miR-203 Inhibits the Proliferation and Self-Renewal of Esophageal Cancer Stem-Like Cells by Suppressing Stem Renewal Factor Bmi-1

Abstract

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.

MicroRNA-203 inhibits cellular proliferation and invasion by targeting Bmi1 in non-small cell lung cancer

“…Whether miRNAs act as oncogenes or tumor suppressor genes depends on the context. For example, miR-203 behaves as a tumor suppressor and is downregulated in pancreatic, glioma and esophageal cancer, while it is upregulated in epithelial ovarian cancer and acts as an oncogene (9,(20)(21)(22). The present study demonstrated that miR-203 was downregulated in NSCLC specimens, which is in agreement with a …”

“…A previous study revealed that molecular markers of cancer stem-like cells were connected with malignancies by using gene microarray and sequencing analysis (9). Another study demonstrated that miRNAs are critical in the carcinogenesis of lung cancer (10).…”

“…B-cell-specific moloney murine leukemia virus insertion site 1 (Bmi1) is a member of the polycomb repressive complex 1 (PRC1) and is highly expressed in several types of cancer, including lung neoplasm (14,15). Yu et al (9) demonstrated that miR-203 inhibited the proliferation of esophageal cancer cells by suppressing Bmi1 directly. However, the level of miR-203 expression and its role in NSCLC remains unclear.…”

MicroRNA-203 inhibits the malignant progression of neuroblastoma by targeting Sam68

“…It can also target Hakai and inhibit the growth of human colon adenocarcinoma (28). Additionally, those genes involved in the regulation of cell proliferation, apoptosis, cell cycle progression, migration and invasion, are also the targets of miR-203, including Robo1, Kif5b, E2F3, LASP1, ASAP1, PKCα, BIRC5, Bmi-1 and DeltaNp63 (23)(24)(25)(26)(29)(30)(31)(32)(33). Whether these miR-203 targets are also involved in the development and progression of NB remains to be elucidated.…”

Low expression of microRNA-202 is associated with the metastasis of esophageal squamous cell carcinoma

“…The application of high-throughput sequencing and microarray technology has produced notable alterations in the miRNA expression profiles of tumor tissue, as compared with normal tissue (9,10). Variations in miRNA expression levels between tumor tissues and normal tissues may lead to the dysfunction of downstream signaling pathways, which are associated with proliferation, invasion, angiogenesis and the metastasis of tumors (11,12,13). Furthermore, miRNA molecules are highly stable, which facilitates their survival in tissue fluid, blood and urine (14).…”