemcitabine by acting as sponges for mi-RNA or regulating pathways.LncRNA HOTTIP not only leads to gemcitabine resistance by promoting the expression of HOXA13 but also leads to cisplatin resistance by acting as a ceRNA sponged miR-150-5p.LncRNA GAS5 promotes both 5-FU and gemcitabine resistance of pancreatic cancer cells.LncRNA UPK1A-AS1 promotes oxaliplatin resistance.LncRNA HOTAIR promotes cisplatin resistance while leading to radiation resistance.LINC01410 leads to radiation resistance by acting as a ceRNA sponged miR-205-5p.LncRNA MALAT1 leads to immunotherapy resistance by increased PD-L1 expression.LncRNA PSMB8-AS1 leads to immunotherapy resistance through regulating miR-382-3p to target STAT1, transcriptionally regulating PD-L1 to inhibit the activity of CD8+ T cells.LncRNA PVT1 alters the tumor immune microenvironment through Schwann cells and leads to immunotherapy resistance.Arrows represent the promoting effect of lncRNAs; The horizontal lines represent the inhibitory effect of lncRNA.

Table 1 .
LncRNAs associated with the diagnosis and prognosis of pancreatic cancer.

Table 2 .
LncRNAs associated with therapy resistance of pancreatic cancer.