MicroRNA-25 promotes gastric cancer proliferation, invasion, and migration by directly targeting F-box and WD-40 Domain Protein 7, FBXW7

Abstract

Increasing evidence shows that abnormal microRNA (miRNA) expression is involved in tumorigenesis. MiR-25 was previously reported to act as tumor suppressor or oncogene in diverse cancers. However, their expression, function, and mechanism in gastric cancer (GC) are not well known. Here, we show that miR-25 was overexpressed in primary tumor tissues of GC patients and was significantly correlated with a more aggressive phenotype of GC in patients. MiR-25 inhibition significantly decreased the proliferation, invasion, and migration of GC cells in vitro. Furthermore, miR-25 repressed F-box and WD-40 domain protein 7 (FBXW7) expression by directly binding to 3-untranslated region (UTR) of FBXW7, and the inverse correlation was observed between the expressions of miR-25 and FBXW7 mRNA in primary GC tissues. Moreover, the restoration of FBXW7 led to suppressed proliferation, invasion, and migration of GC cells. In vivo, miR-25 promotes tumor growth of GC. Taken together, miR-25 promotes GC progression by directly downregulating FBXW7 expression and may be employed as a novel prognostic marker and therapeutic target of GC.

Fbxw7 Tumor Suppressor

“…Xiang et al 62 found that miRNA-25 was significantly upregulated in nonsmall cell lung cancer (NSCLC) and promoted NSCLC cells proliferation and motility partially by targeting Fbxw7. Gong et al 63 showed that miRNA-25 was overexpressed in primary tumor tissues of GC patients and promoted GC progression by directly downregulating Fbxw7 expression. In a study from Li et al, 64 they showed that a sequential expression of miR-503 and miR-182 in benign adenoma cooperatively regulated Fbxw7, contributing to the malignant transformation of colon adenoma to adenocarcinoma.…”

MicroRNA regulation of F-box proteins and its role in cancer

“…The MRE within the 3′-UTR of FBXW7 is recognized by miR-25, directly repressing FBXW7 levels in gastric cancer and prostatic small cell neuroendocrine carcinoma cells [62, 63], which promotes rapid proliferation and aggressive behavior of these cancer cells. Interestingly, miR-25 upregulation in prostatic small cell neuroendocrine carcinoma cells was driven by mutated p53, which lead to increased Aurora kinase A expression due to miR-25 suppression of FBXW7 levels [63].…”

“…Whether suppression of FBXW7 by miR-25 also contributes to maintenance and self-renewal of cancer stem-like cells needs further exploration. In contrast to the oncogenic function of miR-25 in gastric cancer [62], ovarian cancer [65] and esophageal squamous cell carcinoma [66], miR-25 was found to be downregulated in human colon cancer and thyroid carcinoma [67, 68]. It will be interesting to determine whether FBXW7 levels are altered in colon cancer and thyroid carcinoma, which exhibit decreased miR-25 expression, and the role of FBXW7 in these cancers.…”

The Role of Immune Modulatory MicroRNAs in Tumors

“…The ligands of the activating NK cell receptor NKG2D are the major histocompatibility complex class Irelated molecules (MIC) A and B and the human cytomegalovirus UL16-binding proteins (ULBP) [73]. The expression of MICA and MICB is controlled by several oncogenic miRNAs, like miRNA-10b, miRNA-17-5p, miRNA-20a, miRNA-25, miRNA-93, and miRNA-106b, which increase the proliferative, invasive, and angiogenic potential of tumors [73,[75][76][77][78][79][80][81][82][83] and affect the NK cell cytotoxicity. The tumor-suppressive miRNA-302c, miRNA-376a, and miRNA-433-3p showed a reduced expression in cancer and target the 3′-UTR of MIC [73,[84][85][86][87].…”