Abstract
ABSTRACTMicroRNAs (miRNAs) are a conserved class of ∼22 nucleotide RNAs that playing important roles in various biological processes including chemoresistance. Recently, many studies have revealed that miR-204 is significantly attenuated in colorectal cancer (CRC), suggesting that this miRNA may have a function in CRC. However, whether miR-204 modulates chemosensitivity to 5-fluorouracil (5-Fu) in colorectal cancer is still unclear. In our present study, we discuss this possibility and the potential mechanism exerting this effect. We identified high mobility group protein A2 (HMGA2) as a novel direct target of miR-204 and showed that miR-204 expression was decreased while HMGA2 expression was increased in CRC cell lines. Additionally, both MiR-204 overexpression and HMGA2 inhibition attenuated cell proliferation, whereas forced expression of HMGA2 partly restored the inhibitory effect of miR-204 on HCT116 and SW480 cells. Moreover, the miR-204/HMGA2 axis modulated the resistance of tumor cells to 5-Fu in HCT-116 and SW480 colon cancer cells via activation of the PI3K/AKT pathway. These results demonstrate that the miR-204/HMGA2 axis could play a vital role in the 5-Fu resistance of colon cancer cells. Taken together, our present study elucidated that miR-204 upregulated 5-Fu chemosensitivity via the downregulation of HMGA2 in colorectal cancer and provided significant insight into the mechanism of 5-Fu resistance in colorectal cancer patients. More importantly, our present study suggested that miR-204 has potential as a therapeutic strategy for 5-Fu-resistant colorectal cancer.
Highlights
Nowadays, among diverse cancers, colorectal cancer is the third most common one and the third leading cause of cancer death in people worldwide (Siegel et al, 2015)
high mobility group protein A2 (HMGA2) mRNA is a direct target of miR-204 We predicted potential targets of miR-204 using the TargetScan, miRanda and miRWalk online tools (Esquela-Kerscher and Slack, 2006; Hwang and Mendell, 2007; Manikandan et al, 2008) to clarify the molecular mechanism by which miR-204 exerts its inhibitory effect on HCT116 and SW480 cell line
Results showed that co-transfection of miR-204 mimics and wild-type HMGA2 vector lead to an obvious reduction of luciferase activity, while co-transfection of miR-204 mimics and mutant-type HMGA2 vector eliminated the repression of luciferase activity, suggesting that miR-204 targets HMGA2 by directly binding to its 3′ untranslated region
Summary
Among diverse cancers, colorectal cancer is the third most common one and the third leading cause of cancer death in people worldwide (Siegel et al, 2015). For the past 10 years, a class of noncoding RNA molecules known as microRNAs (miRNA) have been found to be associated with cancer development by acting as either tumor suppressors or oncogenes (Di Leva et al, 2014; Siegel et al, 2015). They are mainly endogenous, noncoding RNAs with a length of 19 to 24 nucleotides (Bartel, 2004). MiRNAs exert their effect on the gene expression downregulation via base pairing to complementary sites in the 3′-untranslated regions (UTR) of their target mRNAs (He and Hannon, 2004)
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