Study On Expression Of COX-2 And MTOR Signaling Pathway In The Peutz-Jeghers Polyps

BackgroundPeutz-Jeghers syndrome(PJS) is a rare autosomal dominant hereditary disease characterized by gastrointestinal hamartomatous polyps and mucocutaneous melanin deposition.In earlier studies,PJS polyps were thought to be hamartomatous or hyperplastic polyps which had rare risk of risk of canceration.Along with the research on PJS,it is found that some PJS polyps are adenomatoid polyps which have higher risk of canceration.But there is no conclusion whether the adenomatous polyposis is evolved from hamartomas,or the PJS hamartoma and adenoma are two different clinical subtypes of its own.PJS polyps is not only a higher rate of cancer risk with digestive tract,but usually with much of organs outside the gastrointestinal tract,incidence of cancer in PJS families is higher than the general population.PJS patients up to repeated intussusception,gastrointestinal bleeding and abdominal pain mainly gastrointestinal polyps many hair after treatment by surgical resection of high recurrence rate,a serious threat to their health and life,society and the family give a heavy burden.At present,PJS-related gene,PJS polyps canceration mechanism has not been completely clarified,there is no intervention to cure and prevention of malignant transformation of PJS morbidity and the occurrence of polyps.Cyclooxygenase-2(Cyclooygenase,COX-2) are in the process of prostaglandin synthesis of the key rate-limiting enzyme in the tumor occurrence and development, transfer,inhibitor of apoptosis and the promotion of tumor angiogenesis,such as play an important role,while the targets and specific inhibitors of COX-2(NSAIDs,etc.), has become a tumor chemoprevention agents;studies have shown that COX-2 is the early case in the evolution of the colon adenoma to adenocarcinoma, epidemiological studies have proved taking COX-2 selective inhibitors and non-selective inhibitors will enable the risk of colon cancer decreased;the present study found that COX-2 at PJS nude models and in patients with PJS hamartomatous polyps in the increased expression,but not yet in the malignant transformation of PJS polyps assessment process.Mammalian target of rapamycin,mTOR(mammalian target of rapamycin, mTOR) is a serine/threonine kinase,an acceptable growth factor,nutrition,energy and many other signals,cell growth and proliferation are key regulatory molecules, and in tumor formation,the development process,but also plays an important role in everolimus,so put mTOR as a relevant therapeutic target of tumor targeted therapy has become the new hot spot for a research,that rapamycin mTOR inhibitor (Rapamycin) and its derivatives add Letrozole(temsirolimus,CCI-779),according to Division(everolimus,RAD001) in the treatment of tumor has aroused widespread public concern,the current CCI-779 has been FDA approved for the treatment of advanCed renal cell carcinoma and become a primary liver cancer,bile duct cancer and esophageal cancer,breast cancer,neuroendocrine tumors,lymphoma potential targeted therapy drugs;In addition,mTOR inhibitors has also become the tuberous cerebral sclerosis(TSC),PTEN hamartoma syndrome benign tumors,such as potential therapeutic drugs;recently,Michael N.and other scholars at cell level study shows that STK11 gene mutation may be mTOR signaling pathway caused by the excessive activation,suggesting that mTOR inhibitor rapamycin and PJS is expected to become potential therapeutic drugs.There is no mTOR signaling pathway in PJS polyps in the evolution of pathological studies have reported.Therefore this issue at great collection of PJS patients with information and samples on the basis of the proposed the clinicopathological features of its analysis, and to explore the COX-2 molecules and mTOR signaling pathway in PJS polyps in the evolution of expression,for the prevention and treatment of malignant transformation of PJS polyps provide new ideas.Materials and Methods:1.Retrospective analysis of 2001 -2008 from 19-year pedigree of the 26 PJS patients with clinical features and genetic characteristics,and 74 polyps for the site, size and histology types of analysis;2.Collected on behalf of PJ polyps at different stages of evolution of tissue samples:20 normal mucosa,36 PJS hamartomas,22 hamartomas with dysplasstic changes,and 2 PJS carcinomas,in addition,20 colon adenocarcinoma to do the control specimens.Immunohistochemistry was performed to examine COX-2 expression in different tissues.3.In the serial sections using in situ hybridization on these specimens mTOR Detect the mRNA expression by immunohistochemical assay mTOR,p-mTOR and S6K expression.Results:1.46%(12/26) patients have a clear family history,46%(12/26) patients are sporadic,and the offspring of sporadic cases also have the incidence.2.After analysis of histology type of 74 PJS polyps in 26 cases of patients,we found three stages of PJ polyps,that is,68%(50/74) PJS hamartomas,30%(22/74) hamartomas with dysplasstic changes and 2.7%(2/74) PJS carcinomas.At the same time,through changes in adenomatous polyps in PJ Immunohistochemical Ki67 staining,Ki67 can be drawn adenomatoid change happen regional and distinguish between normal epithelial and reliably reflect the changes happen gland adenomatoid proliferative activity of the body.3.Through the analysis of PJ polyps histology type,size and location of the distribution,shows that 78%(39/50) PJ hamartomatous polyps 20mm in diameter at the following,and is widely distributed in the entire digestive tract;72%(16/22) PJ adenomatous polyps become more than 30mm in diameter,of which 45%(10/22) of adenomatous polyps PJ change happen at the sigmoid colon,40%(9/22) at caecum happen.4.COX-2 expression level of PJ polyps with malignant transformation of the evolution process of gradually increased:COX-2 expression in normal colorectal mucosa negative or only 15%(3/20) with mild to moderate expression,but in hamartomatous PJ polyps,COX-2 expression began to increase,and as from normal mucosa→PJ hamartomatous polyps→PJ hamartomatous polyps with dysplasstic changes→colon adenocarcinoma,expression gradually increased,COX-2 expression rate and intension were significantly different from the above groups (Kruskal-Wallis H test,χ~2=41.238,P=0.000).5.Situ hybridization results showed that:In normal mucosa,PJ hamartomatous polyps,PJ hamartomatous polyps with dysplasstic changes and colon adenocarcinoma,mRNA of mTOR positive expression rate followed by 15%(3/20), 47.2%(17/36),61.9%(13/21) and 80%(16/20),which was significantly different from different groups(R×Cχ~2 test,χ_p~2=18.293,P=0.000).6.Immunohistochemical results showed that mTOR,p-mTOR and S6K at various stages of malignant transformation of PJS polyps expression there was a significant difference(χ~2=9.927,22.508,8.034,P＜0.05),and p-mTOR and S6K in adenomatous polyps and variable PJ colorectal carcinoma the positive rates were 42.9%(9/21),70%(14/20) and 52.4%(11/21),65%(13/20),significantly higher than that of normal mucosa and hamartomatous polyps in group expression,the positive rates were 15.0%(3/20),13.9%(5/36) and 15.0%(3/20),19.4%(7/36).Conclusion:1.PJS sporadic cases were incompatible with autosomal dominant inheritance of genetic disease,and offsprings of sporadic cases may also have the incidence.2.The results support the mode "PJ hamartomatous polyps→PJ hamartomatous polyps with dysplasstic changes→colon adenocarcinoma"3.The study suggests that more than 3cm in size and is located in the sigmoid colon and ileocecal PJ polyps have higher risk of malignant transformation. 4.COX-2 expression with the malignant transformation of PJ polyps gradually increased in the evolution of the process.5.mTOR signaling pathway is excessive activation with the malignant transformation of PJ polyps.