Xu Haitao, Zhao Liang, Fang Qiuju, Sun Jianmin, Zhang Songyan, Zhan Chao, Liu Shujie, Zhang Yubao
Department of Hepatopancreatobiliary Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.
Department of Internal Medicine, The Heilongjiang Provincial Hospital, Harbin, Heilongjiang, P.R. China.
PLoS One. 2014 Dec 22;9(12):e115565. doi: 10.1371/journal.pone.0115565. eCollection 2014.
Hypoxia is a common feature of solid tumors and an important contributor to anti-tumor drug resistance. Hypoxia inducible factor-1 (HIF-1) is one of the key mediators of the hypoxia signaling pathway, and was recently proven to be required for sorafenib resistance in hepatocarcinoma (HCC). MicroRNAs have emerged as important posttranslational regulators in HCC. It was reported that miR-338-3p levels are associated with clinical aggressiveness of HCC. However, the roles of miR-338-3p in HCC disease and resistance to its therapeutic drugs are unknown. In this study, we found that miR-338-3p was frequently down-regulated in 14 HCC clinical samples and five cell lines. Overexpression of miR-338-3p inhibited HIF-1α 3'-UTR luciferase activity and HIF-1α protein levels in HepG2, SMMC-7721, and Huh7 cells. miR-338-3p significantly reduced cell viability and induced cell apoptosis of HCC cells. Additionally, HIF-1α overexpression rescued and HIF-1α knock-down abrogated the anti-HCC activity of miR-338-3p. Furthermore, miR-338-3p sensitized HCC cells to sorafenib in vitro and in a HCC subcutaneous nude mice tumor model by inhibiting HIF-1α. Collectively, miR-338-3p inhibits HCC tumor growth and sensitizes HCC cells to sorafenib by down-regulating HIF-1α. Our data indicate that miR-338-3p could be a potential candidate for HCC therapeutics.
缺氧是实体瘤的常见特征，也是抗肿瘤耐药性的重要促成因素。缺氧诱导因子-1（HIF-1）是缺氧信号通路的关键介质之一，最近被证明是肝癌（HCC）中索拉非尼耐药所必需的。微小RNA已成为肝癌中重要的翻译后调节因子。据报道，miR-338-3p水平与肝癌的临床侵袭性相关。然而，miR-338-3p在肝癌疾病及其治疗药物耐药性中的作用尚不清楚。在本研究中，我们发现miR-338-3p在14例肝癌临床样本和5种细胞系中经常下调。miR-338-3p的过表达抑制了HepG2、SMMC-7721和Huh7细胞中HIF-1α 3'-UTR荧光素酶活性和HIF-1α蛋白水平。miR-338-3p显著降低了肝癌细胞的活力并诱导其凋亡。此外，HIF-1α的过表达挽救了miR-338-3p的抗肝癌活性，而HIF-1α的敲低则消除了该活性。此外，miR-338-3p通过抑制HIF-1α在体外和肝癌皮下裸鼠肿瘤模型中使肝癌细胞对索拉非尼敏感。总体而言，miR-338-3p通过下调HIF-1α抑制肝癌肿瘤生长并使肝癌细胞对索拉非尼敏感。我们的数据表明，miR-338-3p可能是肝癌治疗的潜在候选物。
