Role of miR-200c/miR-141 in the regulation of epithelial-mesenchymal transition and migration in head and neck squamous cell carcinoma

Abstract

Epithelial-mesenchymal-transition (EMT) is a critical step in tumor invasion and metastasis, while its fate is mainly defined by the balanced expression between the miR-200 family and ZEB transcription factors. In this study, we observed a reciprocal correlation between miR-200c/mir-141 and ZEB1, as well as between ZEB2 and E-cadherin expression in a panel of 13 head and neck squamous cell carcinoma (HNSCC) cell lines. We also confirmed that the enforced expression of miR-200c and miR-141 significantly reduced the migration capacity of HNSCC cells. Accordingly, the enforced expression of miR-200c and mir-141 resulted in a significant upregulation in E-cadherin expression, contrary to the significant downregulation in ZEB1 expression in 3 cell lines (UTSCC-24A, UTSCC-24B and UTSCC-6A cells). Another pair of cell lines, UTSCC-60A and UTSCC‑ 60B failed to show a significant change in the expression of E-cadherin or ZEB1/ZEB2 during the enforced expression of miR-200c/miR-141. To address the issue, we focused on the hypermethylation status of the ZEB1/2 promoters, which have both been shown to include wide CpG islands. We observed a marked upregulation in both ZEB1 and ZEB2 mRNA expression following treatment with a demethylating agent in both pairs of UTSCC cell lines. In conclusion, our findings confirm the existence of a reciprocal correlation between the mir-200 family and the ZEB family, and demonstrate the role of the miR-200 family in EMT, as well as in the migration and invasion ability of HNSCC cells. Furthermore, our data suggest that the promoter hypermethylation of ZEB1 and ZEB2 may play an essential role and may overshadow the effects of the miR-200 family in the regulation of EMT during carcinogenesis.

Demethylation drug 5-Aza-2′-deoxycytidine-induced upregulation of miR-200c inhibits the migration, invasion and epithelial-mesenchymal transition of clear cell renal cell carcinoma in vitro

“…As Aza treatment markedly upregulated the expression levels of miR-200c, the results of the present study suggest that miR-200c may have a suppressive effect on ccRCC cell migration and invasion, and the inhibitory effect of Aza treatment on ccRCC cell migration and invasion may be partly due to the direct upregulation of miR-200c expression levels. A suppressive role of miR-200c in cell migration and invasion has additionally been identified in other types of human cancer (23,24). Liu et al (13) identified that miR-200c inhibited invasion, migration and proliferation of bladder cancer cells.…”

“…MicroRNAs (miRs) are a type of small non-coding RNA (19)(20)(21)(22)(23)(24)(25) nucleotides) that possess prominent roles in the regulation of genes (6). MiRs typically inhibit gene expression by directly binding the 3'-untranslated region of their target messenger (m)RNAs, causing repression of translation or mRNA degradation (7).…”

Potential use of microRNA-200c as a prognostic marker in non-small cell lung cancer

“…The present study indicated that miR-200c is associated with lymph node metastasis, suggesting that miR-200c may be upregulated in the metastatic process. However, miRNA-200c has been shown to restrict the epithelial-mesenchymal transition (EMT) and metastasis through direct targeting of the cell adhesion pathway (27,28), particularly the zinc finger E-box binding homeobox (ZEB)-cadherin 1 axis (29). However, the pleiotropic effect of miR-200c in the metastatic process is contradictory in in vitro and in vivo studies (30).…”

Dysregulation of miR-200 family microRNAs and epithelial-mesenchymal transition markers in oral squamous cell carcinoma

“…Tumor invasion and metastasis have previously been demonstrated to be tightly controlled by the balanced expression of the miR-200 family members and zinc finger E-box-binding homeobox (ZEB) transcription factors (9,11). In previous studies, it has been demonstrated that miR-200 expression is downregulated within cancer cells, enabling a positive regulatory loop to maintain ZEB1/ZEB2 expression (11,13). Inhibition of miR-200 reduces E-cadherin expression, increases vimentin expression and induces the EMT mechanism (14).…”