Wu Haijun, Liang Yu, Shen Lin, Shen Liangfang
Department of Oncology, Xiangya Hospital, Central South University, 87 Xiang Ya Road, Changsha 410008, China.
Department of Oncology, Xiangya Hospital, Central South University, 87 Xiang Ya Road, Changsha 410008, China
Biol Open. 2016 May 15;5(5):563-70. doi: 10.1242/bio.015008.
MicroRNAs (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.
微小RNA（miRNA）是一类保守的约22个核苷酸的RNA，在包括化疗耐药性在内的各种生物学过程中发挥重要作用。最近，许多研究表明，miR-204在结直肠癌（CRC）中显著下调，这表明该miRNA可能在CRC中发挥作用。然而，miR-204是否调节结直肠癌对5-氟尿嘧啶（5-Fu）的化疗敏感性仍不清楚。在我们目前的研究中，我们探讨了这种可能性以及发挥这种作用的潜在机制。我们确定高迁移率族蛋白A2（HMGA2）是miR-204的一个新的直接靶点，并表明在CRC细胞系中miR-204表达降低而HMGA2表达增加。此外，miR-204过表达和HMGA2抑制均减弱细胞增殖，而HMGA2的强制表达部分恢复了miR-204对HCT116和SW480细胞的抑制作用。此外，miR-204/HMGA2轴通过激活PI3K/AKT途径调节HCT-116和SW480结肠癌细胞对5-Fu的耐药性。这些结果表明，miR-204/HMGA2轴可能在结肠癌细胞的5-Fu耐药中起关键作用。综上所述，我们目前的研究阐明了miR-204通过下调结直肠癌中的HMGA2上调5-Fu化疗敏感性，并为结直肠癌患者5-Fu耐药机制提供了重要见解。更重要的是，我们目前的研究表明，miR-204有潜力作为5-Fu耐药结直肠癌的治疗策略。
