J Cancer 2021; 12(23):7138-7146. doi:10.7150/jca.63836 This issue

Research Paper

Downregulation of miR-375 contributes to ERBB2-mediated VEGFA overexpression in esophageal cancer

Shuchang Ren1, Xiaohui Tan1, Melinda Z. Fu1, Shuyang Ren1, Xiaoling Wu2, Tao Chen2, Patricia S. Latham3, Paul Lin4, Yan-gao Man5, Sidney W. Fu1✉

1. Department of Medicine, Division of Genomic Medicine, and Department of Microbiology, Immunology and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC.
2. Department of Medicine, Chengdu Military General Hospital, Chengdu, Sichuan, China.
3. Department of Pathology, The George Washington University School of Medicine and Health Sciences, Washington, DC.
4. Department of Surgery, The George Washington University School of Medicine and Health Sciences, Washington, DC.
5. Department of Pathology, Hackensack Meridian Health-Hackensack, University Medical Center, Hackensack, NJ; the International Union for Difficult to treat Diseases (IUDD), Silver Spring, MD.

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Citation:
Ren S, Tan X, Fu MZ, Ren S, Wu X, Chen T, Latham PS, Lin P, Man Yg, Fu SW. Downregulation of miR-375 contributes to ERBB2-mediated VEGFA overexpression in esophageal cancer. J Cancer 2021; 12(23):7138-7146. doi:10.7150/jca.63836. Available from https://www.jcancer.org/v12p7138.htm

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Abstract

Graphic abstract

Esophageal cancer (EC) is a lethal cancer with an extremely aggressive nature and poor survival rate. However, the molecular mechanisms driving the occurrence and progression of EC are not well understood. MicroRNAs (miRNAs) are small RNA molecules that regulate the expression of protein-coding genes. miRNA-mediated gene regulation plays an important role in EC. By cross-referencing studies from NCBI, we found that microRNA-375 (miR-375) is one of the most frequently downregulated miRNAs in EC. We assessed expression of miR-375 in EC cell lines and primary EC tissues and their matched normal tissues. We found significant downregulation of miR-375 in both cell lines and EC tissues. Forced expression of miR-375 attenuated EC cell proliferation and invasion. Human epidermal growth factor receptor 2 (HER2, ERBB2), a known proto-oncogene, was identified here as one of the potential target genes of miR-375. Ectopic expression of miR-375 significantly suppressed the expression of ERBB2 and subsequently downregulated one of its target genes, vascular endothelial growth factor A (VEGFA), which is related to cancer invasion and metastasis. These findings suggest that miR-375 acts as a tumor suppressor by blocking the ERBB2/VEGFA pathway with the potential to modulate the occurrence and/ or progression of EC.