MiR-183-5p通过破坏HIF-1α/NDUFA4L2介导的缺氧适应抑制肺鳞状细胞癌存活

MiR-183-5p inhibits lung squamous cell carcinoma survival through disrupting hypoxia adaptation mediated by HIF-1α/NDUFA4L2 axis

ONCOGENE

影响因子:7.3

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

DOI: 10.1038/s41388-024-03129-7

摘要

缺氧是肺鳞状细胞癌（LUSC）的常见特征，而缺氧诱导因子-1（HIF-1）过表达与LUSC的预后不良相关。NADH脱氢酶1α亚基复合物亚基4样蛋白2（NDUFA4L2）是HIF-1的新近靶标，但其在LUSC中的作用尚不清楚。本文研究了NDUFA4L2在LUSC中的表达及调控机制，以及其对LUSC细胞氧代谢和存活的影响。通过预测microRNA靶向NDUFA4L2，并检测其在LUSC细胞中的作用。结果显示，NDUFA4L2在LUSC组织中高度表达，且与较短的总生存期相关。在缺氧条件下，NDUFA4L2受HIF-1α调控，且NDUFA4L2通过抑制线粒体复合物I活性，减少线粒体反应性氧种（mitoROS）产生。敲低NDUFA4L2显著抑制LUSC细胞生长，并通过诱导mitoROS积累增强细胞凋亡。此外，NDUFA4L2是miR-183-5p的靶标，高表达的miR-183-5p患者预后更佳。miR-183-5p通过负向调控NDUFA4L2，显著促进mitoROS生成，抑制LUSC细胞存活（体内外均如此）。结果提示，HIF-1α调控NDUFA4L2是促进LUSC在缺氧环境中发展的重要机制。利用强制表达miR-183-5p抑制NDUFA4L2可能成为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.