MicroRNA-495 confers inhibitory effects on cancer stem cells in oral squamous cell carcinoma through the HOXC6-mediated TGF-β signaling pathway

Abstract

Background: Oral squamous cell carcinoma (OSCC) is associated with high morbidity and ranks sixth among malignancies worldwide. Increasing evidence suggests that microRNAs (miRNAs or miRs) play a critical role in regulating cancer stem cells (CSCs), which drive the proliferation and spread of OSCC. Therefore, based on the alteration of aberrantly expressed miR-495 and homeobox C6 (HOXC6) by Gene Expression Omnibus (GEO) analysis, we subsequently explore the potential effect of miR-495 on the progression of CSCs in OSCC. Methods: After the isolation of CSCs from the clinical tissue samples of OSCC patients, the expression of miR-495 and HOXC6 was determined, followed by the validation of the relationship between miR-495 and HOXC6. Subsequently, gain-and loss-function approach was performed to detect the role of miR-495 and HOXC6 in cell proliferation, migration, invasion, cell cycle entry, apoptosis, and epithelial-mesenchymal transition (EMT) of CSCs in OSCC, as well as the tumor growth in vivo. Results: HOXC6 was highly expressed while miR-495 was poorly expressed in OSCC. HOXC6 was verified to be a target gene of miR-495, and miR-495 could inhibit the activation of the TGF-β signaling pathway. CSCs with miR-495 overexpression or HOXC6 silencing exhibited reversed EMT process; reduced abilities of proliferation, migration, and invasion; and promoted cell apoptosis in vitro. Moreover, inhibited tumor growth was observed in vivo after injection with miR-495 agomir or sh-HOXC6. In contrast, the downregulation of miR-495 showed an induced role in the progression of OSCC. Conclusion: These findings suggest that miR-495 may suppress HOXC6 to inhibit EMT, proliferation, migration, and invasion while promoting apoptosis of CSCs in OSCC by inhibiting the TGF-β signaling pathway.

Human umbilical cord mesenchymal stem cell-derived exosomal miR-27b attenuates subretinal fibrosis via suppressing epithelial–mesenchymal transition by targeting HOXC6

“…9a). Previous studies reported that HOXC6 played a vital role in EMT [28][29][30]; therefore, it was chosen as the candidate. In addition, the dual-luciferase reporter assay was applied to confirm whether HOXC6 was a target for miR-27b-3p.…”

Transforming Growth Factor-β: A Multifunctional Regulator of Cancer Immunity

“…The microRNA miR-495 is one that inhibits the expression of homeobox C6 and the function of TGF-β1. Its overexpression in CSCs contributes to EMT reversion, apoptosis, and the decreased proliferation and migration of CSCs [ 66 ]. The miRNA-200 family is another important group of microRNAs that promote cyst formation and ovarian cancer spread through targeting TGF-β expression [ 67 ].…”

Integrated analysis of deregulation microRNA expression in head and neck squamous cell carcinoma

“…[ 32 ] You has reported that miRNA-495 confers inhibitory effects on cancer stem cells in oral squamous cell carcinoma through the HOXC6-mediated TGF-β signaling pathway. [ 33 ] Similar to the TGF-β signaling pathway, Hippo signaling pathway dysregulation has been shown to contribute to the development of cancer. Martin confirmed that FAT1 acts as a tumor suppressor in HNSCC cells by inhibiting the Hippo signaling pathway.…”