Gastric cancer (GC) is the leading cause of cancer-related death in China (Siegel et al., 2023). Since symptoms of early gastric cancer are lacking, most cases are diagnosed at an advanced stage. The overall survival (OS) rate for GC remains extremely low. Therefore, biomarkers of the occurrence and progression of GC remain warranted (Sexton et al., 2020).
Co-amplification of genes with ERBB2 on 17q12 is common in GC. The expression of CAB1, GRB7, C51, and ERBB2, in correspondence with amplification, has been reported in primary gastric carcinoma tissues and the GC cell line MKN-7 (Kishi et al., 1997). Simultaneous amplification of GAS and ERBB2 at 17q12-q21 has also been reported (Vidgren et al., 1999). We have previously reported that PGAP3 was co-amplified and co-overexpressed with ERBB2 at 17q12, associated with a poor prognosis in GC (Wang et al., 2023). Therefore, further functional validation of the candidate genes is required.
Migration and invasion enhancer 1 (MIEN1), located on chromosome 17q12, whose protein product is mainly found in the cytoplasm, with only a minor amount expressed on the cytoplasmic side of the plasma membrane, is a primary regulator of cancer cell migration and invasion in breast cancer (Evans et al., 2006). Correlation analysis of copy number aberrations (CNAs) and gene expression levels identified GRB7, MIEN1, PGAP3, and STARD3, which are co-amplified with ERBB2, as potential candidate oncogenes (Kwon et al., 2017). miR-124-5p can inhibit MIEN1 expression, whereas MIEN1 overexpression can reverse the inhibitory effect of miR-124-5p on invasion and migration of GC SGC7901 cells (Liang et al., 2020). However, the function of MIEN1 in GC remains unclear in vivo. The relationship between MIEN1 expression, clinical pathology, and the survival of patients with GC remains largely unclear.
Interleukin-6 (IL-6) is a pleiotropic cytokine involved in cell proliferation, survival, and invasiveness of tumors (Lederle et al., 2011). High expression of IL-6 and exceptional signaling pathways can promote the growth and migration of breast cancer (Hollier et al., 2013), GC (Zhu et al., 2014), and liver cancer (Sugimoto et al., 2015). IL-6 combines with IL-6Rα to induce gp130 homodimerization, thereby inducing Janus kinase 2 (JAK2) phosphorylation to activate downstream signaling pathways (Morris et al., 2018). Signal transducer and activator of transcription 3 (STAT3) regulates tumor growth promotion and immunosuppression (Yu et al., 2009). In the inactive state, STAT3 remains as a monomer in the cytoplasm. Following JAK2 activation, STAT3 is subsequently phosphorylated at Tyr705, leading to STAT3 dimerization and translocation into the nucleus (Xin et al., 2020). In GC tissues, activated STAT3 is commonly accompanied by the secretion of cytokines, specifically IL-6 (Siveen et al., 2014).
Here, we hypothesize that MIEN1’s carcinogenic effects via the IL-6/JAK2/STAT3 pathway are involved in the pathological processes associated with GC. In the present study, we first validated the amplification and overexpression of the MIEN1 gene co-occurring with ERBB2 on chromosome 17q12 in GC NCI-N87 cells. We also assessed the clinical pathology and biological implications of MIEN1 expression in 543 tumor tissues from patients with GC and determined the carcinogenic role of MIEN1 and its involvement in the IL-6/JAK2/STAT3 pathway during gastric tumorigenesis and metastasis in vitro and in vivo.