ADAMTSL5 is an epigenetically activated gene underlying tumorigenesis and drug resistance in hepatocellular carcinoma
ADAMTSL5 is an epigenetically activated gene underlying tumorigenesis and drug resistance in hepatocellular carcinoma
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DOI：
10.1016/j.jhep.2020.11.008
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发表时间：
2021-03-15
影响因子：
25.7
通讯作者：
Maina, Flavio
中科院分区：
文献类型：
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作者：
Arechederra, Maria;Bazai, Sehrish K.;Maina, Flavio
背景和目的：肿瘤微环境通过细胞通讯（包括直接相互作用和分泌因子）塑造肿瘤生长。本研究的目的是表征分泌型糖蛋白 ADAMTSL5 对肝细胞癌 (HCC) 的影响（之前尚未研究过其在癌症中的作用）。方法：通过亚硫酸氢盐测序和公开数据分析评估 ADAMTSL5 甲基化状态。在小鼠模型和 HCC 患者样本中评估了 ADAMTSL5 RNA 和蛋白质表达，并与已发布数据集中的数据进行比较。在细胞和体内模型中进行了功能研究，包括 ADAMTSL5 耗竭与对临床相关药物的反应之间的关联。使用蛋白质组学、生物化学和逆转录定量 PCR 来确定与 ADAMTSL5 靶向相关的分子改变。结果：甲基化组分析显示，在小鼠和人类 HCC 中，ADAMTSL5 基因座处的基因体 CpG 岛高度甲基化，与较高的 ADAMTSL5 表达相关。 ADAMTSL5 靶向干扰体外和体内 HCC 细胞的致瘤特性，而 ADAMTSL5 过表达则通过适度水平的 MET 受体表达赋予对转化敏感的肿瘤前肝细胞致瘤性。从机制上讲，ADAMTSL5 的废除导致与 HCC 相关的几种致癌输入减少，包括受体酪氨酸激酶 MET、EGFR、PDGFRb、IGF1Rb 或 FGFR4 的表达和/或磷酸化水平降低。这种表型与 HCC 细胞对临床相关药物（即索拉非尼、仑伐替尼和瑞戈非尼）的敏感性显着增加相关。此外，ADAMTSL5 的缺失显着增加了 AXL 的表达，并伴有对 bemcentinib 的敏感性。结论：我们的结果表明 ADAMTSL5 在维持关键致癌信号通路的功能中发挥作用，表明它可能作为 HCC 致瘤性和耐药性的主要调节因子。总结：癌细胞的环境对肿瘤的形成、进展和治疗反应具有深远的影响。在此，我们发现ADAMTSL5（一种由肝癌细胞分泌、迄今为止在癌症中被忽视的蛋白质）在这种肿瘤类型中增加，是肿瘤形成所必需的并支持耐药性。 Adamtsl5 的去除赋予肝癌细胞对当前治疗中使用的药物的敏感性。这表明 ADAMTSL5 是肝癌的潜在标志物以及可能的药物靶点。 (C) 2020 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
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.