HNF1A-AS1 promotes growth and metastasis of esophageal squamous cell carcinoma by sponging miR-214 to upregulate the expression of SOX-4

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies in the world, marked by dysphagia and weight loss, bringing great suffering to patients. HNF1A‑AS1 (HAS1), a long non-coding RNA (lncRNA), has been identified prevalently involved in various human cancers. However, the exact effects and molecular mechanisms of HAS1 in ESCC progression are still elusive. In this study, upregulated expression of HAS1 was detected in ESCC tissues and four human ESCC cell lines (KYSE70, KYSE450, EC109 and EC970) compared with normal tissues and cell lines. Small interfering RNA (siRNA)-mediated knockdown of HAS1 largely suppressed cell proliferation and promoted cell apoptosis in KYSE70 and EC109 cells. The decreased expression of proliferation marker proteins and elevated level of apoptosis marker proteins further verified that HAS1‑siRNA suppressed cell viability in ESCC cells. Besides, the silence of HAS1 strongly reduced the wound closing rate and the number of invasive cells compared with control group. HAS1-siRNA also restrained the expression of migration marker proteins matrix metalloproteinase-9 (MMP-9) and vascular endothelial cell growth factor (VEGF). In addition, miR‑214 was predicted as a direct target of HAS1 by bioinformatics analysis. Downregulated expression of miR‑214 was elevated in KYSE70 and EC109 cells transfected with HAS1-siRNA. Subsequently, elevated expression of miR‑214 was suppressed by co-transfecting with miR‑214 inhibitor in EC109 cells pretreated with HAS1-siRNA. The result of luciferase activity assay showed that luciferase activity was strongly weakened by the combination of LncR-HAS1 WT and miR‑214 mimic. Moreover, the expression of SOX-4, a predicted target gene of miR‑214, was suppressed by HAS1-siRNA and was increased by miR‑214 inhibitor. HAS1-siRNA counteracted the effect of miR‑214 inhibitor on cell viability and mobility in EC109 cells. Finally, the in vivo experiment revealed that HAS1-siRNA abated the role of miR‑214 inhibitor in promoting tumor growth and metastasis. miR-214 also mediated the effect of HAS1 on upregulating the expression of SOX-4 in vivo. Taken together, our study indicated a HAS1-miR‑214-SOX-4 pathway in regulating the growth and metastasis of ESCC, providing a promising target for ESCC therapy.

Long non-coding RNAs in esophageal cancer: molecular mechanisms, functions, and potential applications

“…HNF1A-antisense 1 (HNF1A-AS1) is the sole lncRNA reported to modulate VEGF thus far. Recently, Wang reported that the knockdown of HAS1 suppressed the expression of VEGF in ESCC cells [ 123 ]. However, direct supporting evidence that HAS1 inhibits angiogenesis requires further studies.…”

LncRNA MIR205HG Drives Esophageal Squamous Cell Carcinoma Progression by Regulating miR-214/SOX4 Axis

“…Interestingly, SOX4 was reported to be a direct target gene of miR-214 and SOX4 served as an important oncogene to promote ESCC development. 19,26 Here, we found SOX4 was elevated in ESCC tissues and patients with high SOX4 expression had shorter overall survival rates. These findings were consistent with previous reports.…”

“…Previous study identified that SOX4 was a direct downstream gene of miR-214 in ESCC cells. 19 We found that SOX4 was up-regulated in multiple cancers including ESCC in the GEDS database ( Figure 7A). 20 Similarly, there was a remarkable increase of SOX4 mRNA expression in ESCC tissues based on the analysis of GEPIA database and Oncomine (https:// www.oncomine.org/) ( Figure 7B and C).…”

LncRNA LOC146880 promotes esophageal squamous cell carcinoma progression via miR-328-5p/FSCN1/MAPK axis

“…For example, lncRNA sponging of miR-224, TUSC7 suppresses chemotherapeutic resistance in ESCC cells by modulating the DESC1/EGFR/AKT pathway [ 12 ]. And by sponging miR-214, LncRNA HNF1A-AS1 promotes ESCC by upregulating SOX-4 expression [ 13 ].…”