Dysfunction of miR‐802 in tumors

Abstract Recent studies have shown that miR‐802 is abnormally expressed in many tumors. miR‐802 is expressed at low levels in tissues and cells of gastric cancer, colorectal cancer, breast cancer, cervical cancer, epithelial ovarian cancer, tongue squamous cell carcinoma, oral squamous cell carcinoma, esophageal squamous cell carcinoma, laryngeal squamous cell carcinoma, and melanoma. In contrast, miR‐802 is overexpressed in hepatocellular carcinoma, bladder urothelial cancer, osteosarcoma, and cholesteatoma tissue cells. It should be noted that the results of studies on the expression of miR‐802 in pancreatic cancer, prostate cancer, and lung cancer are inconsistent. Current studies have found that miR‐802 can target and regulate genes in different tumors, and affect the regulation of the Wnt signaling pathway, EMT signaling pathway, PI3K/AKT signaling pathway, ERK signaling pathway, and Hedgehog signaling pathway. At the same time, miR‐802 is regulated by the endogenous competition of four ceRNAs, including circDONSON, IGFL2‐AS1, MIR155HG, and MIR4435‐2HG. This article reviews the abnormal expression of miR‐802 in a variety of tumors, expounds the mechanism by which miR‐802 affects tumor progression by regulating different target genes, and elaborates the network of miR‐802‐related ceRNAs. We also summarized the limitations of miR‐802 research and looked forward to the potential application of miR‐802 in the diagnosis and prognosis of tumors.


| PROG NOS TIC VALUE OF AB NORMAL E XPRE SS I ON OF MIR-8 02
As shown in Table 2, our study found that the expression level of miR-802 is related to the prognosis of patients with tumors. miR-802 expression is found to be reduced in ESCC, CRC, and EOC (Table 2).
In ESCC, high expression of miR-802 is significantly associated with the increase in overall survival (OS) and progression-free survival (PFS). 7 In EOC, highly expressed miR-802 can be used as an independent prognostic factor and is significantly related to the increase in PFS and time to progression (TTP). 37 In CRC, low expression of miR-802 is an independent prognostic factor affecting OS in patients, and decreased expression of miR-802 is associated with the progression of CRC and poor prognosis of patients. 14 In contrast, high expression of miR-802 was significantly associated with poor OS and cancer-specific survival (CSS) of CRC. 38 However, miR-802 expression is elevated in HCC and PCa. The OS and disease-free survival (DFS) of HCC patients with high expression of miR-802 are shorter. 24 Jiang et al. further found that the median survival time of patients with high blood miR-802 levels was much shorter than that of patients with low blood miR-802 levels. 22 Low blood miR-802 expression is significantly related to the good prognosis of HCC patients, but the expression level of miR-802 in tissues is not significantly correlated with the prognosis of HCC patients. 22 In PCa, the 3-year survival rate and OS of the miR-802negative group were significantly higher than those of the miR-802positive group. 2

| MIR-8 02 AFFEC TS TUMOR PROG RE SS I ON BY REG UL ATING THE E XPRE SS I ON OF TARG E T G ENE S
As shown in Figures 1 and 2

| miR-802 and the Wnt signaling pathway
As one of the most classic signaling pathways, the Wnt signaling pathway plays a key role in the occurrence and development of many cancers. 39 NKD1 was found to be an evolutionary conservative feedback inhibitor of the Wnt signaling pathway. 40 TCF7L2 is an important part of the Wnt/β-catenin signaling pathway. 41 TCF4 encodes a transcription factor in the Wnt signaling pathway. 30 As shown in Figures 1A and   2, overexpressed miR-802 can up-regulate the expression of its target gene NKD1, thereby inhibiting the proliferation, migration, invasion of CRC cells, and promoting apoptosis of CRC cells. 42 Meanwhile, overexpressed miR-802 exerts a tumor suppressor effect by down-regulating the expression of the target gene TCF7L2. 42 In PC, the up-regulated miR-802 inhibits the expression of the target gene TCF4, thereby inhibiting the proliferation of tumor cells. 30 In lung cancer, overexpressed miR-802 promotes the proliferation of lung cancer cells by targeting the expression of the tumor suppressor gene Menin. 35 The increased expression of β-catenin during this process suggests that miR-802 may activate the Wnt/β-catenin signaling pathway. 35

