| Object: Gastric cancer in China is one of the most common malignant tumor， thesecond-most frequent cause of cancer deaths，its incidence is the highest in malignantdigestive tumors, the5-year survival rate of patients is still low. Owing to lacking ofspecific clinical symptoms and signs in the early stage of gastric carcinoma, mostcases are diagnosed in advanced stage, and some of them with distant metastasis,leading to some patients lost the optimal timing of surgery. Despite some advancesin the chemotherapy and surgical techniques for treating gastric cancer, the overallsurvival of patients is still low. Therefore, identification of new prognostic andpredictive markers to determine the risk of poor prognosis is important for earlymolecular diagnosis, risk analysis and the development of new therapies.Different types of living organisms are driven by the daily light–dark cycles of theearth. Such circadian rhythm is one of the basic characteristics of an organism’s lifeactivities and is controlled by the circadian system, which is composed of a series of circadian clock genes. Circadian rhythms influence many physiologic processes andpathologic conditions. Disruption of the circadian clock may deregulate normalcellular biological functions and have significant effects on human health, e.g.,causing conditions such as sleep disorders, gastrointestinal and cardiovascularillnesses and depression. Growing evidence shows that alterations in circadian rhythmcan be a risk factor for the development of cancers in animals and humans. Thehuman circadian rhythm is controlled by several core circadian genes, includingpositive activators such as the three transcription factors CLOCK, neuronal PASdomain protein2(NPAS2) and BMAL1, negative effectors, such as twocryptochromes (CRY1and CRY2) and three period (PER1, PER2and PER3) genes.Of all the known clock genes, PER1and PER2have been shown to play a major rolein cancer development. Overexpression of PER1or PER2in cancer cells inhibits theirneoplastic growth and increases their apoptotic rate. In recent years many studieshave indicated that deregulation of PER1and PER2expression was highly linked tothe carcinogenesis and development of malignant tumors, including breast cancer,prostate cancer, colorectal carcinoma and gliomas. However, the expression andprognostic value of the PER1and PER2genes in gastric patients have not beenreported.We examined the expression levels of those genes in gastric cancer and adjacentnon-tumorous tissues. so as to explore the relationship between PER1and PER2ingastric carcinoma, the role plays in outcomes and clinicopathological features, whichprovides the basis for gastric cancer diagnosis, treatment and clues. Methods: We collect pathology and postoperation wax specimen of the gastric cancertissues of246cases with complete clinical data from the Cancer Center of SunYat-sun University during January2000and July2010, select the adjacent non-cancertissues of45cases among them, Immunohistochemistry was used to evaluate theexpression of two circadian genes, PER1and PER2, in246gastric carcinoma samplesand adjacent non-tumorous tissues, and in accordance with the age of the patients withgastric cancer, gender, location, depth of invasion, and the degree of differentiation,lymph node metastasis and TNM stage on a comprehensive analysis. The clinical andclinicopathological classification and stage of each tumor were classified according tothe7th Union International Cancer Control (UICC) TNM staging system. Allstatistical analyses were carried out using the SPSS software (version16.0; Chicago,IL, USA). The relationship between PER1and PER2expression and theclinicopathologic characteristics were calculated using the chi-square test, and weredisplayed in cross-tables. Survival curves were plotted using the Kaplan-Meiermethod and compared using the log-rank test. Cox proportional-hazard analysis wasused for Univariate and Multivariate analyses to explore the effect ofclinicopathological variables and PER1and PER2expression on survival. Theassociation between PER1and PER2were assessed using Spearman’s correlationcoefficient analysis. All p values were two-sided, and p <0.05was determined to bestatistically significant.Results:（1）According to the scoring system, high PER1and PER2proteinexpression was detected in103(41.9%) and86(35%) of the tumor samples, respectively, while low staining was observed in143(58.1%) and160(65%) of thetumor samples, respectively. Our statistical analyses showed that PER1expressionwas significantly correlated with the stage of disease (p <0.001), pathologicdifferentiation (p <0.001), depth invasion (p <0.001) and presence of lymph nodemetastasis (p <0.001). The expression of PER2was significantly correlated with thestage of the disease (p=0.015) and depth invasion (p=0.006). Higher staging wasassociated with lower PER1and PER2expression. Consistently, PER1expressionwas negatively correlated with pathologic differentiation.(2) Our data revealed thatPER1and PER2expression levels were lower in gastric cancer samples than inmatched, adjacent, non-tumorous tissues (p <0.001, p=0.003, respectively). Sixpairs of representative slides are shown in Figure3A-B. We detected decreasedexpression of PE1and PER2in24/45(53.73%) and30/45(66.7%) of the gastriccancer tissue samples, respectively, compared with only6/45(13.3%) and15/45(33.3%) in adjacent, non-tumorous tissues. The results indicated that the expressionlevels of PER1were positively correlated with the expression levels of PER2, the rcoefficient was0.378, and p <0.001.(3) The gastric cancer patients with low PER1and PER2expression had significantly shorter overall survival time than those withhigh PER1and PER2expression (p <0.001, p=0.002). When the survival of patientswith a high PER1/high PER2was compared with that of those with low PER1/lowPER2, Kaplan-Meier analysis revealed a significant difference on overall survival (p<0.001). By Multivariate Cox Regression analysis, we suggested that PER2may be aprognostic factor for the survival of gastric cancer patients. Conclusion: In the present study, we found that patients with lower PER1and PER2expression had a shorter survival time than those with higher expression. PER1andPER2expression was significantly down-regulated in advanced (stage III and IV)gastric cancer tissues compared with stage I and II gastric cancer tissues. PER1expression was associated with clinical stage, depth invasion, lymph node metastasisand pathologic differentiation. On the other hand, PER2was associated with clinicalstage and depth invasion. The expression of PER1was positively correlated withPER2expression in gastric cancer patients, and the protein levels of PER1and PER2in gastric cancer tissues were down-regulated when compared with matched, adjacent,non-tumorous tissues. In summary, we demonstrate that the expression of PER1andPER2may play an important role in tumor development, invasion and prognosis andthat PER2may serve as a novel prognostic biomarker of human gastric cancer. |
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