miR-203 inhibits the proliferation and self-renewal of esophageal cancer stem-like cells by suppressing stem renewal factor Bmi-1.
Cancer stem-like cells exist in many malignancies and several stem cell-related genes and microRNAs, such as Bmi-1 and miR-203, have been identified as cancer stem-like cell regulators using gene microarray or sequencing analysis. Previously, we used side population (SP) sorting to enrich cancer stem-like cells from esophageal squamous cell carcinoma (ESCC) cell line EC9706. Our results demonstrated that EC9706 SP cells shared common features of cancer stem-like cells. In this study, we examined the expression of Bmi-1 and miR-203 in ESCC SP and non-SP (NSP) cells. Our results showed that, when compared with NSP cells, Bmi-1 was up-regulated and miR-203 was down-regulated in SP cells. During the differentiation from SP to NSP cells, the expression levels of Bmi-1 were gradually decreased. Overexpression of miR-203 resulted in a significant reduction of endogenous Bmi-1 protein level in EC9706 cells. SP and NSP analyses revealed that the SP cell fraction was markedly decreased in miR-203 overexpressed cells. miR-203 overexpressed cells also showed a significant reduction in colony formation, which was resistant to chemotherapeutic drug treatment and tumorigenicity in nude mice. Rescue experiments demonstrated that ectopic expression of Bmi-1 in miR-203 overexpressed cells increased the SP fraction and restored cell proliferation. Taken together, these results indicated that stem renewal factor Bmi-1 was a direct target of miR-203. The regulation of Bmi-1 by miR-203 may play an important role in controlling cell proliferation and self-renewal of esophageal cancer stem-like cells. It may also promote the development of new therapeutic strategies and efficient drugs that target ESCC stem-like cells.
State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China .
Xiying
X
Yu
Xingran
X
Jiang
Hongxia
H
Li
Liping
L
Guo
Wei
W
Jiang
Shih-Hsin
SH
Lu
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics* / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism; D000077277:Esophageal Squamous Cell Carcinoma; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*
C069077:BMI1 protein, human; C489421:Bmi1 protein, mouse; C546703:MIRN203 microRNA, human; C575934:MIRN203 microRNA, mouse; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D063150:Polycomb Repressive Complex 1