| Background and objectiveGastric cancer is the second leading cause of cancer death around the world. Many cases failed to be diagnosed until middle or late stage and lost the chance of operation. What we need now is looking for a new treatment and prognosis target. G protein coupled receptor kinase6(GRK6) is an important serine/threonine kinase in the human body, belonging to the GRK superfamily. By making GPCR phosphorylation, GRK can improve the affinity between GPCR and arrestins, the formed heterotrimer then induce GPCR desensitization and endocytosis, thereby blocking the downstream signal transduction. Present studies revealed that GRK6play an important role in the development of a variety of malignant tumors. Lack of GRK6can promote the proliferation and metastasis of lung cancer cells, GRK6is also one of the important kinases for multiple myeloma, and related to the poor prognosis in hepatocellular carcinoma, but at present the role of GRK6in gastric cancer is less reported. In this study, we examined the expression of GRK6in gastric cancer by using immunohistochemical method (SP), and explore the relationship between GRK6and related clinicopathological parameters and prognosis of survival, in order to provide some guidance for clinical treatment.Materials and MethodsChoose142gastric cancer samples from Provincial Hospital affiliated to Shandong University from January2007to December and make them into tissue microarray. All these cases were confirmed by pathology and none of them were given radiotherapy or chemotherapy before operation. Among them,132cases have complete follow-up data, including100male patients and32female patients. There were120cases of gastric adenocarcinoma, contained tubular adenocarcinoma, papillary adenocarcinoma and mucous cell carcinoma and signet ring cell carcinoma. According to the seventh edition of TNM staging system,7cases in stage Tis,24cases in stage â…¡,15cases of stage â…¡,67cases with stage â…¢, and7cases in stage â…£. It also included4cases of malignant stromal tumor,3cases of neuroendocrine tumor,3cases of ulcer type squamous carcinoma,1case of lymphoma,1case of sarcomatoid carcinoma, and8cases of gastric benign lesion tissue as control. By tissue microarray and immunohistochemical technique, we examined the GRK6expression in the132cases of gastric malignant tumors and8cases of benign gastric disease. All the data were processed by spss19.0software, using the chi square test and the multi-factor Logistic regression to analyze the relationship between expression of GRK6and clinical pathological data, the Long-rank and Kaplan-Meier test to carry out univariate survival analysis and draw the survival curve, cox regression analyse the prognosis factors.Results1. The expression of GRK6in gastric adenocarcinoma cells were mainly distributed in the cytoplasm. Gastric malignant lymphoma, neuroendocrine tumor squamous cell carcinoma can also be seen the expression of GRK6, and the expression level is different. There is no expression of GRK6protein in gastric benign lesions or only low expression, and mainly in the cell membrane.2. Chi square test showed positive expression of GRK6has no obvious correlation with gender, age and distant metastasis, but is associated with the depth of invasion, and tumor lymph node metastasis, tumor differentiation degree, the difference has statistical significance (P<0.05). Further multiple factor Logistic regression analysis found GRK6expression was only related to the degree of differentiation (P<0.05).3. In survival analysis,5year survival rate of patients with high expression of GRK6was28.81%, significantly lower than the low expression67.21%, the difference between the two with statistical significance (P<0.05). The median survival period of cases with high expression of GRK6was24months, more than half of lower expression cases were still alive at the end of follow-up.4. Univariate Long-rank test found prognosis of patients is related to age, tumor invasion depth, lymph node metastasis, distant metastasis, chemotherapy treatment and expression of GRK6(P<0.05). Multivariate Cox regression analysis showed the expression of GRK6were independent prognostic factors for gastric cancer (P<0.05). Conclusions1. GRK6was not expressed in benign diseases or only low expression in membrane, while in tumor tissues GRK6mainly expression in the cytoplasm, and the intensity was significantly higher than in benign diseases. Different position and degree of expression in benign and malignant diseases hinted that GRK6can be used as a new therapeutic target.2. The expression of GRK6is associated with differentiation. The less differentiation degree, the stronger expression, suggesting GRK6expression is related with the malignant degree of tumor, but with age, sex, T stage, N stage, M stage had no significant correlation.3. The5year survival rate of patients with high expression of GRK6was significantly lower than in patients with low expression. As an independent adverse prognostic indicator, GRK6can help to discover gastric malignant tumor and the evaluation of the prognosis of patients. A few cases of rare stomach malignant tumor also see GRK6expression, the expression level has certain differences, but failed to do further analysis because of too little cases.4. GRK is involved in the regulation of multiple signaling pathways; their activity is regulated by many signaling pathways and protein kinases. All related moleculars and signaling pathways formed complex networks. Different GRK subtypes and the corresponding pathways present different effects in malignant tumors, the mechanism need further research. |
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