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Although emerging evidence has indicated that single nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) are associated with susceptibility to gastric cancer, a limited number of studies have revealed the underlying molecular mechanisms. In the present study, the results suggested that miR-1269a rs73239138 has a role in decreasing the risk of gastric cancer. The level of miR-1269a variant expression was significantly downregulated compared with the wild-type miR-1269a in the gastric cells (Fig. 1). Furthermore, overexpression of miR-1269a inhibited apoptosis of gastric cancer cells. Expression of the miR-1269a variant inhibited the function of miR-1269a by increasing the apoptotic rate and the expression of Bik, Bim and Bak was upregulated consistently. In addition, zinc-finger protein 70 (ZNF70) was identified to be a target gene of miR-1269a, which was downregulated by miR-1269a and upregulated by miR-1269a variant. ZNF70 was indicated to exert a role as a tumor suppressor in gastric cancer. To the best our knowledge, the present study for the first time highlights a critical role of miR-1269a variant rs73239138 in decreasing the susceptibility to gastric cancer by downregulating its expression and targeting ZNF70, which promotes apoptosis of gastric cancer cells. This SNP is indicated to serve as a potential biomarker and therapeutic target for gastric cancer.

Abstract. Oxaliplatin-based chemotherapy is a primary treatment for patients with metastatic colorectal cancer (CRC); however, its efficacy is limited. Therefore, novel therapeutic agents are urgently required. MLN4924 is a first-in-class inhibitor of neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme E1, and has entered various phase-I/II clinical trials for cancer therapy due to its significant anticancer efficacy. The aim of the present study was to examine the synergistic effect and underlying mechanisms of MLN4924 and oxaliplatin combined treatment for CRC. It was demonstrated that MLN4924 treatment induced the DNA damage response (DDR) by inactivating cullin-ring ubiquitin ligases, subsequently leading to cell cycle disturbance and apoptosis in CRC cells. MLN4924 treatment increased the oxaliplatin-induced DDR, G2 cell cycle arrest and apoptosis. Protein expression levels of phosphorylated checkpoint kinase 2 (p-CHK2), p21 and p53, which are well-known functional proteins involved in G2 cell cycle arrest, were assessed. p-CHK2 protein expression levels were increased following combined treatment with MLN4924 and oxaliplatin, whereas p21/p53 protein expression levels were not. In conclusion, MLN4924 treatment may sensitize CRC cells to oxaliplatin treatment by inducing the DDR and increasing protein expression levels of p-CHK2, leading to G2 cell cycle arrest and apoptosis. Therefore, combined MLN4924 and oxaliplatin-based chemotherapy may be a potential therapeutic strategy for the treatment of CRC.

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