Abstract
BackgroundUFM1 has been found to be involved in the regulation of tumor development. This study aims to clarify the role and potential molecular mechanisms of UFM1 in the invasion and metastasis of gastric cancer.MethodsExpression of UFM1 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was analyzed by Western blotting, immunohistochemistry, and realtime PCR. Its correlation with the clinicopathological characteristics and prognosis of gastric cancer patients was analyzed. The effects of UFM1 on the invasion and migration of gastric cancer cells were determined by the wound and trans-well assays, and the effect of UFM1 on subcutaneous tumor formation was verified in nude mice. The potential downstream targets of UFM1 and related molecular mechanisms were clarified by the human protein kinase assay and co-immunoprecipitation technique.ResultsCompared with the corresponding adjacent tissues, the transcription level and protein expression level of UFM1 in gastric cancer tissues were significantly downregulated (P < 0.05). The 5-year survival rate of gastric cancer patients with low UFM1 expression was significantly lower than the patients with high UFM1 expression (42.1% vs 63.0%, P < 0.05). The invasion and migration abilities of gastric cancer cells with stable UFM1 overexpression were significantly decreased, and the gastric cancer cells with UFM1 stable knockdown showed the opposite results; similar results were also obtained in the nude mouse model. Further studies have revealed that UFM1 could increase the ubiquitination level of PDK1 and decrease the expression of PDK1 at protein level, thereby inhibiting the phosphorylation level of AKT at Ser473. Additionally, the effect of UFM1 on gastric cancer cell function is dependent on the expression of PDK1. The expression level of UFM1 can improve the poor prognosis of PDK1 in patients with gastric cancer.ConclusionUFM1 suppresses the invasion and metastasis of gastric cancer by increasing the ubiquitination of PDK1 through negatively regulating PI3K/AKT signaling.
Highlights
Ubiquitin-fold modifier 1 (UFM1) has been found to be involved in the regulation of tumor development
UFM1 is downregulated in gastric cancer By qPCR analysis, we found that the transcription level of UFM1 was downregulated in gastric cancer tissues (n = 93, 80.2%) compared with the corresponding adjacent tissues (Fig. 1a)
Using Western blot analysis, we confirmed that protein expression levels of UFM1 were significantly lower (n = 44, 41.9%) in tumor tissues compared with the corresponding adjacent nontumor tissues (n = 61, 58.1%, Fig. 1b, c) among 105 gastric cancer patients
Summary
UFM1 has been found to be involved in the regulation of tumor development. This study aims to clarify the role and potential molecular mechanisms of UFM1 in the invasion and metastasis of gastric cancer. UFM1 is a small molecule ubiquitin protein that was first discovered by Komatsu et al in 2004 [4] It consists of 85 amino acids, has a modification function similar to that of ubiquitin, which is covalently bound to other proteins such as ubiquitin molecules. As an important transduction molecule of PI3K signaling pathway, the binding of PDK1 to PIP3 plays an important role in the activation of AKT and other kinases. It regulates a large number of AGC protein kinase family members to control cellular responses and in physiological processes such as cell growth, proliferation and survival. It is generally believed that GSK3β is a tumor suppressor, and the activity of tumor cells is related to the inhibition of GSK3β, and is a downstream molecule of PI3K/ AKT pathway
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