Oncostatin M is overexpressed in NASH-related hepatocellular carcinoma and promotes cancer cell invasiveness and angiogenesis.
Oncostatin M is overexpressed in NASH-related hepatocellular carcinoma and promotes cancer cell invasiveness and angiogenesis.
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DOI：
10.1002/path.5871
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发表时间：
2022-05
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影响因子：
--
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抑瘤素M（OSM）是白细胞介素（IL）-6家族的一种多效性细胞因子，有助于慢性肝病的进展。在这里，我们研究了OSM在非酒精性脂肪性肝病（NAFLD）/非酒精性脂肪性肝炎（NASH）中肝细胞癌（HCC）发生和进展中的作用。在（1）选定的NAFLD/NASH HCC患者队列、（2）暴露于人重组OSM或稳定转染以过表达人OSM的肝癌细胞、（3）鼠HCC异种移植物和（4）鼠NASH相关肝癌发生模型中研究了OSM的作用。OSM被发现在NAFLD/NASH患者的HCC细胞中选择性过表达，这取决于肿瘤分级。OSM血清水平在单纯性脂肪变性或NASH患者中几乎检测不到，在肝硬化患者中升高，在携带HCC的患者中更明显。在后一组中，OSM血清水平在中/晚期HCC受试者中显著更高，并且与较差的生存率相关。细胞培养实验表明，肝癌细胞中的OSM上调通过诱导上皮向间质转化和癌细胞侵袭性增加以及诱导血管生成（这是至关重要的）而促进HCC进展。在小鼠异种移植物中，OSM过表达与肿瘤生长较慢但肺转移率增加相关。在NAFLD/NASH相关肝癌发生的小鼠模型中也证实了OSM的过表达及其与血管生成开关的正相关性。与此一致，对来自具有血管侵袭的人NASH相关HCC的肝脏标本的分析表明，OSM由侵袭肝血管的肝癌细胞表达。总之，OSM上调似乎是在NAFLD/NASH背景下产生的HCC的特异性特征，并且其与临床参数和疾病结果相关。我们的数据强调了OSM在NAFLD/NASH中的新的促癌作用，表明该因子作为预后标志物和公认的潜在治疗靶点的作用。版权所有© 2022作者。病理学杂志由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
Oncostatin M (OSM) is a pleiotropic cytokine of the interleukin (IL)‐6 family that contributes to the progression of chronic liver disease. Here we investigated the role of OSM in the development and progression of hepatocellular carcinoma (HCC) in non‐alcoholic fatty liver disease (NAFLD)/non‐alcoholic steatohepatitis (NASH). The role of OSM was investigated in (1) selected cohorts of NAFLD/NASH HCC patients, (2) liver cancer cells exposed to human recombinant OSM or stably transfected to overexpress human OSM, (3) murine HCC xenografts, and (4) a murine NASH‐related model of hepatic carcinogenesis. OSM was found to be selectively overexpressed in HCC cells of NAFLD/NASH patients, depending on tumor grade. OSM serum levels, barely detectable in patients with simple steatosis or NASH, were increased in patients with cirrhosis and more evident in those carrying HCC. In this latter group, OSM serum levels were significantly higher in the subjects with intermediate/advanced HCCs and correlated with poor survival. Cell culture experiments indicated that OSM upregulation in hepatic cancer cells contributes to HCC progression by inducing epithelial‐to‐mesenchymal transition and increased invasiveness of cancer cells as well as by inducing angiogenesis, which is of critical relevance. In murine xenografts, OSM overexpression was associated with slower tumor growth but an increased rate of lung metastases. Overexpression of OSM and its positive correlation with the angiogenic switch were also confirmed in a murine model of NAFLD/NASH‐related hepatocarcinogenesis. Consistent with this, analysis of liver specimens from human NASH‐related HCCs with vascular invasion showed that OSM was expressed by liver cancer cells invading hepatic vessels. In conclusion, OSM upregulation appears to be a specific feature of HCC arising on a NAFLD/NASH background, and it correlates with clinical parameters and disease outcome. Our data highlight a novel pro‐carcinogenic contribution for OSM in NAFLD/NASH, suggesting a role of this factor as a prognostic marker and a putative potential target for therapy. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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影响因子：
11.2
作者：
Hoshida Y;Nijman SM;Kobayashi M;Chan JA;Brunet JP;Chiang DY;Villanueva A;Newell P;Ikeda K;Hashimoto M;Watanabe G;Gabriel S;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR
DOI：
10.3233/cbm-2012-00276
发表时间：
2012
期刊：
Cancer biomarkers : section A of Disease markers
影响因子：
--
作者：
Liang H;Block TM;Wang M;Nefsky B;Long R;Hafner J;Mehta AS;Marrero J;Gish R;Norton PA
通讯作者：
Norton PA
影响因子：
13.5
作者：
Morello, Elisabetta;Sutti, Salvatore;Parola, Maurizio
通讯作者：
Parola, Maurizio
影响因子：
3.8
作者：
Jorcyk, Cheryl L.;Holzer, Ryan G.;Ryan, Randall E.
通讯作者：
Ryan, Randall E.
影响因子：
9.8
作者：
Nowak-Sliwinska P;Alitalo K;Allen E;Anisimov A;Aplin AC;Auerbach R;Augustin HG;Bates DO;van Beijnum JR;Bender RHF;Bergers G;Bikfalvi A;Bischoff J;Böck BC;Brooks PC;Bussolino F;Cakir B;Carmeliet P;Castranova D;Cimpean AM;Cleaver O;Coukos G;Davis GE;De Palma M;Dimberg A;Dings RPM;Djonov V;Dudley AC;Dufton NP;Fendt SM;Ferrara N;Fruttiger M;Fukumura D;Ghesquière B;Gong Y;Griffin RJ;Harris AL;Hughes CCW;Hultgren NW;Iruela-Arispe ML;Irving M;Jain RK;Kalluri R;Kalucka J;Kerbel RS;Kitajewski J;Klaassen I;Kleinmann HK;Koolwijk P;Kuczynski E;Kwak BR;Marien K;Melero-Martin JM;Munn LL;Nicosia RF;Noel A;Nurro J;Olsson AK;Petrova TV;Pietras K;Pili R;Pollard JW;Post MJ;Quax PHA;Rabinovich GA;Raica M;Randi AM;Ribatti D;Ruegg C;Schlingemann RO;Schulte-Merker S;Smith LEH;Song JW;Stacker SA;Stalin J;Stratman AN;Van de Velde M;van Hinsbergh VWM;Vermeulen PB;Waltenberger J;Weinstein BM;Xin H;Yetkin-Arik B;Yla-Herttuala S;Yoder MC;Griffioen AW
通讯作者：
Griffioen AW