The Expression And Clinical Significance Of SOCS3 And GPRC5A In Biliary Tract Cancer

Background and objective: Biliary tract cancer(BTC)is a group of highly heterogeneous tumors originating from the gallbladder and bile duct epithelium,including gallbladder carcinoma and cholangiocarcinoma.The incidence of BTC is low,the onset is insidious,and most of the cases are diagnosed in the late stage.About 20% of the patients can be surgically resected,but the postoperative recurrence rate is high,metastasis is easy to occur,and the prognosis is poor.With the development of a new generation of gene sequencing technology,the molecular mechanism of tumors has been further understood,so that more gene mutations have been detected,bringing a new development for clinical diagnosis and treatment.At present,the main research direction of precision therapy of BTC is to explore the abnormal gene expression in tumor tissue,and to find new targets for drug therapy and effective prognostic biomarkers.JAK/STAT signaling pathway is an important intracellular signaling pathway,which plays an important role in the proliferation and apoptosis of tumor cells.Previous studies have shown that abnormal activation of this signaling pathway exists in various malignant tumor cells,such as breast cancer,cervical cancer and liver cancer,which is closely related to the occurrence,development and drug resistance of tumors.Meanwhile,this signaling pathway is also an important inflammatory response signaling pathway and plays an important role in the regulation of inflammatory response.Suppressor of cytokinesignaling-3(SOCS3)is a member of the negative regulatory protein family of cytokine signal transduction,and is an important inhibitor of JAK/STAT signal transduction pathway.Previous studies have shown that silencing or inhibition of SOCS3 expression promotes malignant proliferation and metastasis of non-small cell lung cancer,gastric cancer,hepatocellular carcinoma,breast cancer and other malignant tumors.G protein-coupled receptor C family 5A(GPRC5A)is a core member of the GPRC.It is a gene induced by all-trans retinoic acid.It has been shown to regulate cell proliferation,differentiation and apoptosis.Recent studies have shown that GPRC5 A is involved in the regulation of the JAK/STAT signaling pathway and plays an oncogenic or tumor suppressive role by activating or inhibiting STAT3 phosphorylation,with positive or negative correlations between GPRC5 A and SOCS3.It is abnormally expressed in colorectal cancer,non-small cell lung cancer,breast cancer and oral squamous cell carcinoma.The expression was decreased in oral squamous cell carcinoma and non-small cell lung cancer,but up-regulated in gastric cancer and colorectal cancer,the expression of GPRC5 A is correlated with the survival and prognosis of tumor patients.At present,the expression and clinical significance of SOCS3 and GPRC5 A in BTC had never been elucidated,and there are few related studies,so the study will explore the expression of SOCS3 and GPRC5 A in BTC,analyze the relationship between them and the clinicopathological features of BTC,and explore the relationship between them and the prognosis of BTC patients.Methods: We collected the clinical and pathological data of the patients with BTC who underwent surgical treatment at Zhengzhou University Affiliated Cancer Hospital from January 2015 to December 2020,the wax specimens of cancer tissues and adjacent non-tumor tissues.Immunohistochemical method was used to detect the expression levels of SOCS3 and GPRC5 A in cancer tissues and adjacent non-tumor tissues.The χ2 test was used to analyze the relationship between the expression of SOCS3 and GPRC5 A and the clinicopathological features of BTC.Kaplan-Meier method was used for univariate survival analysis and curve drawing,and Cox proportional hazard regression model was used for multivariate analysis of prognosis.Result: 1.SOCS3 was mainly expressed in the cytoplasm of BTC and adjacent non-tumor tissues,with a positive expression rate of 42.3% in BTC and 67.3% in adjacent nontumor tissues.Statistical analysis showed that the positive expression of SOCS3 in BTC tissues was significantly lower than that in adjacent non-tumor tissues,and the difference was statistically significant(P = 0.002).The expression of SOCS3 was correlated with tumor differentiation(P = 0.045)and TNM stage(P = 0.036),but not with sex(P = 0.576),age(P = 0.708),CA-199(P = 1.000),CEA(P = 0.780),tumor location(P = 0.569),pathological type(P = 0.753)and lymph node metastasis(P = 0.576).2.The expression of GPRC5 A was mainly in the cell membrane,some in the cytoplasm.In BTC,the positive expression rate of GPRC5 A was 55.8%;in adjacent non-tumor tissues,the positive expression rate of GPRC5 A was 32.7%.Statistical analysis showed that the positive expression of GPRC5 A in BTC tissues was significantly higher than that in adjacent non-tumor tissues,and the difference was statistically significant(P = 0.043).The expression of GPRC5 A was correlated with tumor differentiation(P = 0.001),lymph node metastasis(P = 0.023)and TNM stage(P = 0.001),but not with sex(P = 0.259),age(P = 0.721),CA-199(P = 1.000),CEA(P = 0.403),tumor location(P = 0.280)and pathological type(P = 0.539).3.Spearman correlation test showed there was no correlation between the expression of SOCS3 protein and GPRC5 A protein in BTC(r = 0.214,P = 0.128).4.Survival analysis showed that the m OS of SOCS3 positive group was 19.6 months and the m OS of negative group was 19 months.The m OS of SOCS3 positive group was higher than that of negative group.There was no significant difference in SOCS3 expression between positive group and negative group of m OS(P =0.921).The m OS of the GPRC5 A positive group was 15.7 months,and negative group was 31.5 months.The m OS of the GPRC5 A positive group was significantly lower than negative group(P =0.017).5.Kaplan-Meier univariate analysis showed that tumor differentiation(P = 0.023),lymph node metastasis(P = 0.002),TNM stage(P = 0.017)and GPRC5 A expression(P = 0.017)were correlated with OS.The results of Cox multivariate analysis showed that lymph node metastasis(HR 0.307,95%CI 0.113-0.834,P =0.021)and GPRC5 A expression(HR 2.258,95%CI 1.052-4.864,P =0.037)were independent prognostic factors of OS in patients with BTC.Conclusions: 1.The expression of SOCS3 in BTC tissues was lower than that in adjacent nontumor tissues,while the expression of GPRC5 A in BTC tissues was higher than that in adjacent non-tumor tissues.2.In BTC,the expression of SOCS3 is related to the degree of tumor differentiation and TNM stage,while the expression of GPRC5 a is related to the degree of tumor differentiation,lymph node metastasis and TNM stage,suggesting that both of them may be involved in the invasion and metastasis of BTC.3.GPRC5 A may be an independent risk factor for poor prognosis in patients with BTC.