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CCR:上海交大抑癌基因调控机制研究有新进展

2013-3-5 作者:Clin Cancer Res   来源:健康报 我要评论0
Tags: 肿瘤  癌症  抑癌基因  上海交大  

上海交通大学基础医学院王建华研究员领衔的课题组新近发现,前列腺癌中抑癌基因HIC1的启动子(基因的一个组成部分,控制基因表达的起始时间和表达程度)如果出现高度甲基化,可能导致其表达沉默而失去抑癌功能。该研究论文日前发表在国际学术刊物《临床癌症研究》上。专家认为,该研究阐明了抑癌基因在调控前列腺癌发生发展中的作用机制。

前列腺癌是男性泌尿生殖系统常见的恶性肿瘤之一,其发病率和死亡率在西方国家男性恶性肿瘤中居第二位,近年来,在我国也呈显著上升趋势。上海市前列腺癌发病率已从1990年的2.6/10万上升至2005年的16.1/l0万,位列男性肿瘤的第5位。

研究人员发现,在前列腺癌实体肿瘤组织中抑癌基因HIC1启动子呈现高度甲基化,可能导致其表达沉默而失去抑癌功能。采用5-Aza处理前列腺癌细胞系后,HIC1甲基化降低,HIC1表达上调。在进一步的研究中,科研人员通过体内外实验表明,恢复表达HIC1可显著降低癌细胞增殖、侵袭、转移及成瘤等能力;相反,shRNA沉默表达HIC1后,癌细胞这些特性则被显著增强。

王建华说,该研究有助于为前列腺癌的早期诊断和治疗提供新思路。

doi: 10.1158/1078-0432.CCR-12-2888
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HIC1 modulates prostate cancer progression by epigentic modification

Jianghua Zheng1, Jinglong Wang1, Xueqing Sun1, Mingang Hao1, Tao Ding2, Dan Xiong1, Xiumin Wang1, Yu Zhu3, Gang Xiao1, Guangcun Cheng1, Meizhong Zhao4, Jian Zhang5, and Jianhua Wang1,*

Purpose: Prostate cancer (PCa) is the second leading cause of cancer deaths among men in Western counties, which has been also occurred in Chinese male with markedly increasing incidence in recent years. Although the mechanism underlying its progression still remains unclear, epigenetic modifications are important ethological parameters. Exrimental Design: The methylation status of HIC1 promoter were assayed in cell lines, tissues and plasma of PCa patients by using MSP-PCR and bisulfate sequencing (BSP). The ability of HIC1 to regulate proliferation, migration and invasion was assessed by MTT, scratch healing assay and reconstituted extracellular matrices in porous culture chambers. Tumorigenesis,metastases and bone destruction were analyzed in mice bearing PCa cells restoring HIC1 by using Xenogen IVIS with radiographic system and small-animal PET-CT images. Microarrays were searched for genes that had correlated expression with HIC1 mRNA. Results: The methylation status of 11 CpG sites within HIC1 promoter were abundantly methylated in cell lines, tissues and plasma of PCa patients compared with those of respective normal controls. Restoring HIC1 expression in PCa cells markedly inhibited proliferation, migration, and invasion and induced the apoptosis in these cells. Moreover, mice bearing PCa-restoring HIC1 cells had a marked effect on reducing tumor growth,multiple tissue metastases and bone destruction. Notably, we also identified that the chemokine receptor CXCR7 is a direct downstream target gene of HIC1. Conclusions: These findings suggest that therapies targeting epigenetic events regulating HIC1 expression may provide a more effective strategy for PCa treatment.




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