Abstract
Gastric cancer is one of the most common primary tumors of the digestive system. NADH: ubiquinone oxidoreductase subunit C1 (NDUFC1), which is an accessory subunit of the NADH dehydrogenase (complex I), is responsible for the transportation of electrons from NADH to the respiratory chain essential for the oxidative phosphorylation. However, little is known about the roles of NDUFC1 in carcinogenesis. In this study, NDUFC1 protein level in NSCLC tissues was tested by immunohistochemistry (IHC) staining. NDUFC1 mRNA level in gastric cancer cell lines was determined by qRT-PCR. MGC-803 and SGC-7901 cells were transfected with shNDUFC1 lentivirus designed to silence NDUFC1. MTT assay, CCK8 assay, wound healing assay and transwell migration assay were conducted. Cell cycle and apoptosis were detected by flow cytometry. In vivo experiments were performed using nude mice. The results indicated that overexpressed NDUFC1 in gastric cancer was related to more serious tumor infiltrates, a higher risk of lymphatic metastasis, a higher proportion of positive lymph nodes, and a more advanced tumor stage. Compared with shCtrl groups, MGC-803 and SGC-7901 of shNDUFC1 groups had lower abilities of proliferation and migration, higher levels of apoptosis. NDUFC1 knockdown also inhibited SGC-7901 cell growth in vivo and suppressed Ki67 expression in xenograft tumors. More importantly, we found that NDUFC1 downregulation made the levels of P-Akt, P-mTOR, CCND1, CDK6, PIK3CA, Bcl-2, Survivin, and XIAP decreased, and that PI3K/AKT signaling pathway agonist SC79 rescued the inhibitory effects on cell proliferation and migration, reversed the promoted effects on cell apoptosis caused by NDUFC1 knockdown. More importantly, compared with NDUFC1 knockdown group, the expression of P-Akt, Bcl-2, Survivin, and XIAP was raised in shNDUFC1 + SC79 group. Thus, our suspicion was that NDUFC1 exacerbates NSCLC progression via PI3K/Akt pathway. Taken together, our study indicated that targeting NDUFC1 could open innovative perspectives for new multi-targeting approaches in the treatment of gastric cancer.
Highlights
Gastric cancer is one of the most commonly diagnosed malignant tumors originating from the digestive system [1, 2]
To investigate the role of NDUFC1 in the development of gastric cancer, we used immunohistochemical (IHC) analysis to compare the expression of NDUFC1 in tumors collected from patients with gastric cancer and those collected from normal tissues
This demonstrated that high expression levels of NDUFC1 were positively correlated with more serious tumor infiltrates, a higher risk of lymphatic metastasis, a higher proportion of positive lymph nodes, and a more advanced tumor stage, which was confirmed by Spearman rank correlation analysis (Table 3)
Summary
Gastric cancer is one of the most commonly diagnosed malignant tumors originating from the digestive system [1, 2]. Molecular targeted therapy has been considered as one of the most promising treatments for gastric cancer, which is facilitated by the development of molecular mechanisms of malignant biological behaviors such as proliferation, growth, invasion, and metastasis of gastric cancer [5,6,7,8]. The in-depth study of the molecular mechanism of gastric cancer could contribute to develop novel therapeutic target and improve pharmaceutical efficiency of gastric cancer. NADH dehydrogenase is one of the two key rate-limiting enzymes in the de-electronization of substrates, whose activity determines the oxidation efficiency of substrates [12]. We presented the first report of the relationship between NDUFC1 expression and development of gastric cancer. We identified NDUFC1 as a tumor promotor in gastric cancer, which may be a promising therapeutic target for treatment of gastric cancer
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