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Nature子刊:华人科学家发现治疗肺癌新靶点

来源:生物谷 2015-10-08 11:00

2015年10月4日 讯 /生物谷BIOON/ --近年来,肺癌的发病率与致死率都在不断提高,使其持续成为全球范围内最严重的癌症类型之一。其中70%-80%的患者被确诊为非小细胞癌,并且已经进入转移期。尽管目前的诊断与治疗技术已经突飞猛进,许多肺癌仍旧在后期才得以发现。鉴于非小细胞肺癌的严重性,寻找更加有效地癌症相关生物标记显得十分重要。

ID是一类抑制DNA结合/分化的转录因子,ID蛋白能够二聚化并结合调节性的E蛋白来抑制肿瘤抑制基因的表达。之前的研究已经发现在各类癌细胞类型中有ID家族蛋白的高度表达,然而ID蛋白在癌细胞中过表达的具体作用目前并不清楚。针对这一问题,来自南京大学李小军教授课题组研究了ID3基因在A549癌细胞系中的过表达的生理意义,相关结果发表在《nature gene therapy》杂志上。
 
首先,作者向A549细胞系中转入了ID3基因,检测发现:相比于对照组,加入ID3后会引起细胞的大量死亡;而在其基础上又转入ID3-miRNA之后这一效应及受到了抑制。这一结果说明ID3能够促进细胞的凋亡。
 
之后,为了检测ID3对癌细胞迁移的影响,作者设计了一个伤愈实验,即在细胞皿中铺一层A549细胞,待细胞长满后将部分区域人为划破,留出一片空白区域。36hr后观察细胞向这一区域移动的程度。结果显示,对照组细胞可以轻易地向这一区域迁移,而ID3过表达的细胞其迁移能力受到了明显抑制。这一实验说明ID3能够抑制A549细胞系的迁移能力。
 
为了证明这一现象在体内是否有相同效应,作者将对照组与ID3过表达组的A549细胞注入裸鼠体内,并观察期肿瘤增长情况。结果显示,ID3过表达的A549细胞在体内的成瘤速率明显低于对照组。这一实验结果说明ID3的过表达能够抑制肿瘤的体内生长。
 
综上,作者认为他们发现了ID3抑制肿瘤的作用机理,并且可以成为用于诊断与治疗肿瘤恶化的靶点分子。

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PMC:
 
PMID:
 
Effects of upregulation of Id3 in human lung adenocarcinoma cells on proliferation, apoptosis, mobility and tumorigenicity
 
F-F Chen, Y Liu, F Wang, X-J Pang, C-D Zhu, M Xu, W Yu and X-J Li
 
The inhibitor of DNA-binding/differentiation 3 (Id3) protein is a helix-loop-helix transcription factor and may have an important role
 
in cell proliferation and differentiation. This study was to evaluate the effects of upregulation of Id3 in human lung adenocarcinoma
 
cells on proliferation, apoptosis, mobility and tumorigenicity. Short interference RNA suppression of Id3 (miRId3) in A549 cells was used to investigate the functional role(s) of Id3. Next, we used in vitro wound-healing assay and trans-well assay to study the effects of overexpressed Id3 on migration and invasion of A549 cells. Furthermore, to explore the influence of overexpressed Id3 on in vivo tumorigenesis, adenoviruses containing Id3 gene (Ad-Id3) and empty vector (Ad-LacZ) were generated. Co-transfection of pcDNA/ miRId3 and pEGFP/Id3 into A549 cells reversed the Id3-induced cell proliferation inhibition and apoptosis. Upon Id3 transfection, A549 cells displayed decreased migratory and invasive capabilities, however, co-transfection of miRId3 and Id3 into A549 cells reversed the Id3-induced inhibitions of migratory and invasive capabilities. Three groups of nude mice were inoculated with Ad-LacZ, Ad-Id3 transfectants and untransfected A549 cells, respectively. Twenty-eight days after inoculation, tumors induced by Ad-Id3 transfectants grew much more slowly compared with Ad-LacZ transfectants and control group. This study provides for the first time both in vitro and in vivo proofs that forced expression of Id3 in lung adenocarcinoma cells reduces tumor growth rate and may be a potential target for tumor suppression.
 
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