ADAMTSL5 is an epigenetically activated gene underlying tumorigenesis and drug resistance in hepatocellular carcinoma

JOURNAL OF HEPATOLOGY

卷:74

Article

Arechederra, Maria¹  Bazai, Sehrish K.¹  Abdouni, Ahmed¹  Sequera, Celia¹  Mead, Timothy J.²  Richelme, Sylvie¹  Daian, Fabrice¹  Audebert, Stephane³  Dono, Rosanna¹  Lozano, Anthony⁴  Gregoire, Damien⁴  Hibner, Urszula⁴  Allende, Daniela S.⁵  Apte, Suneel S.²  Maina, Flavio¹ 

[1] Aix Marseille Univ, CNRS, Dev Biol Inst Marseille IBDM, UMR7288, Parc Sci Luminy, Marseille, France

[2] Cleveland Clin, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44195 USA

[3] Aix Marseille Univ, CRCM, Marseille Prote, INSERM,CNRS,Inst Paoli Calmettes, Marseille, France

[4] Univ Montpellier, CNRS, Inst Genet Mol Montpellier, Montpellier, France

[5] Cleveland Clin, Pathol Dept, Pathol & Lab Med Inst, Cleveland, OH 44195 USA

关键词: ADAMTSL5;    Liver cancer mouse model;    Hepatocellular carcinoma;    Epi-genetics;    Oncogene;    Drug resistance;    Receptor tyrosine kinase;   

DOI  :  10.1016/j.jhep.2020.11.008

来源: Elsevier

【 摘 要 】

Background & Aims: The tumour microenvironment shapes tumour growth through cellular communications that include both direct interactions and secreted factors. The aim of this study was to characterize the impact of the secreted glycoprotein ADAMTSL5, whose role in cancer has not been previously investigated, on hepatocellular carcinoma (HCC). Methods: ADAMTSL5 methylation status was evaluated through bisulfite sequencing, and publicly available data analysis. ADAMTSL5 RNA and protein expression were assessed in mouse models and HCC patient samples and compared to data from published datasets. Functional studies, including association of ADAMTSL5 depletion with responsiveness to clinically relevant drugs, were performed in cellular and in vivo models. Molecular alterations associated with ADAMTSL5 targeting were determined using proteomics, biochemistry, and reverse-transcription quantitative PCR. Results: Methylome analysis revealed hypermethylated gene body CpG islands at the ADAMTSL5 locus in both mouse and human HCC, correlating with higher ADAMTSL5 expression. ADAMTSL5 targeting interfered with tumorigenic properties of HCC cells in vitro and in vivo, whereas ADAMTSL5 overexpression conferred tumorigenicity to pre-tumoural hepatocytes sensitized to transformation by a modest level of MET receptor expression. Mechanistically, ADAMTSL5 abrogation led to a reduction of several oncogenic inputs relevant to HCC, including reduced expression and/or phosphorylation levels of receptor tyrosine kinases MET, EGFR, PDGFRb, IGF1Rb, or FGFR4. This phenotype was associated with significantly increased sensitivity of HCC cells to clinically relevant drugs, namely sorafenib, lenvatinib, and regorafenib. Moreover, ADAMTSL5 depletion drastically increased expression of AXL, accompanied by a sensitization to bemcentinib. Conclusions: Our results point to a role for ADAMTSL5 in maintaining the function of key oncogenic signalling pathways, suggesting that it may act as a master regulator of tumorigenicity and drug resistance in HCC. Lay summary: The environment of cancer cells has profound effects on establishment, progression, and response of a tumour to treatment. Herein, we show that ADAMTSL5, a protein secreted by liver cancer cells and overlooked in cancer so far, is increased in this tumour type, is necessary for tumour formation and supports drug resistance. Adamtsl5 removal conferred sensitivity of liver cancer cells to drugs used in current treatment. This suggests ADAMTSL5 as a potential marker in liver cancer as well as a possible drug target. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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