HAb18G/CD147 promotes pSTAT3-mediated pancreatic cancer development via CD44s.
HAb18G/CD147 promotes pSTAT3-mediated pancreatic cancer development via CD44s.
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DOI：
10.1158/1078-0432.ccr-13-0621
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发表时间：
2013-12-15
期刊：
影响因子：
--
通讯作者：
Xu L
中科院分区：
文献类型：
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作者：
Li L;Tang W;Wu X;Karnak D;Meng X;Thompson R;Hao X;Li Y;Qiao XT;Lin J;Fuchs J;Simeone DM;Chen ZN;Lawrence TS;Xu L
STAT 3在胰腺癌的发生和发展中起着关键作用。然而，针对STAT 3的治疗在临床上是失败的。我们先前鉴定HAb 18 G/CD 147为癌症治疗的有效靶标。本研究旨在探讨HAb 18 G/CD 147在STAT 3介导的胰腺肿瘤发生中的作用。组织芯片检测HAb 18 G/CD 147、pSTAT 3和CD 44 s的表达。通过体外细胞和克隆生长、报告基因分析、免疫印迹、免疫荧光染色、免疫沉淀和体内肿瘤形成的功能丧失或获得策略，评估HAb 18 G/CD 147的致瘤功能和分子信号传导机制。高表达HAb 18 G/CD 147促进体外细胞生长和克隆形成以及体内致瘤性。CyPA是CD 147的配体，通过HAb 18 G/CD 147依赖性机制刺激STAT 3磷酸化及其下游基因cyclin D1/survivin。HAb 18 G/CD 147与肿瘤干细胞标志物CD 44在脂筏中相关并共定位。STAT 3和Survivin的抑制剂以及CD 44 s中和抗体抑制HAb 18 G/CD 147诱导的细胞生长。胰腺癌组织中HAb 18 G/CD 147高表达与肿瘤分化程度相关，HAb 18 G/CD 147-CD 44 s-STAT 3高表达与胰腺癌患者生存率相关。我们发现HAb 18 G/CD 147是一种新型的STAT 3上游激活因子，通过与CD 44相互作用，在胰腺癌的发生发展中起着关键作用。这些数据表明HAb 18 G/CD 147可能是高度侵袭性胰腺癌的一个有希望的治疗靶点，也可能是STAT 3靶向分子治疗的替代标志物。
STAT3 plays a critical role in initiation and progression of pancreatic cancer. However, therapeutically targeting STAT3 is failure in clinic. We previously identified HAb18G/CD147 as an effective target for cancer treatment. In this study, we aimed to investigate potential role of HAb18G/CD147 in STAT3-involved pancreatic tumorigenesis in vitro and in vivo. The expression of HAb18G/CD147, pSTAT3 and CD44s were determined in tissue microarrays. The tumorigenic function and molecular signaling mechanism of HAb18G/CD147 was assessed by in vitro cellular and clonogenic growth, reporter assay, immunoblot, immunofluorescence staining, immunoprecipitation, and in vivo tumor formationusing loss or gain-of-function strategies. Highly expressed HAb18G/CD147 promoted cellular and clonogenic growth in vitro and tumorigenicity in vivo. CyPA, a ligand of CD147, stimulated STAT3 phosphorylation and its downstream genes cyclin D1/survivin through HAb18G/CD147 dependent mechanisms. HAb18G/CD147 was associated and co-localized with cancer stem cell marker CD44s in lipid rafts. The inhibitors of STAT3 and survivin, as well as CD44s neutralizing antibodies suppressed the HAb18G/CD147-induced cell growth. High HAb18G/CD147 expression in pancreatic cancer was significantly correlated with the poor tumor differentiation, and the high co-expression of HAb18G/CD147-CD44s-STAT3 associated with poor survival of patients with pancreatic cancer. We identified HAb18G/CD147 as a novel upstream activator of STAT3 via interacts with CD44s and plays a critical role in the development of pancreatic cancer. The data suggest HAb18G/CD147 could be a promising therapeutic target for highly aggressive pancreatic cancer and a surrogate marker in the STAT3-targeted molecular therapies.