The hypoxic tumor microenvironment, a fundamental feature of solid tumors, drives hepatocellular carcinoma (HCC) progression through regulating the transcriptional activities of protein-coding and noncoding genes. However, long noncoding RNA (lncRNA)-mediated HCC progression in hypoxic microenvironment remains largely unknown yet. In this study, we found that LINC00674 was upregulated under hypoxic conditions in a HIF-1-dependent manner, and the occupancy of HIF-1 to HRE of LINC00674 gene promoter was essential for its transcription. In addition, LINC00674 level was increased in HCC cell lines and tissues. Clinically, statistical analysis showed that LINC00674 expression was significantly associated with tumor size, venous infiltration, tumor stage and poor prognosis of HCC. Functionally, loss-of-function assays revealed that LINC00674 knockdown inhibited the migration, proliferation and invasion of HCC cells. Furthermore, LINC00674 silencing prominently repressed the mTOR signaling pathway. LINC00674 overexpression-enhanced HCC cell proliferation, migration and invasion were markedly abolished by an mTOR inhibitor rapamycin. NADPH oxidase 1 (NOX1) was positively regulated by LINC00674 in HCC cells. NOX1 knockdown markedly reversed LINC00674-upregulated the p-mTOR level and HCC cells' malignant behaviors. Finally, we found that LINC00674 knockdown attenuated the growth of HCC cells in vivo. Our finding demonstrated that LINC00674 was a new HIF-1 target gene, and hypoxia-induced LINC00674 exerted a pro-proliferative and pro-metastatic role in HCC, possibly by activating the NOX1/mTOR signaling pathway. This study suggested LINC00674 as a promising therapeutic target for HCC.

中文翻译：

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缺氧诱导的LINC00674通过激活NOX1/mTOR信号通路促进肝细胞癌进展

低氧肿瘤微环境是实体瘤的基本特征，通过调节蛋白质编码和非编码基因的转录活性来驱动肝细​​胞癌 (HCC) 进展。然而，在缺氧微环境中，长链非编码 RNA (lncRNA) 介导的 HCC 进展在很大程度上仍然未知。在这项研究中，我们发现 LINC00674 在缺氧条件下以 HIF-1 依赖性方式上调，HIF-1 占据 LINC00674 基因启动子的 HRE 对其转录至关重要。此外，HCC 细胞系和组织中的 LINC00674 水平升高。临床上，统计分析显示LINC00674的表达与HCC的肿瘤大小、静脉浸润、肿瘤分期和预后不良显着相关。在功能上，功能丧失测定表明，LINC00674 敲低抑制了 HCC 细胞的迁移、增殖和侵袭。此外，LINC00674 沉默显着抑制了 mTOR 信号通路。mTOR抑制剂雷帕霉素显着消除了LINC00674过表达增强的HCC细胞增殖、迁移和侵袭。NADPH 氧化酶 1 (NOX1) 在 HCC 细胞中受到 LINC00674 的正向调节。NOX1 敲低显着逆转 LINC00674 上调 p-mTOR 水平和 HCC 细胞的恶性行为。最后，我们发现 LINC00674 敲低减弱了 HCC 细胞的生长 mTOR抑制剂雷帕霉素显着消除了迁移和侵袭。NADPH 氧化酶 1 (NOX1) 在 HCC 细胞中受到 LINC00674 的正向调节。NOX1 敲低显着逆转 LINC00674 上调 p-mTOR 水平和 HCC 细胞的恶性行为。最后，我们发现 LINC00674 敲低减弱了 HCC 细胞的生长 mTOR抑制剂雷帕霉素显着消除了迁移和侵袭。NADPH 氧化酶 1 (NOX1) 在 HCC 细胞中受到 LINC00674 的正向调节。NOX1 敲低显着逆转 LINC00674 上调 p-mTOR 水平和 HCC 细胞的恶性行为。最后，我们发现 LINC00674 敲低减弱了 HCC 细胞的生长在体内。我们的研究结果表明 LINC00674 是一个新的 HIF-1 靶基因，缺氧诱导的 LINC00674 在 HCC 中发挥促增殖和促转移作用，可能是通过激活 NOX1/mTOR 信号通路。该研究表明 LINC00674 是一种有前途的 HCC 治疗靶点。