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

Autor: Timothy J. Mead, Urszula Hibner, Sylvie Richelme, Fabrice Daian, Damien Grégoire, Ahmed Abdouni, Anthony Lozano, María Arechederra, Sehrish K. Bazai, Rosanna Dono, Celia Sequera, Suneel S. Apte, Flavio Maina, Stéphane Audebert, Daniela S. Allende
Přispěvatelé: Aix Marseille Université (AMU), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Epigenomics
Carcinogenesis
Hepatocellular carcinoma
Receptor expression
[SDV]Life Sciences [q-bio]
Bisulfite sequencing
medicine.disease_cause
Receptor Tyrosine Kinase
Mice
0302 clinical medicine
ADAMTS Proteins
Antineoplastic Agents
Immunological
oncogene
Tumor Microenvironment
ComputingMilieux_MISCELLANEOUS
Liver Neoplasms
Sorafenib
3. Good health
Gene Expression Regulation
Neoplastic
Benzocycloheptenes
DNA methylation
Quinolines
liver cancer mouse model
030211 gastroenterology & hepatology
Epigenetics
Liver cancer
medicine.drug
Signal Transduction
Transcriptional Activation
Carcinoma
Hepatocellular
Biology
03 medical and health sciences
ADAMTSL5
medicine
Animals
Humans
drug resistance
Hepatology
Oncogene
Phenylurea Compounds
Triazoles
medicine.disease
030104 developmental biology
Drug Resistance
Neoplasm
Cancer cell
Cancer research
ADAMTS5 Protein
Zdroj: Journal of Hepatology
Journal of Hepatology, Elsevier, 2020, ⟨10.1016/j.jhep.2020.11.008⟩
Journal of Hepatology, 2021, ⟨10.1016/j.jhep.2020.11.008⟩
ISSN: 0168-8278
1600-0641
DOI: 10.1016/j.jhep.2020.11.008⟩
Popis: 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, PDGFRβ, IGF1Rβ, 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.
Databáze: OpenAIRE
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