microRNA‐497‐mediated Smurf2/YY1/HIF2α axis in tumor growth and metastasis of esophageal squamous cell carcinoma

Abstract

Aberrant expression of microRNA‐497 (miR‐497) is associated with tumor progression, but the molecular mechanisms in tumorigenesis remain largely unknown. Here, we report that miR‐497 expression is downregulated in esophageal squamous cell carcinoma (ESCC) clinical samples. Consistently, upregulation of miR‐497 inhibits ESCC cell malignant properties and tumor growth in vivo. Importantly, we uncovered that miR‐497 upregulation suppressed ESCC cell growth and tumor growth by inhibiting Smurf2. Mechanistically, we showed that Smurf2 was a target of miR‐497, and mediated YY1 expression to elevate HIF2α expression, thereby enhancing the malignancy of ESCC cells. Together, our study uncovered the role of the miR‐497‐mediated Smurf2/YY1/HIF2α axis in tumor growth and metastasis, which might provide potential therapeutic targets for human ESCC.

Unraveling the Complex Web of Mechanistic Regulation of Versatile NEDD4 Family by Non-Coding RNAs in Carcinogenesis and Metastasis: From Cell Culture Studies to Animal Models

“…However, the miR-497-mediated targeting of SMURF2 potentiated the YY1-mediated transcriptional repression of HIF2α. There was a notable increase in the number of pulmonary metastatic nodules in mice injected with esophageal squamous cell carcinoma cells stably transfected with miR-497 inhibitors, whereas metastatic nodules were reduced on the surface of lungs in mice injected with SMURF2-silenced or HIF2α-silenced cancer cells [91].…”

Non‑coding RNA: A promising diagnostic biomarker and therapeutic target for esophageal squamous cell carcinoma (Review)

“…The levels of miR-497 have been found to be lower in ESCC tissues and cells when compared with normal tissues (83). An increase in miR-497 expression suppresses ESCC cell growth, 4) Some introns contain specific sequences and form loops, during reverse splicing, which are resistant to degradation.…”

“…while a reduction in miR-497 expression promotes ESCC cell proliferation (83). Furthermore, overexpression of miR-497 in ESCC cells injected into BALB/c nude mice results in a decreased level of proliferating cell nuclear antigen, increased cleaved caspase-3 expression and inhibited tumor growth (83).…”

“…while a reduction in miR-497 expression promotes ESCC cell proliferation (83). Furthermore, overexpression of miR-497 in ESCC cells injected into BALB/c nude mice results in a decreased level of proliferating cell nuclear antigen, increased cleaved caspase-3 expression and inhibited tumor growth (83). Mechanistically, it has been revealed that the YY1 protein can inhibit HIF2α expression by binding to the HIF2α promoter region, and miR-497 upregulates YY1 protein expression (83).…”