Hh Signaling Pathway Regulates EMT And Invasion And Metastasis Of Gastric Carcinoma By Targeting STMN1

AIM Hedgehog(Hh)signaling pathway plays an important role in the tumorigenesis and development of gastric cancer.The aim of this study was to investigate the role of Hh signaling pathway dysfunction in the invasion and metastasis of gastric cancer and to explore the underlay mechanism.We detected and analyzed the different expression status of Hh signaling pathway-related protein between gastric cancer tissues and adjacent non-tumor tissues,such as Gli1,Shh,PTCH and SMO.Also,we analyzed the correction between the expression of Gli1 and clinicopathological factors in our data to explore if Hh signaling pathway can promote the invasion and metastasis of gastric cancer.In additional,we investigated the relationship between the expression of Gli1 and STMN1 to elucidate that the Hh signaling prompted the invasion and metastasis of gastric carcinoma via STMN1.At last,we analyzed the association among the expression of STMN1 and Gli1 and the level of the markers of epithelial mesenchymal transition(EMT)to propose a conclusion that Hh signaling pathway facilitated the EMT in gastric cancer and regulated the invasion and metastasis of gastric carcinoma by targeting STMN1.Method A total of 228 patients and 94 adjacent non-tumor tissues receiving the curative surgical intervention due to gastric cancer were recruited from the Department of Gastroenterology of Tianjin Medical University Cancer Hospital from October 2006 to May 2009.All of the tissues enrolled in this study were sent to Beijing Longmaida Biotech Company(Beijing China)for tissue microarrays.Immunohistochemistry was performed to detect the expression of the Hh-related protein,STMN1,and EMT markers.Relationships among Hh-related proteins,STMN11,and EMT-related markers were analyzed by Spearman test.And the relationship among the expression of Gli1,STMN1 and the clinicopathological characteristics were performed by Chi-square test.All significant factors discovered in the univariate analysis was analyzed by the binary Logistic regression.Kaplan–Meier survival curves were performed to describe survival rates,and the log-rank test was performed to testify the difference between negative and positive protein expression.Cox proportional hazard regressions analysis was performed to calculate crude and adjusted hazard ratio(HR),with 95 % confidence interval(CI).Result The Hh-related proteins were overexpressed in gastric cancer tissues compared non-tumor adjacent tissues.In gastric cancer tissues,Gli1 positive expression was present at a high level(73.7%).However in non-tumor adjacent tissues,Gli1 expression was at a low level(34.0%).Similarly,other Hh-related proteins involved in our study were also overexpressed in the tumor samples.Shh?PTCH?SMO expression rate in the cancer tissues and adjacent normal tissues were 63.2% vs.46.8%,76.3% vs.38.3%,56.1% vs.48.9%.STMN11 expression also was present at a very high level(66.7%;152/228)in cancer samples.The expression of Gli1 was significantly connected to the expression of STMN1 in 228 gastric cases(P<0.05).We found that the marker of epithelial cell was decreased in gastric cancer tissue,while the expression of N-cad and Vimentin were increased.In addition,we found a strong negative correction between the expression of E-cad and the expression level of STMN1 and a significant positive association between N-cad with STMN1.Multivariate analysis revealed that the positive expression of Gli1 and STMN1 were independently risk factor for the depth of tumor invasion,and also were independently prognostic factors for poor survival in gastric carcinoma patients.Conclusion Hh signaling pathway was over activated and was involved in the process of invasion and metastasis of gastric cancer.Gli1,the key molecule of Hh pathway was significant associated with the expression of STMN1.In additional,the expression of STMN1 showed a strong negative correction with the expression of E-cad and a significant positive association with N-cad,Vimentin.Thus,We proposed a conclusion that Hh signaling pathway regulated EMT in gastric cancer and facilitated the invasion and metastasis of gastric carcinoma by targeting STMN1.