Dataset Information

ADAMTSL5 is an epigenetically activated oncogene conferring tumorigenic properties in hepatocellular carcinoma

ABSTRACT: The remarkable molecular heterogeneity in hepatocellular carcinoma (HCC) continues to challenge development of effective treatments and biomarkers. Here we report that the gene encoding a secreted glycoprotein, ADAMTSL5, is overexpressed and displays hypermethylated CpG islands in its gene body region in a clinically relevant mouse genetic model of HCC as well as in a significant proportion of human HCC patients. Immunohistological analysis of human HCCs revealed strong ADAMTSL5 immunostaining in tumour cells and histiocytes, in contrast to normal liver. Functional targeting of ADAMTSL5 in oncogenesis using shRNA interfered with tumorigenic properties of HCC cells both in vitro and in vivo. Furthermore, ADAMTSL5 overexpression conferred tumorigenic capability to genetically sensitized, non-transformed hepatocytes in nude mice. Mechanistically, ADAMTSL5 abrogation led to reduction of several oncogenic inputs, including the receptor tyrosine kinases MET, EGFR, PDGFRβ, IGF1Rβ, and FGFR4, suggesting it as a master regulator of HCC tumorigenicity when overexpressed.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Liver

SUBMITTER: AUDEBERT Stephane

LAB HEAD: Audebert Stephane

PROVIDER: PXD016634 | Pride | 2020-11-17

REPOSITORIES: Pride

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Publications

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

Arechederra Maria M Bazai Sehrish K SK Abdouni Ahmed A Sequera Celia C Mead Timothy J TJ Richelme Sylvie S Daian Fabrice F Audebert Stéphane S Dono Rosanna R Lozano Anthony A Gregoire Damien D Hibner Urszula U Allende Daniela S DS Apte Suneel S SS Maina Flavio F

Journal of hepatology 20201113 4

<h4>Background & aims</h4>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).<h4>Methods</h4>ADAMTSL5 methylation status was evaluated through bisulfite sequencing, and publicly available data analysis. ADAMTSL5 RNA and prote ...[more]

PMID: 33197513

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Project description:Hepatectomy generally offers the best chance of long-term survival for patients with hepatocellular carcinoma (HCC). Many studies have shown that hepatectomy accelerates tumor metastasis, but the mechanism remains unclear. In this study, palliative hepatectomy was performed in an orthotopic nude mice model of HCC (MHCC97H) with high metastatic potential. Using Human Tumor Metastasis Microarray, we screened the metastasis-related genes in tumor tissues following palliative resection, and found that Metastasis suppressor 1 (MTSS1) located in the central position of gene function net of residual HCC; MTSS1 was up-regulated in residual tumor after palliative resection. Further studies found that MTSS1 enhanced the metastasis of residual HCC. In hepatitis B-related HCC patients undergone palliative hepatectomy, those with higher MTSS1 mRNA expression accompanied by the activation of matrix metalloproteinase 2 (MMP2) in residual HCC, had earlier residual HCC detection after hepatectomy and poorer survival when compared to those with lower MTSS1 level. In different cell lines, the levels of MTSS1 mRNA increased in parallel with metastatic potential. MTSS1 down regulation via siRNA decreased MMP2 activity, reduced invasive potentials of HCC by 28.9% in vitro, and averted the deteriorated lung metastatic extent in vivo. In conclusion, the poor prognosis of hepatitis B-related HCC patients following palliative hepatectomy associates with elevated MTSS1 mRNA expression; therefore, MTSS1 may provide a new research field for HCC diagnosis and treatment. Eighteen nude mice bearing HCC xenografts were randomized into three groups 14 days after orthotopic implantation: palliative resection group (mice received partial HCC resection with preservation of 2 mm tumor pedicles), sham operation group (mice only undergone an exposure of liver but without resection), and blank control group (mice without further surgical intervention). All mice were sacrificed by cervical dislocation 14 days following palliative resection based on pre-experimental results. The first time surgically removed HCC tissues were named tumor tissues T1; the second time surgically removed HCC tissues from sham operation group were named tumor tissues T2; Tissues from blank control group were named tumor tissues T3; Tissues from palliative resection group were named tumor tissues T4 that was residual HCC. Randomly selected 5 tumor specimens from each group were used for the screen of genes related to metastasis by microarray techniques.

Dataset Information

ADAMTSL5 is an epigenetically activated oncogene conferring tumorigenic properties in hepatocellular carcinoma

Publications

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

Similar Datasets

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