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Downregulation of TMEM220 promotes tumor progression in Hepatocellular Carcinoma

Abstract

During the process of long-term carcinogenesis, cells accumulate many mutations. Deregulated genes expression causes profound changes in cell proliferation, which is one of the hallmarks of HCC. A comprehensive understanding of these changes will contribute to the molecular mechanism of HCC progression. Through clinical sample analysis, we found that TMEM220 is downregulated in tumor and lower levels of TMEM220 is associated with poor prognosis in HCC patients. Through overexpressing TMEM220 in HCC cell lines, we found that the proliferation of cancer cells was significantly slowed down and metastasis was significantly reduced. For further study of its molecular mechanism, we performed a reverse-phase protein array (RPPA). The results suggest that phenotypic changes caused by TMEM220 in HCC cells might be associated with FOXO and PI3K-Akt pathways. Mechanism studies showed that overexpression of TMEM220 could regulate β-catenin and FOXO3 transcriptional activity by altering their subcellular localization, affecting the expression of downstream gene p21 and SNAIL, and ultimately reducing the progression of HCC. Altogether, our study proposes a working model in which upregulation of TMEM220 expression alters the genes expression involved in cell proliferation, thereby inhibiting HCC progression, which suggests that TMEM220 might serve as a clinical biomarker.

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Fig. 1: TMEM220 is downregulated in human HCC and associated with poor clinical outcomes.
Fig. 2: TMEM220 overexpression suppresses HCC proliferation in vivo and in vitro.
Fig. 3: TMEM220 overexpression suppresses HCC metastasis in vivo and in vitro.
Fig. 4: Protein profiling affected by TMEM220 overexpression in HCC.
Fig. 5: TMEM22 overexpression affects β-catenin and FOXO3 subcellular localization and downstream gene expression.

Availability of data and material

The datasets generated and/or analyzed during the current study are involved in this published article (and its supplementary information files) or available on published databases (TCGA).

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Acknowledgements

We thank Professor Tie-lin Yang, Yan Guo at Xi’an Jiaotong University for helpful data analysis. This work was supported by the National Natural Science Foundation of China (Grant no. 61372151 and Grant no. 31570917).

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Contributions

Conception and design: X.Y.L. and H.Q.Z.; Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): T.L., L.G., G.B.T., B.H., J.W., L.L.H., M.Y.L., Y.X.B.; Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): T.L., G.L., J.W., B.H., J.P.W.; Technical, or material support (reporting or organizing data, constructing databases): S.S.D.

Corresponding author

Correspondence to Huqin Zhang.

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Each patient consented to the approved protocol which was confirmed by the Institute Research Ethics Committee at The First Affiliated Hospital, Xiangya Hospital, and Shanghai Tenth People’s Hospital.

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Li, T., Guan, L., Tang, G. et al. Downregulation of TMEM220 promotes tumor progression in Hepatocellular Carcinoma. Cancer Gene Ther (2021). https://doi.org/10.1038/s41417-021-00370-0

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