Emerging evidence has suggested that long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) is upregulated in hepatocellular carcinoma (HCC) and is associated with cell invasion, migration, and growth. However, the potential modulation mechanism remains to be elucidated. MiR-33a-5p and cyclin-dependent kinase 6 (CDK6) also participate in the pathophysiology of HCC. This work aims to investigate the effect of CRNDE on HCC apoptosis, invasion, and migration and elucidate the role of miR-33a-5p and CDK6 therein. CRNDE and CDK6 were upregulated in HCC tissues and cells, while miR-33a-5p was downregulated. Inhibition of CRNDE suppressed the invasion, migration, and proliferation of HCC cells and enhanced apoptosis by modulating proteins associated with mitochondrial apoptosis (caspase 3, Bax, cytochrome-c, Bcl-2), which were the same as the function of miR-33a-5p overexpression. The dual-luciferase reporter assay demonstrated that miR-33a-5p was a target of CRNDE, and in turn, CRNDE inhibition enhanced the level of miR-33a-5p. CDK6 was also revealed as a target of miR-33a-5p, and both CRNDE inhibition and miR-33a-5p overexpression suppressed CDK6 expression and led to G0/G1 phase block in HCC cells. In vivo experiments using a mouse xenograft tumor model further verified the interaction between CRNDE and miR-33a-5p, showing that miR-33a-5p overexpression or CRNDE inhibition suppressed CDK6 expression and HCC tumorigenesis. Overall, the present work indicated that CRNDE plays an oncogenic function in HCC through regulating the miR-33a-5p/CDK6 axis, revealing a potential therapeutic target in HCC.

中文翻译：

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长的非编码RNA CRNDE通过miR-33a-5p / CDK6轴促进肝细胞癌的恶性进展。

新兴证据表明，在肝细胞癌（HCC）中长时非编码RNA（lncRNA）大肠癌的差异表达（CRNDE）被上调，并且与细胞侵袭，迁移和生长有关。然而，潜在的调制机制仍有待阐明。MiR-33a-5p和细胞周期蛋白依赖性激酶6（CDK6）也参与HCC的病理生理。这项工作旨在调查CRNDE对HCC凋亡，侵袭和迁移的影响，并阐明其中的miR-33a-5p和CDK6的作用。在肝癌组织和细胞中CRNDE和CDK6被上调，而miR-33a-5p被下调。抑制CRNDE可通过调节与线粒体凋亡相关的蛋白（胱天蛋白酶3，Bax，细胞色素C，Bcl-2）抑制HCC细胞的侵袭，迁移和增殖，并增强凋亡。与miR-33a-5p过表达的功能相同。双重荧光素酶报告基因检测证明miR-33a-5p是CRNDE的靶标，而CRNDE抑制反过来又提高了miR-33a-5p的水平。CDK6也被揭示为miR-33a-5p的靶标，CRNDE抑制和miR-33a-5p的过表达均抑制了CDK6的表达并导致HCC细胞中G0 / G1期的阻滞。使用小鼠异种移植肿瘤模型的体内实验进一步验证了CRNDE和miR-33a-5p之间的相互作用，表明miR-33a-5p的过表达或CRNDE抑制抑制了CDK6表达和HCC肿瘤发生。总体而言，目前的工作表明CRNDE通过调节miR-33a-5p / CDK6轴在肝癌中发挥致癌作用，揭示了肝癌的潜在治疗靶点。双重荧光素酶报告基因检测证明miR-33a-5p是CRNDE的靶标，而CRNDE抑制反过来又提高了miR-33a-5p的水平。CDK6也被揭示为miR-33a-5p的靶标，CRNDE抑制和miR-33a-5p的过表达均抑制了CDK6的表达并导致HCC细胞中G0 / G1期的阻滞。使用小鼠异种移植肿瘤模型的体内实验进一步验证了CRNDE和miR-33a-5p之间的相互作用，表明miR-33a-5p的过表达或CRNDE抑制抑制了CDK6表达和HCC肿瘤发生。总体而言，目前的工作表明CRNDE通过调节miR-33a-5p / CDK6轴在肝癌中发挥致癌作用，揭示了肝癌的潜在治疗靶点。双重荧光素酶报告基因检测证明miR-33a-5p是CRNDE的靶标，而CRNDE抑制反过来又提高了miR-33a-5p的水平。CDK6也被揭示为miR-33a-5p的靶标，CRNDE抑制和miR-33a-5p的过表达均抑制了CDK6的表达并导致HCC细胞中G0 / G1期的阻滞。使用小鼠异种移植肿瘤模型的体内实验进一步验证了CRNDE和miR-33a-5p之间的相互作用，表明miR-33a-5p的过表达或CRNDE抑制抑制了CDK6表达和HCC肿瘤发生。总体而言，目前的工作表明CRNDE通过调节miR-33a-5p / CDK6轴在肝癌中发挥致癌作用，揭示了肝癌的潜在治疗靶点。CRNDE抑制增强了miR-33a-5p的水平。CDK6也被揭示为miR-33a-5p的靶标，CRNDE抑制和miR-33a-5p的过表达均抑制了CDK6的表达并导致HCC细胞中G0 / G1期的阻滞。使用小鼠异种移植肿瘤模型的体内实验进一步验证了CRNDE和miR-33a-5p之间的相互作用，表明miR-33a-5p的过表达或CRNDE抑制抑制了CDK6表达和HCC肿瘤发生。总体而言，目前的工作表明CRNDE通过调节miR-33a-5p / CDK6轴在肝癌中发挥致癌作用，揭示了肝癌的潜在治疗靶点。CRNDE抑制增强了miR-33a-5p的水平。CDK6也被揭示为miR-33a-5p的靶标，CRNDE抑制和miR-33a-5p的过表达均抑制了CDK6的表达并导致HCC细胞中G0 / G1期的阻滞。使用小鼠异种移植肿瘤模型的体内实验进一步验证了CRNDE和miR-33a-5p之间的相互作用，表明miR-33a-5p的过表达或CRNDE抑制抑制了CDK6表达和HCC肿瘤发生。总体而言，目前的工作表明CRNDE通过调节miR-33a-5p / CDK6轴在肝癌中发挥致癌作用，揭示了肝癌的潜在治疗靶点。使用小鼠异种移植肿瘤模型的体内实验进一步验证了CRNDE和miR-33a-5p之间的相互作用，表明miR-33a-5p的过表达或CRNDE抑制抑制了CDK6表达和HCC肿瘤发生。总体而言，目前的工作表明CRNDE通过调节miR-33a-5p / CDK6轴在肝癌中发挥致癌作用，揭示了肝癌的潜在治疗靶点。使用小鼠异种移植肿瘤模型的体内实验进一步验证了CRNDE和miR-33a-5p之间的相互作用，表明miR-33a-5p的过表达或CRNDE抑制抑制了CDK6表达和HCC肿瘤发生。总体而言，目前的工作表明CRNDE通过调节miR-33a-5p / CDK6轴在肝癌中发挥致癌作用，揭示了肝癌的潜在治疗靶点。