生物谷導讀：來自SIBS神經(jīng)所王以政博士研究組發(fā)現(xiàn)TRPC6在膠質(zhì)瘤細胞增殖與細胞中的重要作用。該發(fā)現(xiàn)為治療膠質(zhì)瘤提供了新思路,。
中科院上海生科院神經(jīng)科學研究所神經(jīng)信號轉(zhuǎn)導研究組的丁夏,、賀焯皓和周克純等研究生在王以政研究員的指導下發(fā)現(xiàn)瞬時受體電勢通道TRPC6在膠質(zhì)瘤細胞增殖與細胞周期中的重要作用,。6月16日《美國國家癌癥研究所雜志》（Journal of the National Cancer Institute）（IF=14.933 MedSci指數(shù)=6.48 MedSci指數(shù)查詢）在線發(fā)表該工作。文章闡述了一類非選擇性的陽離子通道作為治療膠質(zhì)瘤的靶分子的可能性,。
膠質(zhì)細胞瘤（簡稱膠質(zhì)瘤）是發(fā)生于中樞神經(jīng)系統(tǒng)常見的腫瘤,，有較高致死率，惡性膠質(zhì)瘤（多型性膠質(zhì)母細胞瘤）病人的平均生存期為12個月,。這類腫瘤細胞具有高度的增殖性,、侵襲性和耐藥性，其術后復發(fā)率較高,，容易產(chǎn)生化療藥物耐受,。
鈣離子是細胞內(nèi)的第二信使，它調(diào)節(jié)細胞的多種生物學行為,，如細胞增殖和細胞周期,。作為鈣離子進入細胞內(nèi)的主要門戶，鈣離子通道在調(diào)節(jié)細胞增殖和細胞周期方面的作用逐漸被人們認識,。瞬時受體電勢通道是一類離子通道,，可通透鈣離子，起初在果蠅中被發(fā)現(xiàn),；突變體果蠅的視覺受體對持續(xù)光刺激僅表現(xiàn)出瞬時的受體電勢,，所以該通道由此而得名,。哺乳動物中存在多種瞬時受體電勢通道，TRPC6即為其中之一,。作者們發(fā)現(xiàn)人膠質(zhì)瘤組織中TRPC6的表達明顯高于正常腦組織,，特異地阻斷TRPC6通道能將膠質(zhì)瘤細胞周期阻斷在G2期,，抑制其增殖,。阻斷TRPC6通道減小顱內(nèi)腫瘤體積，顯著提高裸鼠存活率,。另外,，阻斷TRPC6通道后能提高膠質(zhì)瘤細胞對放射線的敏感性。
生物谷推薦最新腫瘤會議：第一屆上海腫瘤基礎和轉(zhuǎn)化醫(yī)學前沿研討會,，2010
http://www.canceraisa.com/
該項研究提出了TRPC6通道作為治療膠質(zhì)瘤的一個新的靶分子的可能性,。此項工作是該實驗室研究TRPC6與腫瘤發(fā)展的又一新的發(fā)現(xiàn)。（生物谷Bioon.net）
生物谷推薦原文出處：
Journal of the National Cancer Institute, doi:10.1093/jnci/djq217
Essential Role of TRPC6 Channels in G2/M Phase Transition and Development of Human Glioma
Xia Ding, Zhuohao He, Kechun Zhou, Ju Cheng, Hailan Yao, Dongliang Lu, Rong Cai, Yening Jin, Bin Dong, Yinghui Xu, Yizheng Wang
Affiliations of authors: Laboratory of Neural Signal Transduction, Institute of Neuroscience, Shanghai Institute for Biological Sciences, State Key Laboratory of Neuroscience (XD, ZH, KZ, JC, HY, DL, YW) and Graduate School (XD, ZH, KZ, JC, HY, DL), Chinese Academy of Sciences, Shanghai, China; Ruijin Hospital, Department of Radiochemotherapy, Jiaotong University School of Medicine, Shanghai, China (RC, YJ); Department of Neurosurgery, First Affiliated Hospital of Dalian Medical University, Dalian, China (BD, YX)
Background: Patients with glioblastoma multiforme, the most aggressive form of glioma, have a median survival of approximately 12 months. Calcium (Ca2+) signaling plays an important role in cell proliferation, and some members of the Ca2+-permeable transient receptor potential canonical (TRPC) family of channel proteins have demonstrated a role in the proliferation of many types of cancer cells. In this study, we investigated the role of TRPC6 in cell cycle progression and in the development of human glioma.
Methods: TRPC6 protein and mRNA expression were assessed in glioma (n = 33) and normal (n = 17) brain tissues from patients and in human glioma cell lines U251, U87, and T98G. Activation of TRPC6 channels was tested by platelet-derived growth factor–induced Ca2+ imaging. The effect of inhibiting TRPC6 activity or expression using the dominant-negative mutant TRPC6 (DNC6) or RNA interference, respectively, was tested on cell growth, cell cycle progression, radiosensitization of glioma cells, and development of xenografted human gliomas in a mouse model. The green fluorescent protein (GFP) and wild-type TRPC6 (WTC6) were used as controls. Survival of mice bearing xenografted tumors in the GFP, DNC6, and WTC6 groups (n = 13, 15, and 13, respectively) was compared using Kaplan–Meier analysis. All statistical tests were two-sided.
Results: Functional TRPC6 was overexpressed in human glioma cells. Inhibition of TRPC6 activity or expression attenuated the increase in intracellular Ca2+ by platelet-derived growth factor, suppressed cell growth and clonogenic ability, induced cell cycle arrest at the G2/M phase, and enhanced the antiproliferative effect of ionizing radiation. Cyclin-dependent kinase 1 activation and cell division cycle 25 homolog C expression regulated the cell cycle arrest. Inhibition of TRPC6 activity also reduced tumor volume in a subcutaneous mouse model of xenografted human tumors (P = .014 vs GFP; P < .001 vs WTC6) and increased mean survival in mice in an intracranial model (P < .001 vs GFP or WTC6).
Conclusions: In this preclinical model, TRPC6 channels were essential for glioma development via regulation of G2/M phase transition. This study suggests that TRPC6 might be a new target for therapeutic intervention of human glioma.
