缺氧微环境中HIF激活的lncRNA MKLN1−AS对肝细胞癌生长和转移的调控机制

缺氧微环境是肝癌进展的重要驱动因素，课题组发表成果证实长链非编码RNA RUNX1-IT1和AGAP2-AS1参与缺氧诱导的肝癌进展，但新长链非编码RNA MKLN1-AS在肝癌缺氧通路中的功能及机制尚不清楚。我们前期发现缺氧诱导肝癌细胞中MKLN1-AS表达上调；肝癌组织中MKLN1-AS高表达提示预后不良；干扰MKLN1-AS抑制缺氧诱导的肝癌细胞增殖和侵袭；MKLN1-AS可能调控HIF-1α转录活性。基于此，我们提出科学假说：缺氧微环境中HIF激活的MKLN1-AS通过增强HIF-1α转录活性促肝癌生长和转移。我们拟通过细胞分子生物学技术和体内外实验明确肝癌组织中MKLN1-AS表达的临床意义；探索缺氧对MKLN1-AS表达的调控机制；验证MKLN1-AS对肝癌细胞增殖和侵袭的影响规律；揭示MKLN1-AS调控HIF-1α转录活性的机制。本项目成果将为筛选抗肝癌新靶点提供理论依据。

Hypoxic microenvironment is an important driving factor for the progression of hepatocellular carcinoma (HCC). Our published results confirm that long noncoding RNA RUNX1-IT1 and AGAP2-AS1 are involved in hypoxia-induced HCC progression. However, the function and mechanism of the novel long noncoding RNA MKLN1-AS in HCC-related hypoxia pathway is unclear. We previously found that hypoxia induced the upregulation of MKLN1-AS expression in HCC cells. The high expression of MKLN1-AS in HCC tissues predicted a poor prognosis. MKLN1-AS knockdown suppressed hypoxia-induced HCC cell proliferation and invasion. MKLN1-AS possibly regulated the transcriptional activity of HIF-1α in HCC cells. Based on the above results, we propose the scientific hypothesis: HIF activated MKLN1-AS promotes the growth and metastasis of HCC by enhancing the transcriptional activity of HIF-1α under hypoxic microenvironment. The cell molecular biology technology and in vivo and in vitro experiments will be carried out to define the clinical significance of MKLN1-AS expression, explore the regulatory mechanism of hypoxia on MKLN1-AS expression, verify the effect of MKLN1-AS1 on the progression and invasion of HCC cells and reveal the mechanism of MKLN1-AS in regulating the transcriptional activity of HIF-1α in HCC. The results of this project will provide a theoretical basis for screening new targets for anti-HCC.