MIEN1 on the 17q12 amplicon facilitates the malignant behaviors of gastric cancer via activating IL-6/JAK2/STAT3 pathway

Abstract

Oncogene amplification is a significant factor contributing to poor prognosis and limited treatment in patients with advanced gastric cancer. Therefore, identifying amplified oncogenes and elucidating their oncogenic mechanisms will provide reliable therapeutic targets for the clinical treatment of gastric cancer. In this study, we identify a high amplification of 17q12, which includes five oncogenes that are co-amplified and co-overexpressed with ERBB2 using array comparative genomic hybridization, with migration and invasion enhancer 1 (MIEN1) being particularly highlighted for its clinical significance, function, and role in gastric cancer progression. By detecting MIEN1 copy number and expression level across eight gastric cancer cell lines and in tissue microarrays from 543 primary gastric cancer tissues, we found that MIEN1 amplification and overexpression correlated with sex and Lauren’s intestinal type classification of gastric cancer. Besides that, elevated MIEN1 expression was associated with poorer patient survival. In vitro experiments have shown that MIEN1 overexpression enhanced cell proliferation, invasion, and migration, whereas MIEN1 knockdown reversed these malignant phenotypes in vitro. Furthermore, MIEN1 knockdown inhibited tumorigenesis and metastasis of gastric cancer cells in nude mice. Mechanistically, MIEN1 activates the IL-6/JAK2/STAT3 signaling pathway, which drives the proliferation, invasion, and migration of gastric cancer cells. This study demonstrates that MIEN1 contributes to the malignant behavior of gastric cancer through the IL-6/JAK2/STAT3 pathway, suggesting that MIEN1 could serve as a valuable therapeutic target for gastric cancer.