miR-342-3p suppresses hepatocellular carcinoma proliferation through inhibition of IGF-1R-mediated Warburg effect.
miR-342-3p suppresses hepatocellular carcinoma proliferation through inhibition of IGF-1R-mediated Warburg effect.
复制标题
miR-342-3p通过抑制IGF-1R介导的Warburg效应抑制肝细胞癌增殖
DOI：
10.2147/ott.s161586
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发表时间：
2018
影响因子：
4
通讯作者：
Zhao C
中科院分区：
文献类型：
--
作者：
Liu W;Kang L;Han J;Wang Y;Shen C;Yan Z;Tai Y;Zhao C
胰岛素样生长因子-1受体（IGF-1 R）是一种被充分研究的致癌因子，其促进细胞增殖和能量代谢，并且在包括肝细胞癌（HCC）在内的许多癌症中过表达。有氧糖酵解是癌症的一个标志，靶向其调节因子（包括IGF-1 R）的药物正在开发中。然而，IGF-1 R抑制的机制和IGF-1 R抑制剂在癌细胞中的生理意义尚不清楚。细胞增殖通过细胞计数Kit-8和集落形成试验来评估。Western blot和实时荧光定量PCR检测相关蛋白、miRNA和基因表达。荧光素酶报告基因测定用于说明miR-342- 3 p和IGF-1 R之间的相互作用。通过葡萄糖摄取、ATP浓度、乳酸产生、细胞外酸化率和耗氧率测定来确定miR-342- 3 p对糖酵解的影响。在体内，在裸鼠中进行皮下肿瘤形成测定和PET。在本研究中，我们证明了microRNA-342- 3 p（miR-342- 3 p）通过直接靶向IGF-1 R的3′-非翻译区（3′-untranslated regions，3 ′-UTR）抑制IGF-1 R介导的PI 3 K/AKT/GLUT 1信号通路。通过抑制IGF-1 R，miR-342- 3 p通过降低肝癌细胞中的葡萄糖摄取、乳酸产生、ATP产生和细胞外酸化速率（ECAR）以及增加耗氧速率（OCR）来抑制糖酵解。重要的是，由miR-342- 3 p调节的糖酵解对于其在体外和体内调节HCC生长至关重要。我们的研究结果提供了关于miR-342- 3 p作为肝癌肿瘤抑制因子的作用的线索，主要是通过抑制IGF-1 R。通过miR-342- 3 p靶向IGF-1 R可能是一种潜在的肝癌治疗策略。
Insulin-like growth factor-1 receptor (IGF-1R) is a well-studied oncogenic factor that promotes cell proliferation and energy metabolism and is overexpressed in numerous cancers including hepatocellular carcinoma (HCC). Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including IGF-1R, are being developed. However, the mechanisms of IGF-1R inhibition and the physiological significance of the IGF-1R inhibitors in cancer cells are unclear. Cell proliferation was evaluated by cell counting Kit-8 and colony formation assay. Western blot and real-time PCR were accordingly used to detect the relevant proteins, miRNA and gene expression. Luciferase reporter assays were used to illustrate the interaction between miR-342-3p and IGF-1R. The effect of miR-342-3p on glycolysis was determined by glucose uptake, ATP concentration, lactate generation, extracellular acidification rate and oxygen consumption rate assays. In vivo, subcutaneous tumor formation assay and PET were performed in nude mice. In this study, we demonstrate that by directly targeting the 3′-UTR (3′-untranslated regions) of IGF-1R, microRNA-342-3p (miR-342-3p) suppresses IGF-1R-mediated PI3K/AKT/GLUT1 signaling pathway both in vitro and in vivo. Through suppression of IGF-1R, miR-342-3p dampens glycolysis by decreasing glucose uptake, lactate generation, ATP production, and extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) in hepatoma cells. Importantly, glycolysis regulated by miR-342-3p is critical for its regulating HCC growth both in vitro and in vivo. Our findings provide clues regarding the role of miR-342-3p as a tumor suppressor in liver cancer mainly through the inhibition of IGF-1R. Targeting IGF-1R by miR-342-3p could be a potential therapeutic strategy in liver cancer.