| miR-802 and the PI3K/AKT and ERK signaling pathways
The PI3K/AKT signaling pathway is important to regulate the initial stage of cancer metastasis and is considered a promising target for the treatment of malignant tumors. 43 As shown in Figures

| miR-802 and the Hedgehog signaling pathway
Hedgehog (Hh) signaling pathway is a key regulator of development, cell proliferation, and stem cell maintenance. 45 RAB23 is an important member of the RAB family, which is involved in the regulation

| miR-802 and the EMT signaling pathway
As an evolutionarily conserved biological process, EMT is related to tumorigenesis and can significantly enhance the ability of cancer cells to invade and metastasize. 48 As shown in Figure 1D MicroRNA can be used as a high-quality diagnostic marker of disease. MicroRNA exists in large amounts in serum and plasma, and it can be encapsulated in exosomes, vesicles, and apoptotic bodies to avoid degradation. 51 This review summarizes significant differences in the expression levels of miR-802 in several diseases, and these differences can provide a potential theoretical basis for miR-802 as a diagnostic biomarker of diseases. MicroRNA is a potential therapeutic target, but its off-target, half-life, and other issues have always been obstacles to the entry of microRNA into clinical applications. 52 It is currently known that circDONSON, 10 lncRNA MIR4435-2HG, 21 and lncRNA IGFL2-AS1 11 can sponge miR-802, which can precisely regulate the biological functions of miR-802. These molecular mechanisms also provide some hints for the future development of miR-802 in the treatment of related diseases.
There are inconsistent results for the expression of miR-802 in some tumors. This may be due to the following reasons. Firstly, there are differences in the sample types of different experiments.
In the study of pancreatic cancer, miR-802 was down-regulated in pancreatic cancer tissues, 30,31 while it was up-regulated in the cyst fluid of high-grade invasive pancreatic cystic lesions. 32 In addition, miR-802 was significantly down-regulated in NSCLC and A549, H522, H1299, H460, and SK-MES-1. 34 Another study found that the expression was up-regulated in lung cancer tissues, but this study did not specify the subtype of lung cancer. 35 29 In summary, we believe that the above speculations may explain, at least in part, the inconsistent expressions of miR-802 in the above-mentioned tumors.
The current research on miR-802 still has some limitations. Many studies have initially explored the relevance of miR-802 and its target genes in cancers, but the specific mechanism is still elusive. For example, in the study of GC, the IGFL2-AS1/miR-802/ARPP19 axis needs to be verified in other tumors. 11 The YWHAZ signaling pathway mediated by miR-802 may play a role in EOC, 20 but the specific regulatory mechanism needs to be further studied. MIR155HG promotes tumorigenesis and development through the negative regulation of miR-802 in PC cells, but whether other mechanisms or targets are involved in the regulation of MIR155HG still needs to be explored. 31 The mechanism by which miR-802 regulates pancreatic β-cell apoptosis still needs to be further studied. 53 In addition, the experimental samples or models in some studies are very limited.
In the study of CC, multiple CC cell lines were not used, and no in vivo experiments were performed. 17 Research on miR-802 and HBV lacks tissues and reliable animal samples that are susceptible to HBV infection and lacks in vivo experiments. 23 In the study of CRC, only the HCT-116 cell line 12 was used. In the study of HCC, the overexpression of miR-802 was only based on SMMU-7721 cancer cells. 49 In oral lichen planus (OLP), the effect of miR-802 on apoptosis has not been validated in OLP animal models. 54 In order to make the results more convincing, it is necessary to conduct further research on miR-802 in more comprehensive and diverse samples and models.
This article reviews the aberrant expression of miR-802 in different tumors can regulate the expression of target genes and the activation or inhibition of different signaling pathways. At the same time, miR-802 can also serve as a potential molecular indicator for the prognosis of human tumors, providing new ideas for the diagnosis and treatment of tumors in the future.

ACK N OWLED G M ENT
This study was supported by K. C. Wong Magna Fund in Ningbo University.

CO N FLI C T O F I NTE R E S T
All authors declare no conflicts of interest.

AUTH O R CO NTR I B UTI O N S
TG, MZ, TS, and SD collected and analyzed the related publications, and wrote this study; SD, MZ, and TG conceived and gave the final approval of the submitted version.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data presented in this study can be found in online repositories.
The name of repositories and reference number can be found in the review.