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Long non-coding RNA CRNDE promotes malignant progression of hepatocellular carcinoma through the miR-33a-5p/CDK6 axis

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Abstract

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.

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Acknowledgments

The authors would like to thank the Biobank of China-Japan Union Hospital of Jilin University for providing human HCC tissues and paired adjacent normal specimens.

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Authors and Affiliations

  1. Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, Jilin, China

    Chao Lin

  2. Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, Jilin, China

    Chao Lin, Yien Xiang, Jiyao Sheng, Shui Liu, Mengying Cui & Xuewen Zhang

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Contributions

This study was conceptualized by CL and XWZ. CL and YEX performed the experiment. CL, JYS, and SL analyzed and interpreted the results. CL and MYC drafted the manuscript. XWZ revised the manuscript. All of the authors read and approved the final manuscript.

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Correspondence to Xuewen Zhang.

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Key points

- CRNDE was involved in the regulation of apoptosis, invasion, and migration of HCC.

- The effect of CRNDE on HCC was associated with the miR-33a-5p/CDK6 axis.

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Lin, C., Xiang, Y., Sheng, J. et al. Long non-coding RNA CRNDE promotes malignant progression of hepatocellular carcinoma through the miR-33a-5p/CDK6 axis. J Physiol Biochem 76, 469–481 (2020). https://doi.org/10.1007/s13105-020-00754-0

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