Relationship Of Mir-140-5p Expression And P53 Function And Contribution To Prognosis Prediction And Treatment Decision Of Patients With Gastric Cancer.

e24185 Background: p53, the most commonly mutated gene in human gastric cancer (GC), acts as an important transcriptional regulator, regulates the cell cycle checkpoint and apoptosis signalling pathways. Its functional status was found to be a vital signature for GC molecular subtyping. MicroRNAs can target p53 directly or other factors in the p53 network, regulating the expression and function of wild-type (or the mutant) p53. Therefore, depending on the wild-type or mutant p53 context, the microRNAs’ changing profile may reflect the suppression or promotion of tumor development and even the tumor response to chemotherapy. Since molecular diagnosis has a great impact on precision medicine decisions, to define the function of p53 is of great importance in GC. Methods: We employed miRNA expression data from TCGA and GEO databases to search for candidate miRNAs which correlate with GC patients’ prognosis and treatment outcomes. qPCR was further carried out in two independent cohorts, one with neoadjuvant chemotherapy and one without, for chemotherapy response and prognosis analysis, respectively. Gene set enrichment analysis (GSEA) was conducted to explore the mechanism. GC cell lines AGS and NUGC4 (p53 wild-type), HGC27, MKN45, cells (p53 mutant-type) were assayed for proliferation, migration and cell viability determination with 5-FU treatment. Results: We identified that GC patients with higher miR-140-5p expression had a better overall survival and disease free survival in intestinal type GC, while an adverse trend in patients with diffuse type GC. GSEA indicated lower miR-140-5p correlated with higher expression of cell-cell adherens junction associated genes. However, upregulation of miR-140-5p in cancer cells with activated p53 increased IC50 of 5-FU. We also confirmed that MDM2 and RBBP6, both of which promote p53 degradation, are targets of miR-140-5p, and may contribute to the cell cycle arrest with drug treatment. Conclusions: These findings suggest that miR-140-5p mediates and reflects the function of p53, and thus may influence the progression and the response of chemotherapy in GC.