Clinical Pathological Significance Of EGFR、HER2、PI3k And PTEN Protein Expressions In Gastric Cancer

Background and Objective: Gastric cancer is one of the most common causes ofcancer-related death worldwide, and our country has a high incidence. The treatment forgastric cancer has been a clinical difficulty. Recently, molecular targeted therapydirectly against tumor specific molecular variations in the carcinogenesis has become atrend of tumor treatment. Molecular targeted therapy for gastric cancer had receivedmore and more attention as well.EGFR is a cell membrane receptor with tyrosine kinase activity. It is activated bycombining with its ligands and participates in the proliferation of cells. The activatingmutation of EGFR and over-expression of HER2played some key rolls in thetumorigenesis. Furthermore, molecular targeted drugs for these variants were widelyused in the treatment for human cancers. Recently, EGFR-TKIs were used in thetreatment for gastric cancer. However, the individual difference was obvious. Activatingmutation of EGFR in tumor cells was the precondition for the use of EGFR-TKI.Therefore, it was important to know about the expression of EGFR protein in gastriccancer for selecting patients who would benefit from EGFR-TKI.HER2, another member of EGFR family, its over-expressing has been found in avariety of human cancers. Trastuzumab, a monoclonal antibody targeting HER2,showed a reliable effect in the treatment of breast cancer patients with HER2proteinover-expression. It has been reported that some gastric cancer patients could benefitfrom trastuzumab. Although the expression of HER2protein in gastric cancer was still controversial, detection of HER2protein expression in gastric cancer could be helpfulfor the treatment of gastric cancer.It was found that some gastric cancer patients did not response to EGFR-TKIalthough their tumor cells expressed EGFR or HER2protein, suggesting that theabnormal activation of downstream pathways occurred. The main downstream pathwaysof EGFR were RAS/RAF/MEK and PI3K/AKT. It was reported that K-ras and B-rafgene mutations were rare in gastric cancer.The abnormal activation of PI3K/AKT pathway might be the important reason ofcontinuous activation of EGFR downstream pathways. PI3K was rarely activated bygene mutation. The over-expression of PI3K protein was mainly induced by the lossof its inhibitors. PTEN protein, the main inhibitor of PI3K protein, was encoded byPTEN gene. The loss of PTEN protein was a main reason for PI3K proteinover-expression.In the present study, we detected EGFR, HER2, PI3K and PTEN proteinexpressions of75gastric cancers and60their surrounding tissues, and analyzed therelationships of these protein expressions to patients’ age, gender, the tumordifferentiation, the tumor invasion, lymph node metastasis and the relationship amongthese protein expressions. It was expected that our work would provide some help forthe clinical application of EGFR-TKI and HER2monoclonal antibody in gastric cancer.Methods: A total of135tissues including75gastric cancers and60theirsurrounding tissues were collected form surgical operation. Immunohistochemistry wasused to detect the protein expressions of HER2, EGFR, PI3K and PTEN in thesecancers and their surrounding tissues. The SPSS statistic software17.0was used toanalyze the correlation of the protein expressions to clinical pathological agents of thepatients and the correlation among these protein expressions. Chi-square test andSpearman correlation analysis with SPSS statistical analysis software were used toassess the results. P<0.05was considered to be statistically significant.Results: The positive rates of EGFR protein expression in gastric cancer tissuesand the surrounding tissues were57.3%and10.0%, there was no significant difference (P>0.05). The positive rates of EGFR protein expression in the group with lymph nodemetastasis and without were67.9%and26.3%, the former was statistically higher thanthe latter (P<0.05). No significant differences were found in comparison of EGFRprotein expression to patients’ age, gender and the differentiation, invasion andpathologic stages of tumors (P>0.05).The positive rates of HER2protein expression in gastric cancer and thesurrounding tissues were25.3%and3.3%, the former was statistically higher than thelatter (P<0.05), these in the group with lymph node metastasis and without were30.3%and10.5%, the former was statistically higher than the latter as well(P<0.05), and thesein the group with Ⅰ-Ⅱ pathologic stages and the ones with Ⅲ-Ⅳ were10%and27.7%, the latter was statistically higher than the former(P<0.05). No significantdifferences were found in comparison of EGFR protein expression to patients’ age,gender and the differentiation and invasion of tumors (P>0.05).The positive rates of PI3K protein expression in gastric cancer and the surroundingtissues were60.0%and21.7%, the former was statistically higher than the latter(P<0.05), these in the group with lymph node metastasis and without were67.9%and36.8%, the former was statistically higher than the latter as well(P<0.05). No significantdifferences were found in comparison of PI3K protein expression to patients’ age,gender and the differentiation, pathologic stages and the invasion of tumors (P>0.05).The loss rates of PTEN protein expression in gastric cancer and the surroundingtissues were82.7%and26.7%, the former was statistically higher than thelatter(P<0.05). No significant differences were found in comparison of PTEN proteinexpression to patients’ age, gender and the differentiation, pathologic stages, invasionand lymph node metastasis of tumors(P>0.05).In gastric cancer, the expression of EGFR protein was positively related to that ofHER2protein(r=0.113, P<0.05). There was no significant difference in comparison ofEGFR protein expression to that of PI3K(r=0.114, P>0.05), EGFR protein expression tothat of PTEN(r=-0.032, P>0.05), HER2protein expression to that of PI3K(r=0.114,P>0.05), HER2protein expression to that of PTEN (r=-0.186, P>0.05). The expression of PI3K protein was negatively related to that of PTEN（r=-0.273, P<0.05).Conclusion:1.The expressions of EGFR and HER2protein were found in gastriccancer, and there may be synergistic effect between them in tumorigenesis of gastriccancer.2. PI3K protein expression was found in gastric cancer, and the over-expressionof PI3K may be one of the initiating factors of gastric cancer.3. The loss of PTEN protein expression could be seen in gastric cancer and wasthe reason of PI3K protein over-expression..4. Lymph node metastasis was easier occurred in these gastric cancers withover-expressions of EGFR、HER2and PI3K protein.5. Detection of EGFR, HER2, PI3K and PTEN protein expressions may behelpful for the choice of molecular targeted agents of gastric cancer.