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LINC01348 suppresses hepatocellular carcinoma metastasis through inhibition of SF3B3-mediated EZH2 pre-mRNA splicing

Oncogene volume 40, pages 4675–4685 (2021)Cite this article

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Abstract

Long non-coding RNAs (lncRNA) play crucial roles in hepatocellular carcinoma (HCC) progression. However, the specific functions of lncRNAs in alternative splicing (AS) and the metastatic cascade in liver cancer remain largely unclear. In this study, we identified a novel lncRNA, LINC01348, which was significantly downregulated in HCC and correlated with survival functions in HCC patients. Ectopic expression of LINC01348 induced marked inhibition of cell growth, and metastasis in vitro and in vivo. Conversely, these phenotypes were reversed upon knockdown of LINC01348. Mechanistically, LINC01348 complexed with splicing factor 3b subunit 3 (SF3B3) acted as a modulator of EZH2 pre-mRNA AS, and induced alterations in JNK/c-Jun activity and expression of Snail. Notably, C-terminal truncated HBx (Ct-HBx) negatively regulated LINC01348 through c-Jun signaling. Our data collectively highlight those novel regulatory associations involving LINC01348/SF3B3/EZH2/JNK/c-Jun/Snail are an important determinant of metastasis in HCC cells and support the potential utility of targeting LINC01348 as a therapeutic strategy for HCC.

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Fig. 1: LINC01348 is positively correlated with a good prognosis in HCC.
Fig. 2: LINC01348 is a tumor suppressor lncRNA in liver cancer.
Fig. 3: LINC01348 is associated with SF3B3 protein.
Fig. 4: The LINC01348/SF3B3 axis regulates EZH2 pre-mRNA alternative splicing.
Fig. 5: The LINC01348/SF3B3 axis regulates Snail and c-Jun pathways.
Fig. 6: LINC01348 is negatively regulated by Ct-HBx in vitro and in vivo.

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Acknowledgements

We would like to thank Taiwan Liver Cancer Network (TLCN) for providing the hepatoma tissue samples and related clinical data (all are anonymous) for our research work.

Funding

This work was supported by grants from Chang Gung Memorial Hospital, Taoyuan, Taiwan (CMRPD1H0631-0633, CMRPD1K0291, NMRPD1G0941-0943, and NMRPD1G0951-0953 to K-HL; CMRPG3H0721-0723, NZRPG3G0171-0173, NMRPG3H0561, NRRPG3J0141 to Y-HL) and from the Ministry of Science and Technology of the Republic of China (MOST 106-2320-B-182-031-MY3; 106-2320-B-182-032-MY3; and 109-2320-B-182-011 to K-HL; MOST 106-2321-B-182A-004-MY3, MOST 107-2320-B-182A-028-, MOST 108-2320-B-182A-004- to Y-HL).

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Authors and Affiliations

  1. Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

    Yang-Hsiang Lin, Chau-Ting Yeh & Kwang-Huei Lin

  2. Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Yang-Hsiang Lin, Meng-Han Wu & Kwang-Huei Lin

  3. Institute of Population Sciences, National Health Research Institutes, Zhunan, Taiwan

    Yi-Chung Liu

  4. Institute of Bioinformatics and Structural Biology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan

    Ping-Chiang Lyu

  5. Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan

    Kwang-Huei Lin

  6. Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Kwang-Huei Lin

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Contributions

Conception and design: Y-HL and M-HW. Data acquisition: Y-HL, M-HW, Y-CL, and P-CL. Data analyses and interpretation of data: Y-HL, M-HW, Y-CL, P-CL, C-TY, and K-HL. Drafting of the manuscript: Y-HL and M-HW. Revising critically the manuscript: C-TY and K-HL. Approval of final manuscript: Y-HL, M-HW, C-TY, and K-HL.

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Correspondence to Chau-Ting Yeh or Kwang-Huei Lin.

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Lin, YH., Wu, MH., Liu, YC. et al. LINC01348 suppresses hepatocellular carcinoma metastasis through inhibition of SF3B3-mediated EZH2 pre-mRNA splicing. Oncogene 40, 4675–4685 (2021). https://doi.org/10.1038/s41388-021-01905-3

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