复旦大学附属中山医院肝癌研究所樊嘉教授领衔的课题组在肝癌细胞、肿瘤微环境和肝癌转移与复发领域又取得新进展，课题组发现人体内一种微小蛋白质——四跨膜蛋白CD151是肝癌侵袭转移的关键因素，四跨膜蛋白CD151与整合素α6β1高表达的肝癌细胞亚群在与肿瘤微环境的相互作用过程中可获得高侵袭和转移的能力，这将为肝癌抗复发和转移治疗提供新的思路和靶点。美国胃肠病学会会刊——著名的《胃肠病学》杂志 Gastroenterology于2月11日在线刊登了该成果。
肝癌是影响人类健康最常见的恶性肿瘤之一，手术切除仍是目前首选的治疗方式，但术后的高复发和转移率明显影响患者的长期生存，因此，探索肝癌侵袭和转移分子机制对于改善肝癌患者的生存具有重要意义。
近来，肿瘤微环境即“土壤”在肿瘤的复发和转移中的作用受到肿瘤学家们高度关注。复旦大学附属中山医院肝外科主任、肝癌研究所常务副所长樊嘉教授领衔的课题组，多年前就开始“肿瘤细胞、肿瘤微环境与肝癌转移复发”的研究，发现四跨膜蛋白CD151是肝癌侵袭转移的关键因素。
据樊嘉教授介绍，CD151是四跨膜蛋白超家族重要成员之一，当前已证实其在肝癌侵袭与转移中扮演重要角色，CD151的过度表达可促进肝癌侵袭与转移。课题组多年潜心攻关，发现CD151和肝细胞生长因子受体（c-Met）过度表达的患者，其预后明显差于仅c-Met过度表达的患者，解释了c-Met不能作为评价肝癌预后的独立预测指标的原因，提出了CD151作为判断肝癌患者预后及抗复发、转移治疗靶点的优势。此成果于2009年刊发在《肝脏病》（Hepatology）上，并被《肝脏病》（Hepatology）、《生物化学》（Journal of Biological Chemistry）等多个国际著名杂志引用。课题组进一步研究发现，CD151过度表达可促进金属基质蛋白酶9（MMP9）的分泌和表达，参与肝癌新生血管形成、侵袭和转移；首次阐述了CD151过度表达在肝癌新生血管形成中的作用，揭示了血管形成和肝癌转移的新机制，此成果于2010年发表在《肝脏病》（Hepatology）上。
该系列研究在“国家科技重大专项”、国家“十一五”支撑计划及国家自然科学基金等资助下，充分利用中山医院肝癌研究所雄厚的基础研究平台、丰富而规范的临床资源，取得丰硕成果，研究观点连续刊登在消化系统最权威的学术期刊《胃肠病学》（影响因子12.9）和《肝脏病》（影响因子10.8）杂志上。不仅阐述了“种子”——肝癌细胞在肿瘤的发生和进展中的地位，还揭示了“种子”与“土壤”——肿瘤微环境如肝细胞生长因子、肿瘤血管及肿瘤基质间有着“千丝万缕”的联系，并在肝癌侵袭和转移中共同起着重要作用，这将推动肝癌转移防治策略的调整，并为肝癌的治疗提供潜在的靶标。（生物谷Bioon.com）
生物谷推荐原文出处：
Gastroenterology doi:10.1053/j.gastro.2011.02.008
CD151 Amplifies Signaling by Integrin α6β1 to PI3K and Induces the Epithelial–Mesenchymal Transition in HCC Cells
Ai-Wu Ke1, 2, Guo-Ming Shi1, Jian Zhou1, 2, Xiao-Yong Huang1, Ying-Hong Shi1, Zhen-Bin Ding1, Xiao-Ying Wang1, Ranjan Prasad Devbhandari1 and Jia Fan1, 2,
Abstract
Background & Aims
Overexpression of CD151 is associated with poor prognosis for hepatocellular carcinoma (HCC), yet its role in pathogenesis is not known.
Methods
We analyzed the expression of the integrin subunit α6 by quantitative, real-time PCR and immunoblot analyses of 120 HCC tissue samples; its clinical significance was investigated using tissue microarray (TMAs) analysis of samples from 335 patients with HCC. Immunoprecipitation was used to assess the relationship between α6 and CD151. The molecular effects of high expression levels of α6 and CD151 in HCC cells were determined using RNA interference and pharmacological approaches.
Results
Overexpression of α6 correlated with poor prognosis of patients with HCC; α6 formed a complex with endogenous CD151 in HCC cells. In cells that expressed high levels of α6 and CD151, laminin-5 (Ln-5) promoted cell spreading by inducing the epithelial–mesenchymal transition (EMT); this effect was not observed in cells that expressed high levels of only α6 or CD151. Cells that expressed high levels of α6 and CD151 underwent the EMT in response to Ln-5, through hyperactivation of phosphatidylinositol-3-kinase (PI3K), primarily induced via the PI3K–Akt–Snail–PTEN feedback pathway. The EMT was reversed by PI3K inhibitors and antibodies against CD151 or α6 in vitro, and was delayed by specific interference with CD151 and α6 in vivo.
Conclusion
High expression levels of CD151 and α6 promote invasiveness of HCC cells. Either of these proteins, or PI3K signaling, might be targets for therapeutics for subgroups of patients with HCC.
Keywords: liver cancer, tumor progression, metastasis, tumor invasion
