| [Background and Purpose]Colorectal cancer is a malignant tumor which serious threat to human health in ourcountry. Because of serrated lesions with malignant potential of CRC, attractwidespread attention in recent years. WHO (2010) digestive system tumor classificationis defined serrated lesions as: a group of lesions that characterized by the serratedstructure, include:①hyperplastic polyp, according to the type of mucus is divided intomicrovesicula HP, goblet cell rich HP, mucin poor HP;②sessile serratedadenoma/polyp;③traditional serrated adenoma;④serrated adenocarcinoma. Theselesions is a continuous spectrum, there is significant heterogeneity, with specialmolecular changes that present a new cancer approach which same as the classic"adenoma–carcinoma sequnce ", called the serrated pathway. Latest studies suggestedthat60%of colon cancer are from ordinary adenomas,35%from serrated pathway,especially from CpG island methylation phenotype of serrated lesions. Serrated pathwayis a complex process with continuous multi-factor, multi-stage, multiple genes changeand gradual accumulation. Epigenetic changes involves in many kinds of cancer andtumor suppressor genes, abnormal changes of these gene leads to the special structure ofserrated lesions. DNA methylation is a main regulatory mechanism of epigenetics,abnormal methylation will cause suppressor gene expression silence, even leading to theoccurrence of tumor.RUNX3is a newly found tumor suppressor genes in recent years, located in humanchromosome1p36.1, RUNX3protein play an important role in the TGF-beta signaling pathways. The expression down or silence of RUNX3gene plays an importantrole in a variety of human tumors, promoter CpG island hypermethylation is the mainmechanism of RUNX3gene inactivation. The study found that RUNX3gene guidanceTGF-beta signal transduction and inhibition of cell proliferation and promote apoptosis,which plays an important role in the pathogenesis of colorectal cancer, but there is noreport about RUNX3gene in epigenetic changes of serrated pathway. In this study, weused taqman probe-based real-time quantitative PCR to analysis serrated lesions ofRUNX3gene promoter CpG island methylation status. And observed the RUNX3protein expression and analysed the relationship between the RUNX3gene methylationand RUNX3protein expression, to explore its role in serrated lesions and serratedcarcinogenesis pathway.[Method]A total of291cases of serrated lesions from the Beijing Military Region GeneralHospital during2007-2012years were retrospectively reviewed. All slices wereclassified based on WHO standards. Screened out77cases of serrated lesions as theexperimental group, and collected16normal colorectal tissues and14cases of CRC ascontrol group. Application of TaqMan probe-based RT-PCR detected RUNX3geneCpG island methylation status in29cases of HP,29cases of SSA/P,19cases of TSA,14cases of CRC and16cases of normal colorectal tissue. Immunohistochemicalstaining observed RUNX3protein expression with above cases. Analysis of therelationship between the results of the RUNX3gene methylation and expression ofRUNX3protein.[Results]1. RUNX3gene CpG island methylation was not detected in normal tissues; SSA/P,TSA, CRC three groups methylation were significantly higher than normal and HP groups (P<0.05); but there were no difference between HP and normal groups, andbetween SSA/P, TSA,CRC three goups (P>0.05).2. The immnohistochemicalpositive rate of RUNX3in SSA/P, TSA, CRC were significantly lower than in normalgroup, and there were significant difference between SSA/P, TSA, CRC three groupsand the normal group (P <0.05); significant difference between TSA, CRC and HP,significant difference betweeen SSA/P and CRC (P <0.05); but there were nodifference between HP and normal, SSA/P; SSA/P and TSA (P>0.05).3. RUNX3methylation and protein expression in SSA/P, TSA and CRC were negative correlation(P <0.05); and normal and HP were no correlation (P>0.05).[Conclusion]1. The/Immunohistochemical positive rate of RUNX3in normal tissue, serrated lesionsand CRC showed a decreasing trend, especially in SSA/P, TSA and CRC wassignificantly lower; which suggested that the expression reduction or absence ofRUNX3protein was necessary for serrated lesions to develop and change intomalignant lesions.2. Methylation rate tended to increase with the each goup of serrated lesions, RUNX3gene promoter CpG island methylation played an important role in the pathogenesis ofserrated lesions and malignant changes.3. RUNX3gene promoter methylation may be induced RUNX3protein decreasing orabsence, promoted the serrated lesions, especially serrated adenoma become cancer. [Background and Purpose]In recent years, colorectal cancer is one of the common malignant tumors; studies showthat the main reason is the lack of a correct understanding and recognice to the serratedlesions. The changes in morphological, biological behavior and molecular genetics ofserrated lesions are different from ordinary polyps and adenomas. WHO (2010)digestive system tumor classification is defined serrated lesions as: a group of lesionsthat characterized by the serrated structure, include:①hyperplastic polyp, according tothe type of mucus is divided into microvesicula HP, goblet cell rich HP, mucin poor HP;②sessile serrated adenoma/polyp;③traditional serrated adenoma;④serratedadenocarcinoma. Because the serrated lesions developed in naming and classification,and morphological characteristics were different explanation, there were differentdiagnosis in each slides even experienced gastrointestinal pathologist. Consistent rate ofdiagnosis was low; especially SSA/P and TSA.Recent studies suggest that SSA/P and TSA have malignant potential, respectively gothrough traditional serrated pathway and sessile serrated pathway. SSA/P can becomemicrosatellite instability CRC, the TSA also surely can become cancerous, althoughcancer molecular pathway is not clear; it should pay our more attention for theirmalignant potential. Our studies investigated41cases of SSA/P and23cases of TSAand observed clinical pathology, immunohistochemistry and carcinogenesis pathway features. Designed to improve the diagnostic accuracy rate in SSA/P and TSA, reducethe incidence rate of CRC.[Method]A total of2481cases of colorectal polyps and adenomas from the Beijing MilitaryRegion General Hospital during2007-2012years were retrospectively reviewed. Allslices were classified based on WHO standards,291cases of serrated lesions werefound. Amongst291cases of serrated lesions,41cases of SSA/P,23cases of TSA wereselected.34cases of HP,24cases of normal colorectal tissues and28cases of CRCwere collected as control group. All sections were stained using immunohistochemicalmethods and antibodies including MGMT, MLH1, β-catenin, p16, CDX2, RUNX3andKi-67.[Results]SSA/P and TSA occured in the left colon, with a male predominance in SSA/P patients.Histologically, the SSA/P presented serrated structure and the glands close to themuscularis mucosa, and basal crypt was inverted “T” or “L”-type branching. TSAglands also showed visible serrated structure, ectopic crypt and cell dysplasia. Filiformserrated adenomas (FSA) showed significantly serrated structure, long filiform and ahigher malignant potential. The expression of Ki-67showed significant differencesbetween experimental group and normal, HP (P<0.05).The expression of β-catenin, p16and RUNX3showed significant differences between experimental group and controlgroup.[Conclusion]1. SSA/P presented serrated change and the glands close to the muscularis mucosa, andbasal crypt was inverted “T” or “L”-type branching; Glands also showed visibleserrated structure of TSA, ectopic crypt and cell dysplasia; the FSA has long fibersvillous typical characteristics, a higher degree of dysplasia.2. β-catenin, p16and RUNX3immunohistochemical results suggested that SSA/P and TSA were higher malignant potential than HP, β-catenin, p16and RUNX3maybeplayed an important role in SSA/P and TSA occurrence of the malignant process.3. Immunohistochemical results suggested that Ki-67in the SSA/P and TSA has higherproliferative activity than the HP. The Ki-67proliferative activity can be used as thebasis tool for differential diagnosis of HP, SSA/P and TSA. |
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