川大博导PNAS发现5种非编码RNA促癌发生

　　

生物通报道，来自四川大学生命科学院的博士生导师，宋旭教授近期在非编码RNA与肿瘤关联研究领域取得新的进展，相关成果文章Role of human noncoding RNAs in the control of tumorigenesis公布在最近的PNAS上。

 

人体中编码蛋白质的基因大约有2万个，编码蛋白质的DNA在基因组中不足2%，除约5%的非转录区外，其余约93%的基因组DNA可转录产生非编码RNA（ncRNA）。 这些非编码的RNA虽然不直接参与基因编码、克隆和蛋白质的合成，但是它们是基因转录、表达、加工、剪切、修饰和调控的调节者，进而调节基因、细胞和机体的一切生理功能，与人体所有疾病的发生、发展和防治都有着密切的关系。它们是RNA生物学研究的新世界，因此ncRNA研究是当前分子生物学最热门的重要前沿领域。

 

宋旭教授实验室发现5种来源于人的大分子ncRNA可通过与PSF（PTB-associated splicing factor）蛋白相互作用调控原癌基因的转录，从而将成纤维细胞转化成肿瘤细胞，还可促进肿瘤的恶性生长，说明大分子ncRNA的异常高表达可能是肿瘤的重要成因之一。该发现有可能使人们对肿瘤成因产生新的认识，可利用这些大分子ncRNA开发出新型的肿瘤治疗药物和肿瘤诊断试剂。

 

这也是继宋旭教授之前在《美国国家科学院院刊》(PNAS)上发表的三篇关于大分子ncRNA-蛋白相互作用的作用机制论文后的又一突破性科研进展。

 

（生物通 小茜）

联川生物microRNA分析产品

生物通推荐原文检索

Role of human noncoding RNAs in the control of tumorigenesis

Ling Lia,b,1, Tingting Fenga,1, Yingying Liana, Guangfeng Zhanga, Alan Garena,b,c,2 and Xu Songa,b,2

 

aCenter for Functional Genomics and Bioinformatics, College of Life Science, Sichuan University, Chengdu, Sichuan 610064, China;

bState Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; and

cDepartment of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520

↵1 L.L. and T.F. contributed equally to this work.

 

【Abstract】

Related studies showed that the protein PSF represses proto-oncogene transcription, and VL30–1 RNA, a mouse noncoding retroelement RNA, binds and releases PSF from a proto-oncogene, activating transcription. Here we show that this mechanism regulates tumorigenesis in human cells, with human RNAs replacing VL30–1 RNA. A library of human RNA fragments was used to isolate, by affinity chromatography, 5 noncoding RNA fragments that bind to human PSF (hPSF), releasing hPSF from a proto-oncogene and activating transcription. Each of the 5 RNA fragments maps to a different human gene. The tumorigenic function of the hPSF-binding RNAs was tested in a human melanoma line and mouse fibroblast line, by determining the effect of the RNAs on formation of colonies in agar and tumors in mice. (i) Expressing in human melanoma cells the RNA fragments individually promoted tumorigenicity. (ii) Expressing in human melanoma cells a shRNA, which causes degradation of the endogenous RNA from which an RNA fragment was derived, suppressed tumorigenicity. (iii) Expressing in mouse NIH/3T3 cells the RNA fragments individually resulted in transformation to tumorigenic cells. (iv) A screen of 9 human tumor lines showed that each line expresses high levels of several hPSF-binding RNAs, relative to the levels in human fibroblast cells. We conclude that human hPSF-binding RNAs drive transformation and tumorigenesis by reversing PSF-mediated repression of proto-oncogene transcription and that dysfunctional regulation of human hPSF-binding RNA expression has a central role in the etiology of human cancer.

 

宋旭

简历:

1993年毕业于四川大学生物工程系获学士学位

1996年毕业于四川大学生物工程系获硕士学位

1999年毕业于中国协和医科大学获博士学位

1999年起在美国耶鲁大学分子生物物理与生物化学系作博士后研究

2002年起任美国耶鲁大学分子生物物理与生物化学系Associate Research Scientist

2006年起任四川大学生命科学学院教授

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 研究方向:

肿瘤以及干细胞相关的长非编码RNA；肿瘤靶向治疗。

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 研究内容:

筛选及鉴定与肿瘤相关蛋白结合的长非编码RNA，并研究其作用机制。

筛选及鉴定与发育、分化相关的长非编码RNA，并研究其作用机制。

研究长非编码RNA在染色质表观修饰水平的调控。

以肿瘤或新生血管表面特异高表达的受体为靶点进行肿瘤靶向治疗。

 

发表论文

Ling Li, …, Xu Song.(2009)Role of human noncoding RNAs in the control of tumorigenesis. Proc. Natl. Acad. Sci. USA. 106 (31):12956-61

Alan Garen，Xu Song. (2008) Regulatory roles of tumor-suppressor proteins and noncoding RNA in cancer and normal cell functions. Int J Cancer 122(8):1687-9.

Xu Song, et al. (2005) From the cover: Roles of PSF protein and VL30 RNA in reversible   gene regulation. Proc. Natl. Acad. Sci. USA. 102(34):12189-93. (封面)

Xu Song, et al. (2004) Binding of mouse VL30 retrotransposon RNA to PSF protein induces genes repressed by PSF: Effects on steroidogenesis and oncogenesis. Proc. Natl. Acad. Sci. USA. 101(2): 621-6

Xu Song, et al. (2002) Retroviral-mediated transmission of a mouse VL30 RNA to human  melanoma cells promotes metastasis in SCID mice. Proc. Natl. Acad. Sci. USA. 99(9): 6269-73

Xu Song, et al. (1999)Advanced glycation in D-galactose induced mouse aging model. Mech Ageing Dev. 108:241-253