miR-942 promotes cancer stem cell-like traits in esophageal squamous cell carcinoma through activation of Wnt/β-catenin signalling pathway

Abstract

The Wnt/β-catenin signalling pathway is known to play a vital role in the maintenance of cancer stem cells (CSCs), which are reported to be the origine of malignant cancers, and result in poor prognosis of multiple kinds of cancer. Therefore, it is of great importance to illuminate the mechanism by which the Wnt/β-catenin pathway regulates the cancer stem cell-like traits in cancers. Here, we report that miR-942 is significantly upregulated in esophageal squamous cell carcinoma (ESCC), and miR-942 levels are associated with poor prognosis in ESCC patients. Overexpression of miR-942 promotes, whereas inhibition of miR-942 decreases, the tumor sphere formation, the CD90+ subpopulation cells and the expression of pluripotency associated markers. Moreover, in vivo assay shows that miR-942 overexpressing cells form larger tumors and display higher tumourigenesis. Furthermore, we demonstrate that miR-942 upregulates the Wnt/β-catenin signaling activity via directly targeting sFRP4, GSK3β and TLE1, which are multiple level negative regulators of the Wnt/β-catenin signaling cascade. In addition, our results indicate that c-myc directly binds to the miR-942 promoter and promotes its expression. Taken together, our findings establish an oncogenic role of miR-942 in ESCC and indicate that miR-942 might be an effective therapeutic target for ESCC.

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

“…Similarly, miR-429 contributes to hepatocyte self-renewal, malignant proliferation, tumorigenicity, and chemoresistance, making it an attractive potential target to inactivate tumor-initiating cells in the liver (33). We show that miR-644a functions as an upstream activator of the Wnt/b-catenin pathway in ESCC, a pathway well characterized in the development of stem cell-like properties in a wide variety of cancer types, including ESCC (25,26). Therefore, we hypothesized that the levels of miR-644a could influence the stemness of ESCC cells via regulation of PITX2.…”

“…Various studies have documented that the Wnt/b-catenin signaling pathway is constitutively activated in many types of human cancer, and plays an important role in triggering aggressive cellular features that constitute a malignant phenotype (23)(24)(25). It was reported that PITX2 and the Wnt/b-catenin pathway exert positive-feedback regulation, while aberrant activation of Wnt/b-catenin signaling is strongly involved in ESCC tumorigenesis and/or progression (8,26). These results collectively suggest that the Wnt/b-catenin axis is one of the critical downstream pathways activated by PITX2 accumulation in ESCC malignancy that we now propose is miR-644a-mediated.…”

HIV-1 Vpr Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by Inducing MicroRNA miR-942-5p and Activating NF-κB Signaling

“…Moreover, miR-942 is inversely correlated with the expression of interferon-stimulated gene 12a (ISG12a) and modulates tumor necrosis factor-related apoptosisinducing ligand (TRAIL) sensitivity in cancer tissues and cells (77). Recently, miR-942 was shown to be upregulated in esophageal squamous cell carcinoma (ESCC) and to promote the stem cell-like traits by inhibiting three negative regulators of the Wnt/ ␤-catenin pathway, including secreted Frizzled-related protein 4 (sFRP4), glycogen synthase kinase 3␤ (GSK3␤), and transducinlike enhancer of split 1 (TLE1) (78). In addition, the high expression levels of miR-942 have been detected in nephrotic syndrome patients and lung cancer cases (79,80).…”

Expression and clinical significance of C14orf166 in esophageal squamous cell carcinoma

“…Abnormal expression of PI3K-AKT-mTOR is frequent in melanoma and indicates a poor prognosis, and thus inhibition of the mTOR pathway will benefit numerous patients in the clinic (29). Ge et al (30) demonstrated that through abnormal activation of Wnt/β-catenin pathway, miR-942 aided to maintain cancer stem cell-like traits in ESCC, inducing poor prognosis and unsatisfactory drug effects. In addition, GSK-3β can promote esophagus carcinoma cells metastasis and spread by degrading β-catenin (31,32).…”