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LncRNA XXYLT1-AS2 promotes tumor progression via autophagy inhibition through ubiquitinated degradation of TFEB in hepatocellular carcinoma

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Abstract

Purpose

There is compelling evidence that long-stranded non-coding RNAs (lncRNAs) play an important role in the progression of hepatocellular carcinoma (HCC). The aim of this study was to investigate the role of lncRNA XXYLT1 antisense-2 (XXYLT1-AS2) in HCC progression.

Methods

Real-time PCR was used to assess the levels of XXYLT1-AS2 in plasma from HCC and normal patients. Cell proliferation, apoptosis, migration, and invasion were monitored, and tumor xenografts were established to investigate the biological functions of XXYLT1-AS2 by gain-of-function and loss-of-function studies in vitro and in vivo, the expression of autophagy biomarkers and transcriptional factor EB (TFEB) was examined by immunoprecipitation, ubiquitination assays, and western blotting. Autophagy inhibitor, 3-methyladenine (3MA), and proteasome inhibitor, MG132, were used to verify the role of autophagy in HCC progression and the effect of XXYLT1-AS2 on TFEB ubiquitination, respectively.

Results

In this study, we identified that lncRNA XXYLT1-AS2 is highly expressed in HCC plasma and promotes tumor growth in vivo. In functional studies, it was found that silent expression of XXYLT1-AS2 inhibited HCC proliferation, migration, invasion, and activated autophagy of HCC cells, which were attenuated by autophagy inhibitor, 3MA. Mechanistically, XXYLT1-AS2 decreased the protein level of TFEB through promoting its degradation by ubiquitin proteasome pathway.

Conclusion

XXYLT1-AS2 plays an oncogenic role in HCC progression through inhibition of autophagy via promoting the degradation of TFEB, and thus could be a novel target for HCC treatment.

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Funding

The present study was supported by the Hubei Provincial Natural Science Foundation (2020CFB235), the Research Program for Hepatobiliary and Pancreatic Malignancy of Chen-Xiaoping Foundation (CXPJJH12000001-2020340).

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Authors and Affiliations

  1. Department of Laboratory Medicine, Jinzhou Medical University Graduate Training Base, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, People’s Republic of China

    Xuejie Li, Shirong Yan & Pei Hu

  2. Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, People’s Republic of China

    Xuejie Li

  3. Biomedical Engineering College, Hubei University of Medicine, Shiyan, 442000, Hubei, People’s Republic of China

    Xuejie Li, Pingfeng Wang, Jiangxue Gu & Yuan Zhang

  4. Central Operating Room, Taihe Hospital, Shiyan, 442000, Hubei, People’s Republic of China

    Yuqin Wu

  5. Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan City, 442000, Hubei, People’s Republic of China

    Pingfeng Wang & Pei Hu

  6. Blood Transfusion Department, Taihe Hospital, Shiyan, 442000, Hubei, People’s Republic of China

    Ying Li

  7. Hubei Key Laboratory of Wudang Local Chinese Medicine Research, School of Pharmaceutical Sciences, Hubei University of Medicine, No. 30, South Renmin Road, Shiyan City, 442000, Hubei, People’s Republic of China

    Shirong Yan

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  1. Xuejie Li
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  6. Yuan Zhang
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Corresponding authors

Correspondence to Shirong Yan or Pei Hu.

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The authors declare no conflict of interest.

Ethical approval

The study was approved by Ethical Committee of The Hubei University of Medicine and conducted in accordance with the ethical standards. The animal experiment abided by Laboratory Animal Management Regulations.

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Written informed consent was obtained from all the participants.

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Li, X., Wu, Y., Wang, P. et al. LncRNA XXYLT1-AS2 promotes tumor progression via autophagy inhibition through ubiquitinated degradation of TFEB in hepatocellular carcinoma. Clin Transl Oncol 26, 698–708 (2024). https://doi.org/10.1007/s12094-023-03294-3

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  • DOI: https://doi.org/10.1007/s12094-023-03294-3

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