1. Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, P.R. China.
2. Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, P.R. China
*Dr. Xiaoli Wei and Jiejie Zhu contributed equally to this work and serve as co-first authors.
MiRNAs have been widely reported to be involved in the occurrence and development of cancers. So far, some studies have revealed that miR-338-5p has the functions of tumorigenesis and tumor suppression. However, the role of miR-338-5p in the pathogenesis, progression and treatment of gastric cancer (GC) has not been reported. MiRNAs microarray analysis showed for the first time that miR-338-5p was significantly lower-expression in cisplin-resistant GC cells SGC7901/DDP, and cell viability assay and flow cytometry confirmed that overexpression of miR-338-5p could significantly increase cisplatin-sensitivity of SGC7901/DDP and BGC823 cells. Subsequently, we found that the expression of miR-338-5p in postoperative cancer tissues of GC patients was also significantly lower than the corresponding paracancer tissues. The expression of miR-338-5p in peripheral blood serum of GC patients is generally lower than that of healthy people. Moreover, the low expression of miR-338-5p in the cancer tissues and serum of GC patients was closely associated with larger tumor volume, lymph node metastasis, later stage, and even poorer survival, which was confirmed by close 5-year cases follow-up. ZEB2, as a predictive target of miR-338-5p, its expression was negatively regulated by miR-338-5p and can promote cisplatin-resistance in SGC7901/DDP and BGC823 cells. The expression of ZEB2 in cisplatin-resistant SGC7901/DDP cells and GC tissues were significantly higher than SGC7901 cells and paracancer tissues, respectively. Moreover, the expression of ZEB2 in tumor tissues was negatively correlated with miR-338-5p in tumor tissues and peripheral blood serum of GC patients, and the abnormally high expression of ZEB2 in prospective case studies is positively related with more serious clinical pathology and worse survival. More meaningfully, in a retrospective case study, we found that high ZEB2 expression predicts worse clinical efficacy of platinum chemotherapy. Thus, miR-338-5p-ZEB2 axis have novel diagnostic, therapeutic predictive, and prognostic value in GC patients.
Keywords: Gastric cancer, miR-338-5p, ZEB2, cisplatin resistance