| Cancer is one of the biggest threat to human life, study on the mechanism of cancer development is a hotspot and foreland. There is a common point in both tumor and embryo: fast cell division. It has been long speculated that the signaling pathway genes related to embryonic development, may play an important role in carcinogenesis. This hypothesis was confirmed in basal cell carcinoma(BCC) firstly. Patched(Ptc), one of Hedgehog signaling pathway genes, has much to do with embryonic development, was found to lose of function at early stage of carcinogenesis. And the function of Ptc varies with the quantity of Ptc gene expression. This find presents a new target of investigational drug for cancer therapies.Hedgehog signaling pathway, is crucial for the development of various embryonic development. Abnormal function of Hh pathway results in kinds of human diseases and cancers, including BCC, brain cancer, lung cancer, prostate cancer, pancreatic cancer and other gastrointestinal tumours. The studies indicated that inhibition of this pathway could delay tumor growth in childhood brain tumor and some kinds of lung cancers. Therefore, research on Hh pathway is very important for both basic science and clinic science.Gastrointestinal cancer is frequent in Chinese. Gastric and oesophageal cancer are the most common upper gastrointestinal malignancies in China. Study on the mechanism of Hh signaling pathway in upper gastrointestinal cancers, is very important for cancer preventiion and therapy. Works on animal model indicate, Hh pathway is crucial for gastrointestinal development. To investigate if abnormal Hh pathway could cause gastrointestinal cancers, a research group in John-Hopkins University, leaded by Philip Beachy, has analyzed cancers of esophagus, stomach, pcncreas, cholecyst and colon. In the first 4 kinds of cancers, activity of Hh, Ptc and Gli were found 20~5000times increase in tumors than that in normal tissues.However Beachy mainly used cell lines as research objective, and only worked on few genes. For the moment , at transcript level, no systemic report about expression of Hh signaling pathway in gastrointestinal cancers.We systemically studied the expression of Shh pathway-related molecules (Shh, Ptc1, Gli1, Gli3, Sufu) in upper gastrointestinal embryonic development and tumor tissues, by in situ hybridization, immunohistochemistry and RT-PCR.To discuss the role of these genes in upper gastrointestinal development and carcinogenesis, and manage to get new data to clarify the related molecule mechanism of upper gastrointestinal development and carcinogenesis, to provide theoretical foundation for clinical diagnoses, prevention , cure and exploiture of new drugs.New discovery of this study:1 , Statistical analysis was done on the expressions of Keratin, CyclinB1, CDK1, PCNA and Ki67.There was significant difference between carcinoma tissues and paracarcinoma tissues. A significant difference between well differentiated adenocarcinoma, moderate differentiated adenocarcinoma and poorly differentiated adenocarcinoma was found also. No significant difference was found between early stage group (â… ,â…¡) and late stage (â…¢, â…£) group.2, In tuomr tissues , the number of DNA copy is a little higher than that in paracarcinoma normal tissues.3 , The expression of Shh and Ptc1 on translation level:(1) In embryonic upper gastrointestinal tissues, Shh and Ptcl were expressed in mucosa layer, submucosa layer, not expressed in muscular layer of esophagus and stomach.(2) Shh, Ptcl expression weren't found in esophageal paracarcinoma squamous epithelia, but highly expression was found in squamous cell in esophageal squamous cell carcinoma(ESCC),which were consistant with the expression of PCNA and Ki67, namely , there was a significant difference between well differentiated adenocarcinoma, moderate differentiated adenocarcinoma and poorly differentiated adenocarcinoma.(3) In stomach paracarcinoma tissues, Shh was expressed in mucous layerepithelial cell, boundary of gastric pit and stomach gland. Low or no expression wad found in stomach fundic gland. Ptc was expressed in lamina propria. In gastric adenocarcinoma, the epithelial expression of Shh and Ptc has positive correlation with cancer malignant degree.4% Expression of Hh signaling pathway- related moleculars in upper gastrointestinal embryonic tissues and cancer tissues on transcription level.(1) In upper gastrointestinal embryo tissue, Expression of Shh, Ptcl, Glil, Sufu and Gb'3 differ in varied period, embryonic tissues.(2) In esophageal paracarcinoma tissue, Shh,Ptcl,Glil,Gli3 and Sufu were not expressed in squamous cells, except sufu. In esophageal squamous cell carcinoma, the expression of Shh , Ptc and Glil has positive correlation with malignant degree.GH3 expression was not detected while Sufu expressed.(3) In stomach paracarcinoma tissue, Shh,Ptcl,Gli] were expressed in columnar epithelium of gastric pit, and weak or no expression was found in gland epidermis of lamina propria. In gastric adenocarcinoma tissues, the expression of Shh, Ptc and Glil in gland epithelium of lamina propria was strong , and has positive correlation with malignant degree.Gli3 expression was not detected in both paracarcinoma and carcinoma tissues while Sufu expression can be found.(4) In different types of stomach cancers, the expression of Shh pathway-related molecules was different.There is a high expression of Shh pathway-related genes in gastric adenocarcinoma, squamous cell carcinoma and stromal tumor. However, in signet ring cell carcinoma, no expression of Shh, Ptch], Glil, GH3 was detected. Conclusion:1 -. There existed significant and positive correlation between expression of Keratin, CyclinBl, CDK1, PCNA, Ki67, and pathology grade while no correlation with clinic stage. High expression of these antigens is an important biological parameter for upper gastrointestinal tumors' diagnosis and therapy.2^ In upper gastrointestinal tumors, expression of Shh mRNA is higher than in paracarcinoma normal tissue. There are strong correlation between the expression and tumor cell invasion and metastasis, It might be the reason of the increase of the DNAcopies.3^ The activation of Shh-Ptc-Glil pathway in upper gastrointestinal decelopment indicate the important role of Hh signaling pathway in gastrointestinal development.4^ The abnormal activation of Shh-Ptc-Glil pathway in esophageal squamous cell carcinoma, indicate the role of hedgehog signaling pathway in it.5n The abnormal activation of Shh-Ptc-Glil pathway in gastric adenocarcinoma, squamous cell carcinoma and stromal tumor, might be one inducement of carcinogenesis. But in signet ring cell carcinoma, No abnormal expression of Shh molecules was detected. All of those suggests that, there might be different mechanism of gastric carcinogenesis.6% Sufu was expressed in both embryonic and tumor tissues while no expressed in normal adult tissue, further discussion about its biological function is needed. Taken together, our achievements are as follows:( 1) First to systemic study on the expression of Shh pathway-related molecules (Shh, Ptcl, Glil, gli3 and Sufu) in upper gastrointestinal cancer tissues on nucleic acid and Protein level. The results indicate the relationship between activation of Shh-Ptc-Glil signaling pathway and upper gastrointestinal carcinogenesis, support the theory that Shh signal could induce adjacent cells differentiation through epithelial-mesenchymal interaction.(2) The expression of Shh signaling pathway-related moleculars were studied in kinds of primary stomachic cancers for the first time. The activation of Shh signaling was found in gastric adenocarcinoma, squamous carcinama and stromal tumor, no expression was found in Signet ring cell carcinoma, which indicate the complicacy mechanism of gastric carcinogenesis.(3 ) For the first time to study of the expressions of Shh signaling pathway-related moleculars (Shh, Ptc, Gli 1, GH3 and SuFu) in embryonic upper gastrointestinal tissues and found its expression pattern in human upper gastrointestinal embryonic tissue.This study will provide new data for elucidating the mechanism of Hh signaling pathway in human upper gastrointestinal tumors and development.
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