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转录因子Hes1参与结直肠癌干细胞的自我更新和致瘤性

摘要 : 暨南大学第一附属医院(广州华侨医院)高飞博士课题组与南方医科大学肿瘤研究所合作证实,转录因子Hes1在维持结肠癌干细胞的自我更新中起重要的作用。相关成果日前发表于Nature旗下的《Scientific Reports》上。
Nature子刊:转录因子Hes1参与结直肠癌干细胞的自我更新和致瘤性

人正常结肠组织和不同分化程度结肠癌组织中Hes1表达免疫组化分析

暨南大学第一附属医院(广州华侨医院)高飞博士课题组与南方医科大学肿瘤研究所合作证实,转录因子Hes1在维持结肠癌干细胞的自我更新中起重要的作用。相关成果日前发表于Nature旗下的《Scientific Reports》上。

据了解,Hes1广泛表达于哺乳动物胚胎以及成体的脑、胆囊、神经及胰腺等多种组织中,并与神经发生、造血和肌形成等有密切关系。有研究表明,Hes1基因在维持机体各种前体细胞的未分化状态中起重要作用,可以保持未分化细胞的数量以确保正确的分化方向,且Hes1在某些肿瘤的发生和化疗敏感性中起重要作用。近年来发现,Hesl基因可以负调控干细胞的不对称有丝分裂,维持其自我更新,通过某些干细胞和祖细胞的维持并通过Notch通路影响消化器官的发育,可作为结肠干细胞的一个标志。研究表明Hes1的高表达可能导致结肠癌的发生。Hes1的这些独特作用使得其有望成为肿瘤治疗新的靶标,然而目前Hes1在结肠癌及结肠癌干细胞中的作用和机制尚未明确。

此次研究人员发现Hes1在结肠癌中的表达较正常结肠组织显著上调,并和分化程度相关。并且,Hes1在组织中的表达与干细胞标志物(CD133、CD44、ALDH1、Bmi-1、Oct4和Sox2)呈正相关。另外,他们还发现Hes1过表达的细胞株中CD133+细胞和SP细胞比例增高,上述干细胞标志物的表达较对照组高,且体内成瘤能力极大程度增强。研究结果提示Hes1在结肠癌的发生发展中起了关键作用,并且对结肠癌细胞的干性产生影响。

由于肿瘤干细胞对化疗有较大的抵抗作用,肿瘤干细胞对治疗不敏感则会导致肿瘤继续发展,进而转移。据介绍,基于上述实验结果研究人员推测Hes1可能是参与调节结肠癌化疗敏感性和转移能力的因素之一,日前已找到相关信号通路,相关研究也在进一步证实中。研究人员还认为这一信号通路有可能还适用于其他肿瘤,并正对此开展深入的研究。

原文摘要:

Hes1 is involved in the self-renewal and tumourigenicity of stem-like cancer cells in colon cancer

Fei Gao, YuQin Zhang, ShengChun Wang, YuanQiang Liu,Lin Zheng, JianQuan Yang, Wei Huang, YanFen Ye, WeiRen Luo and Dong Xiao

 

A small subpopulation of cancer cells with stem cell-like features might be responsible for tumour generation, progression, and chemoresistance. Hes1 influences the maintenance of certain stem cells and progenitor cells and the digestive systems. We found upregulated Hes1 in poorly differentiated cancer samples compared with well-differentiated tumour samples, and most of the adenocarcinomas exhibited significantly higher levels of Hes1 mRNA compared with that observed in matched normal colon samples. Moreover, Hes1 expressi0n was found to be correlated with the expressi0n of stem cell markers in colon cancer samples, and Hes1 upregulates the expressi0n of stemness-related genes in colon cancer cells. In addition, Hes1 enhances the self-renewal properties of the stem-like cells by increasing the sizes of CD133+ cells and SP cells and the ability of tumour sphere formation. Additionally, the Hes1-overexpressing cells formed significantly larger and higher number of colonies, as determined through the colony and the soft agar assays. More imp0rtantly, Hes1 enhances the tumourigenicity of colon cancer cell lines in nude mice and exhibits a strong tumour-formation ability at a cell density of 1×103. Taken together, our data indicate that Hes1 induces stem-like cell self-renewal and increases the number of tumour-initiating cells in colon cancer.

来源: 暨南大学第一附属医院 浏览次数:57

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