復旦大學附屬中山醫(yī)院肝癌研究所樊嘉教授領銜的課題組在肝癌細胞,、腫瘤微環(huán)境和肝癌轉移與復發(fā)領域又取得新進展,，課題組發(fā)現人體內一種微小蛋白質——四跨膜蛋白CD151是肝癌侵襲轉移的關鍵因素，四跨膜蛋白CD151與整合素α6β1高表達的肝癌細胞亞群在與腫瘤微環(huán)境的相互作用過程中可獲得高侵襲和轉移的能力,，這將為肝癌抗復發(fā)和轉移治療提供新的思路和靶點,。美國胃腸病學會會刊——著名的《胃腸病學》雜志 Gastroenterology于2月11日在線刊登了該成果。
肝癌是影響人類健康最常見的惡性腫瘤之一,，手術切除仍是目前首選的治療方式,，但術后的高復發(fā)和轉移率明顯影響患者的長期生存，因此，探索肝癌侵襲和轉移分子機制對于改善肝癌患者的生存具有重要意義,。
近來,，腫瘤微環(huán)境即“土壤”在腫瘤的復發(fā)和轉移中的作用受到腫瘤學家們高度關注。復旦大學附屬中山醫(yī)院肝外科主任,、肝癌研究所常務副所長樊嘉教授領銜的課題組,，多年前就開始“腫瘤細胞、腫瘤微環(huán)境與肝癌轉移復發(fā)”的研究,，發(fā)現四跨膜蛋白CD151是肝癌侵襲轉移的關鍵因素,。
據樊嘉教授介紹，CD151是四跨膜蛋白超家族重要成員之一,，當前已證實其在肝癌侵襲與轉移中扮演重要角色,，CD151的過度表達可促進肝癌侵襲與轉移。課題組多年潛心攻關,，發(fā)現CD151和肝細胞生長因子受體（c-Met）過度表達的患者,，其預后明顯差于僅c-Met過度表達的患者，解釋了c-Met不能作為評價肝癌預后的獨立預測指標的原因,，提出了CD151作為判斷肝癌患者預后及抗復發(fā),、轉移治療靶點的優(yōu)勢。此成果于2009年刊發(fā)在《肝臟病》（Hepatology）上,，并被《肝臟病》（Hepatology）,、《生物化學》（Journal of Biological Chemistry）等多個國際著名雜志引用。課題組進一步研究發(fā)現,，CD151過度表達可促進金屬基質蛋白酶9（MMP9）的分泌和表達,，參與肝癌新生血管形成、侵襲和轉移,；首次闡述了CD151過度表達在肝癌新生血管形成中的作用,，揭示了血管形成和肝癌轉移的新機制，此成果于2010年發(fā)表在《肝臟病》（Hepatology）上,。
該系列研究在“國家科技重大專項”,、國家“十一五”支撐計劃及國家自然科學基金等資助下，充分利用中山醫(yī)院肝癌研究所雄厚的基礎研究平臺,、豐富而規(guī)范的臨床資源,，取得豐碩成果，研究觀點連續(xù)刊登在消化系統(tǒng)最權威的學術期刊《胃腸病學》（影響因子12.9）和《肝臟病》（影響因子10.8）雜志上,。不僅闡述了“種子”——肝癌細胞在腫瘤的發(fā)生和進展中的地位,，還揭示了“種子”與“土壤”——腫瘤微環(huán)境如肝細胞生長因子、腫瘤血管及腫瘤基質間有著“千絲萬縷”的聯系,，并在肝癌侵襲和轉移中共同起著重要作用,，這將推動肝癌轉移防治策略的調整，并為肝癌的治療提供潛在的靶標。（生物谷Bioon.com）
生物谷推薦原文出處：
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
