| Background: Gastric cancer is the most deadly digestive tumor in the world.Because of the lack of early symptoms of gastric cancer and effective early diagnosis methods,many patients were already in advanced stages when they were found.At this time,the effect of simple surgical treatment is not ideal,adjuvant chemotherapy has become an important treatment.As a more important treatment method,cisplatin is widely used as a representative of platinum drugs for chemotherapy of gastric cancer and other digestive tract tumors.However,the emergence of drug resistance leads to lower remission rate of gastric cancer patients,and complete remission is extremely rare.Previous studies have found that the platinum-resistant mechanism of tumor cells involves multiple links,multiple signaling pathways,and multiple regulatory aspects,and this highlights the difficulty of overcoming clinical resistance.However,cisplatin plays an important role in the clinical treatment of gastric cancer.Therefore,finding an effective cisplatin therapeutic target for improving the prognosis of gastric cancer patients and increasing their survival rate is of utmost importance.Cullin-RING E3 ubiquitin ligases(CRLs)are the largest E3 ligase family in eukaryotes,in the CRL ubiquitin ligase complex,the substrate recognition subunit protein(SRS)is mainly used to identify and recruit substrate proteins.Different cullin proteins have different substrate recognition subunits.For example,SKP2 is a substrate recognition subunit of the SCFSKP2 ubiquitin ligase complex.It has been extensively studied that SKP2 is highly expressed in various tumors,and the reduction of SKP2 expression level by RNA interference technology can inhibit the growth of various tumors.DDB1 and Cullin 4 associated factor 12(DCAF12)as another substrate recognition receptor has been shown to be abnormally expressed in many tumors.Objective: The purposes of this study were to investigate the role of DDB1 and Cullin 4 associated factor 12(DCAF12)in gastric cancer and its effect on the sensitivity of chemotherapeutic drug cisplatin(DDP)after it were knockdown,and to provide a new idea for solving the clinical resistance to cisplatin.Methods: According to the TCGA Cancer Database,our group found that DCAF12 is highly expressed in different stages of gastric cancer.We reduce the expression of DCAF12 in MGC803 gastric cancer cells through RNA interference technology.After treatment with DDP,the cloning experiments was used to assesse the proliferation of cells,therefore we can analyze the sensitivity of MGC803 cells to cisplatin when DCAF12 were knockdown.And by the method of co-immunoprecipitation(IP),we sought the downstream substrate of DCAF12 and explored their interaction.Results: The expression level of DCAF12 in gastric cancer tissues was significantly higher than that in adjacent normal tissues.After treatment with DDP in gastric cancer cell line MGC803,the proliferation ability of the knockdown of DCAF12 group was significantly lower than the NC group,while the overexpression of DCAF12 group was more proliferative than NC group.Through the post-IP eluent mass spectrometry it was found that the downstream of DCAF12 might interact with XIAP,CCT1,etc.Conclusions: 1.DCAF 12 is highly expressed in gastric cancer,suggesting a potential association with gastric cancer.2.DCAF12 is involved in the regulation of cisplatin sensitivity in gastric cancer cells.3.The sensitivity of DCAF12 to regulate gastric cancer cells to cisplatin is potentially related to downstream substrates XIAP and TCP1. |
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