miR-183-5p通过破坏由HIF-1α/NDUFA4L2轴介导的缺氧适应性抑制肺鳞状细胞癌的生存
MiR-183-5p inhibits lung squamous cell carcinoma survival through disrupting hypoxia adaptation mediated by HIF-1α/NDUFA4L2 axis
影响因子:7.30000
分区:医学1区 Top / 生化与分子生物学1区 遗传学1区 细胞生物学2区 肿瘤学2区
发表日期:2024 Sep
作者:
Peng Han, Boxiang Zhang, Yixing Li, Rui Gao, Xinru Li, Hui Ren, Puyu Shi, Aomei Zhao, Jianjun Xue, Aimin Yang, Yiqian Liang
摘要
缺氧是肺鳞状细胞癌（LUSC）的常见特征，低氧诱导因子-1（HIF-1）过表达与LUSC的临床结果差有关。 NADH脱氢酶1α亚复合子复合4类样2（NDUFA4L2）是HIF-1的最近确定的靶标，但其在LUSC中的作用尚不清楚。在此，在LUSC中研究了NDUFA4L2的表达和调节机制，并确定了对LUSC细胞氧化代谢的影响和NDUFA4L2的存活。鉴定了针对NDUFA4L2的电势靶标，并检测到其在LUSC细胞上的作用。我们发现NDUFA4L2在LUSC组织中过表达，并且NDUFA4L2表达与较短的总生存期相关。 NDUFA4L2在缺氧下由HIF-1α调节，NDUFA4L2通过抑制LUSC细胞中的线粒体复合物I活性而降低了线粒体活性氧（Mitoros）的产生。 NDUFA4L2沉默有效地抑制了LUSC细胞的生长，并通过诱导Moritoros的积累增强了凋亡。此外，NDUFA4L2是miR-183-5p的靶标，而miR-183-5p水平高的LUSC患者的预后更好。 miR-183-5p通过负调节NDUFA4L2的体外和体内诱导了Moritoros的产生，并抑制了LUSC的存活。我们的结果表明，HIF-1α对NDUFA4L2的调节是促进缺氧下LUSC进展的重要机制。使用强制miR-183-5p表达的NDUFA4L2抑制可能是LUSC治疗的有效策略。
Abstract
Hypoxia is a common feature of lung squamous cell carcinoma (LUSC), and hypoxia-inducible factor-1 (HIF-1) overexpression is associated with poor clinical outcome in LUSC. NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2) is a recently identified target of HIF-1, but its roles in LUSC remain unclear. Herein, the expression and regulatory mechanisms of NDUFA4L2 were investigated in LUSC, and the influences on LUSC cell oxidative metabolism and survival of NDUFA4L2 were determined. The potential microRNA targeting to NDUFA4L2 was identified and its roles on LUSC cell were detected. We found that NDUFA4L2 were overexpressed in LUSC tissues, and that NDUFA4L2 expression correlated with shorter overall survival. NDUFA4L2 was regulated by HIF-1α under hypoxia, and NDUFA4L2 decreased mitochondrial reactive oxygen species (mitoROS) production through inhibiting mitochondrial complex I activity in LUSC cells. NDUFA4L2 silencing effectively suppressed LUSC cell growth and enhanced apoptosis by inducing mitoROS accumulation. Additionally, NDUFA4L2 was a target for miR-183-5p, and LUSC patients with high miR-183-5p levels had better prognoses. MiR-183-5p significantly induced mitoROS production and suppressed LUSC survival through negatively regulating NDUFA4L2 in vitro and in vivo. Our results suggested that regulation of NDUFA4L2 by HIF-1α is an important mechanism promoting LUSC progression under hypoxia. NDUFA4L2 inhibition using enforced miR-183-5p expression might be an effective strategy for LUSC treatment.