J Cancer 2020; 11(9):2529-2539. doi:10.7150/jca.30995

Research Paper

miR-23a-3p/SIX1 regulates glucose uptake and proliferation through GLUT3 in head and neck squamous cell carcinomas

Hongming Wang1*, Weishuang Xue2*, Wunyu Ouyang1, Xiaoze Jiang1, Xuejun Jiang1✉

1. Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
2. Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
* Equal contribution

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Citation:
Wang H, Xue W, Ouyang W, Jiang X, Jiang X. miR-23a-3p/SIX1 regulates glucose uptake and proliferation through GLUT3 in head and neck squamous cell carcinomas. J Cancer 2020; 11(9):2529-2539. doi:10.7150/jca.30995. Available from http://www.jcancer.org/v11p2529.htm

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Abstract

SIX1 overexpression has been reported in several cancers. However, its involvement in head and neck squamous cell carcinoma (HNSCC) remains unclear. In this study we investigated the clinical significance and biological roles of SIX1 in HNSCC. SIX1 expression was upregulated in HNSCC and correlated with TNM stage and nodal metastasis. Analysis of TCGA dataset demonstrated that high SIX1 expression correlated with poor patient prognosis. Overexpression of SIX1 in the Fadu cell line upregulated cell proliferation, colony formation, glucose uptake and ATP production. In contrast, SIX1 depletion in the Detroit562 cell line downregulated cell proliferation, colony formation, glucose uptake and ATP production. We analyzed a series of genes involved in glucose metabolism and found that SIX1 overexpression upregulated GLUT3, an important glucose transporter, at both mRNA and protein levels. Using the TRANSFAC database, we found that SIX1 had potential binding sites on the GLUT3 promoter, which was validated by chromatin immunoprecipitation (ChIP) assays. Next, we focused on miR-23a-3p, which could target SIX1 in HNSCC cells. The miR-23a-3p mimic downregulated SIX1 expression while the miR-23a-3p inhibitor upregulated SIX1 expression. The binding of miR-23a-3p to the 3'-UTR of SIX1 was confirmed using the luciferase reporter assay. Analysis of TCGA dataset showed a negative correlation between the miR-23a-3p and SIX1. Furthermore, the miR-23a-3p mimic inhibited cell proliferation, ATP production and glucose uptake, which could be rescued by transfection with the SIX1 plasmid. In summary, our study demonstrated that SIX1 facilitated HNSCC cell growth through regulation of GLUT3 and glucose uptake. miR-23a-3p targeted the SIX1/GLUT3 axis and suppressed glucose uptake and proliferation in HNSCC.

Keywords: SIX1, head and neck squamous cell carcinoma, glucose metabolism, GLUT3, miR-23a-3p