miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis.
miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis.
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DOI：
10.1136/gutjnl-2016-312270
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发表时间：
2018-05
期刊：
影响因子：
24.5
通讯作者：
Lupberger J
中科院分区：
文献类型：
--
作者：
Van Renne N;Roca Suarez AA;Duong FHT;Gondeau C;Calabrese D;Fontaine N;Ababsa A;Bandiera S;Croonenborghs T;Pochet N;De Blasi V;Pessaux P;Piardi T;Sommacale D;Ono A;Chayama K;Fujita M;Nakagawa H;Hoshida Y;Zeisel MB;Heim MH;Baumert TF;Lupberger J
HCV感染是肝细胞癌（HCC）的主要危险因素。然而，即使在病毒清除后，HCC风险仍然升高。HCV干扰宿主细胞信号传导以维持感染，而脱轨的信号传导电路是致癌的关键驱动因素。由于蛋白磷酸酶是信号事件的调节剂，我们的目的是确定磷酸酶，响应丙型肝炎病毒感染与肝癌的发生。我们评估了原代人肝细胞、肝活检和HCC患者切除中的mRNA和microRNA（miRNA）表达谱，并分析了HCC患者配对肝活检的微阵列和RNA-seq数据。我们通过基因集富集分析揭示了转录网络的变化，并将磷酸酶表达水平与患者生存和肿瘤复发相关。我们证明，肿瘤抑制蛋白酪氨酸磷酸酶受体δ（PTPRD）是受损的HCV感染在体内和肝细胞癌病变的配对肝活检组织炎症或纤维化的独立。在邻近肿瘤的肝组织中，高PTPRD水平与STAT 3的转录活性减弱、HCC患者存活率增加和手术切除后肿瘤复发减少相关。我们鉴定了miR-135 a-5 p作为HCV患者肝脏PTPRD表达的机制调节剂。我们以前证明STAT 3是HCV感染所必需的。我们的结论是，HCV通过上调miR-135 a-5 p抑制其调节因子PTPRD来促进患者肝脏中的STAT 3转录程序。我们的研究结果表明，存在一个扰动的PTPRD-STAT 3轴可能驱动HCV相关肝病的恶性进展。
HCV infection is a leading risk factor of hepatocellular carcinoma (HCC). However, even after viral clearance, HCC risk remains elevated. HCV perturbs host cell signalling to maintain infection, and derailed signalling circuitry is a key driver of carcinogenesis. Since protein phosphatases are regulators of signalling events, we aimed to identify phosphatases that respond to HCV infection with relevance for hepatocarcinogenesis. We assessed mRNA and microRNA (miRNA) expression profiles in primary human hepatocytes, liver biopsies and resections of patients with HCC, and analysed microarray and RNA-seq data from paired liver biopsies of patients with HCC. We revealed changes in transcriptional networks through gene set enrichment analysis and correlated phosphatase expression levels to patient survival and tumour recurrence. We demonstrate that tumour suppressor protein tyrosine phosphatase receptor delta (PTPRD) is impaired by HCV infection in vivo and in HCC lesions of paired liver biopsies independent from tissue inflammation or fibrosis. In liver tissue adjacent to tumour, high PTPRD levels are associated with a dampened transcriptional activity of STAT3, an increase of patient survival from HCC and reduced tumour recurrence after surgical resection. We identified miR-135a-5p as a mechanistic regulator of hepatic PTPRD expression in patients with HCV. We previously demonstrated that STAT3 is required for HCV infection. We conclude that HCV promotes a STAT3 transcriptional programme in the liver of patients by suppressing its regulator PTPRD via upregulation of miR-135a-5p. Our results show the existence of a perturbed PTPRD–STAT3 axis potentially driving malignant progression of HCV-associated liver disease.
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影响因子：
64.8
作者：
Karin M;Clevers H
通讯作者：
Clevers H
影响因子：
8
作者：
McGivern, D. R.;Lemon, S. M.
通讯作者：
Lemon, S. M.
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作者：
Lu TP;Lee CY;Tsai MH;Chiu YC;Hsiao CK;Lai LC;Chuang EY
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Chuang EY
影响因子：
15.8
作者：
Chan, Timothy A.;Glockner, Sabine;Yi, Joo Mi;Chen, Wei;Van Neste, Leander;Cope, Leslie;Herman, James G.;Velculescu, Victor;Schuebel, Kornel E.;Ahuja, Nita;Baylin, Stephen B.
通讯作者：
Baylin, Stephen B.
影响因子：
13.5
作者：
Fuchs, Bryan C.;Hoshida, Yujin;Fujii, Tsutomu;Wei, Lan;Yamada, Suguru;Lauwers, Gregory Y.;McGinn, Christopher M.;DePeralta, Danielle K.;Chen, Xintong;Kuroda, Toshihiko;Lanuti, Michael;Schmitt, Anthony D.;Gupta, Supriya;Crenshaw, Andrew;Onofrio, Robert;Taylor, Bradley;Winckler, Wendy;Bardeesy, Nabeel;Caravan, Peter;Golub, Todd R.;Tanabe, Kenneth K.
通讯作者：
Tanabe, Kenneth K.