Hes1调控肿瘤干细胞特性和EMT在结肠癌化疗耐药中的机制研究

Colon cancer is one of the most frequent cancers and a major cause of cancer-related death due to the poor efficacy and prognosis. Cancer stem cells (CSCs) are the driving force of tumorigenesis, recurrence, and metastases, contributing to the failure of some cancer treatments. Epithelial-mesenchymal transition (EMT) is an important process in tumor metastasis and chemotherapy and radiotherapy resistance, and can promote cancer stem cells to ditach from other tumor cells’ adhesion. Bmi-1 plays an important role in the stem cell proliferation, differentiation and aging in several types of cancer, and promotes drug resistance and cellular invasion in cancer cells and cancer stem cells. Hes1 is a transcription factor that influences cell proliferation and differentiation in embryogenesis and influences the maintenance of certain stem cells and progenitor cells. However, the roles and mechanisms of Hes1 in colon cancer and colon cancer stem cells are not yet clear. In this study, we found that the expression of Hes1 in poorly differentiated cancer samples was up-regulated compared to its expression in well-differentiated tumour samples, and most of the adenocarcinomas exhibited significantly higher levels of Hes1 mRNA than their matched normal colon samples. Moreover, Hes1 expression was found to be correlated with the expression of stem cell markers including Bmi-1 in colon cancer samples, and Hes1 upregulates the expression 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, and 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. What’s more, Hes1 could increase the expression of Bmi-1 by associating at the Bmi-1 locus as well, and Bmi-1-silencing abrogated Hes1-induced invasion, "stemness" maintain and chemotherapy resistance. The results from our previous studies indicate that Hes1 plays a quantitative role in the development and progression of colon cancer and the maintenance of the stemness of cancer stem cells, which remains to be fully characterised. The aim of this study is to assess the effect of Hes1 on the “stemness”, EMT and chemosensitivity in human colon cancer. Furthermore, our study intends to increase the sensitivity of colon cancer stem cells to chemotherapy by controlling the expressin of Hes1. This research will further reveal the mechanisms of colon cancer chemoresistance, and provide a promising target for therapeutic intervention of colon cancer.

多数进展期结肠癌对化疗和放疗不敏感，疗效和预后不佳。目前主要观点认为肿瘤干细胞与肿瘤发生、复发、治疗抵抗有密切相关，EMT是肿瘤治疗中细胞形态转变造成治疗抵抗的重要因素。研究表明Bmi-1参与多种肿瘤的形成和发展，并参与干细胞的增殖、分化、化疗耐药和转移。Hes1在维持机体各种前体细胞的未分化状态中起重要作用，其高表达可能导致结肠癌的发生，然而，Hes1在结肠癌及结肠癌干细胞中的作用和机制尚未明确。前期研究发现Hes1在结肠癌组织中高表达，且与分化程度呈负相关。Hes1过表达的细胞株中CD133+细胞和SP细胞比例增高，干细胞标志基因表达上调，体内成瘤能力增强。并且，Hes1可能通过Bmi-1调节结肠癌的干性、促进EMT进程和Akt磷酸化，从而诱导化疗耐药。因此，本研究拟探讨Hes1调节结肠癌干细胞特性、EMT与化疗耐受的作用及其机制，为结肠癌细胞化疗耐受提供治疗策略。

多数进展期结肠癌对化疗和放疗不敏感，疗效和预后不佳。目前主要观点认为肿瘤干细胞与肿瘤发生、复发、治疗抵抗有密切相关，EMT是肿瘤治疗中细胞形态转变造成治疗抵抗的重要因素。研究表明Bmi-1参与多种肿瘤的形成和发展，并参与干细胞的增殖、分化、化疗耐药和转移。Hes1在维持机体各种前体细胞的未分化状态中起重要作用，其高表达可能导致结肠癌的发生，然而，Hes1在结肠癌及结肠癌干细胞中的作用和机制尚未明确。前期研究发现Hes1在结肠癌组织中高表达，且与分化程度呈负相关。Hes1过表达的细胞株中CD133+细胞和SP细胞比例增高，干细胞标志基因表达上调，体内成瘤能力增强，证实Hes1对于维持结肠癌干细胞的自我更新中起重要的作用。在本研究中，我们研究发现，Hes1可能通过Bmi-1调节结肠癌的干性、促进EMT进程和Akt磷酸化，从而诱导化疗耐药。因此，本研究探讨了Hes1调节结肠癌干细胞特性、EMT与化疗耐受的作用及其机制，为结肠癌细胞化疗耐受提供治疗策略。