Abstract
Abstract Although chemotherapeutic regimens often suppress tumor growth, cancer patients show high variability in their responses and commonly develop resistance to these drugs and recurrence of the tumor. To explain this phenomenon, the cancer stem cell hypothesis suggests that tumors contain a small number of tumor-forming, self-renewing, cancer stem cells (CSCs) within a population of non-tumor-forming cancer cells. In our study, we have identified that CD133+/CD44+/ALDH1+ colon cancer cells are able to self-renew, form tumors in immunodeficient (rag2-/-gammac-/-) mice and are highly resistant to 5-fluorouracil (5-FU) chemotherapy treatment. Several studies have identified that microRNAs are central regulators of oncogenesis, however their role in CSC formation and maintenance has not been elucidated. In order to identify microRNAs that suppress the growth of CD133+/CD44+/ALDH1+ colon cancer stem HCT-116 cells, we transfected a library of 810 microRNAs in these cells and evaluated their viability 24h post transfection. The microRNA library screen revealed 8 microRNAs that suppressed more than 80% colon CSC growth. Specifically, miR-26b inhibited most effectively (96%) colon CSC growth. In addition, microRNA microarray analysis revealed that miR-26b expression is highly decreased in colon CSCs in comparison to colon non-stem cancer cells (NSCCs), suggesting the importance of miR-26b in colon CSC growth. Bioinformatic and molecular analyses revealed that miR-26b targets directly the 3’UTR of the enhancer of zeste homolog 2 (EZH2). Overexpression of EZH2 in colon NSCCs resulted in formation of colon CSCs, suggesting the importance of EZH2 in colon CSC formation. Furthermore, chromatin-immunoprecipitation-sequencing (ChIP-seq) analysis showed that miR-26b overexpression in colon CSCs reactivates the expression of genes repressed by H3K27 tri-methylation. Interestingly, we have identified that miR-26b promoter area is a direct target of EZH2 suppressed by H3K27 tri-methylation. The transcriptional signature of the miR-26b-EZH2 network was also identified in colon CSCs derived from human colon cancer tumors. In addition, miR-26b targeted selectively colon CSCs and acted together with 5-FU chemotherapy to block tumor growth and prolong remission in colon cancer mouse models. Taken together, these data suggest the identification of novel epigenetic-microRNA network in colon CSCs and provide the rationale and experimental basis for using the combination of miR-26b and chemotherapy drugs to improve treatment of patients with colon cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 972. doi:10.1158/1538-7445.AM2011-972
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