Tumor‐suppressive roles of ΔNp63β‐miR‐205 axis in epithelial–mesenchymal transition of oral squamous cell carcinoma via targeting ZEB1 and ZEB2

Abstract

We previously revealed that epithelial‐to‐mesenchymal transition (EMT) was mediated by ΔNp63β, a splicing variant of ΔNp63, in oral squamous cell carcinoma (OSCC). Recent studies have highlighted the involvement of microRNA (miRNA) in EMT of cancer cells, though the mechanism remains unclear. To identify miRNAs responsible for ΔNp63β‐mediated EMT, miRNA microarray analyses were performed by ΔNp63β‐overexpression in OSCC cells; SQUU‐B, which lacks ΔNp63 expression and displays EMT phenotypes. miRNAs microarray analyses revealed miR‐205 was the most up‐regulated following ΔNp63β‐overexpression. In OSCC cells, miR‐205 expression was positively associated with ΔNp63 and negatively with zinc‐finger E‐box binding homeobox (ZEB) 1 and ZEB2, potential targets of miR‐205. miR‐205 overexpression by miR‐205 mimic transfection into SQUU‐B cells led to decreasing ZEB1, ZEB2, and mesenchymal markers, increasing epithelial markers, and reducing cell motilities, suggesting inhibition of EMT phenotype. Interestingly, the results opposite to this phenomenon were obtained by transfection of miR‐205 inhibitor into OSCC cells, which express ΔNp63 and miR‐205. Furthermore, target protector analyses revealed direct regulation by miR‐205 of ZEB1 and ZEB2 expression. These results showed tumor‐suppressive roles of ΔNp63β and miR‐205 by inhibiting EMT thorough modulating ZEB1 and ZEB2 expression in OSCC.

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

“…Extensive studies have confirmed that ZEB1 is upregulated in the EMT and plays a key role in the development of tumors and fibrosis . It was reported that the Np63‐miR‐205 axis increased epithelial marker gene expression and decreased mesenchymal marker gene expression in oral squamous cell carcinoma by downregulating ZEB1 and ZEB2 . Moreover, the heterogeneous expression of ZEB1 induced by EMT played an important role in metastasis through the regulation of miR‐200c .…”

“…99,100 It was reported that the Np63-miR-205 axis increased epithelial marker gene expression and decreased mesenchymal marker gene expression in oral squamous cell carcinoma by downregulating ZEB1 and ZEB2. 101 Moreover, the heterogeneous expression of ZEB1 induced by EMT played an important role in metastasis through the regulation of miR-200c. 102 In addition, miR-302a-3p exerted a protective role via inhibiting ZEB1 and EMT in diabetic kidney disease.…”

A Natural Isoquinoline Alkaloid With Antitumor Activity: Studies of the Biological Activities of Berberine

“…miRNAs play a central role in many cellular biology processes, and their dysregulation is a ubiquitous feature in tumors. Epigenetic effects have been shown to be a major cause of miRNA dysregulation in tumors (Hashiguchi et al, 2017). In the TGF-β1-induced colorectal cancer model, berberine significantly decreased the expression of miR-152 (targeting DNMT1), miR-429 (targeting DNMT3A), and miR-29a (targeting DNMT3A/3B), which suggested that berberine inactivates some tumor suppressor factors, including DNMT1 and DNMT3A/3B, through the regulation of the expression of the above miRNAs during colon cancer development.…”

Prospective applications of microRNAs in oral cancer: A review (Review)

“…ZEB was reported as an EMT-related transcription factor, which was shown to directly combine with the E-cadherin promoter and inhibit its transcription (77,78). Hashiguchi et al (79) identified an association between miR-205 and the EMT phenotype in SQUU-B cells and demonstrated that overexpression of miR-205 downregulated ZEB1, ZEB2 and N-cadherin, and upregulated E-cadherin. Another study reported that overexpression of miR-375 significantly upregulated SCC-4 cell radiation-induced apoptosis by directly regulating the insulin-like growth factor 1 receptor (IGF1R) (32).…”

“…A possible treatment strategy may involve anticancer drugs that selectively regulate the expression of such miRNAs. Certain genes or signaling pathways are regulated by two or more miRNAs, for instance, tripartite motif containing 14 is targeted by miR-195-5p (31) and miR-15b (89); IGF1R is targeted by miR-98 (132) and miR-375 (32); ZEB1 is targeted by miR-205 (79) and miR-200c (87); and PTEN is targeted by miR-221/222 (115) and miR-24 (116). Therefore, the combination of more specific inhibitors or activators of cancer-associated genes or signaling pathways may be a suitable therapeutic strategy.…”