Expression And Significance Of EGFR And HER-2 In Pten-deficient Solid Pattern Of Salivary Adenoid Cystic Carcinoma

Background:Salivary adenoid cystic carcinoma(SACC) is the second most common salivary malignant tumor in humans. It is characterized by endless growth, diffuse invasion, a high rate of local recurrence and metastasis, causing a substantial mortality. Based on the components of its histological cell types, SACC is roughly divided into three major patterns, i.e. cribriform, tubular, and solid pattern. Among the three, solid pattern of SACC is the most poorly differentiated, high grade malignancy with higher rate of recurrence and metastasis. Meanwhile, solid pattern of SACC has the lowest survival rate in more than ten years patient’s follow-up. As we know, the activity of carcinogenesis, the absence or mutation of tumor suppressor gene and the out of control of growth factor and its receptor are the important transforming signaling system to regulate biological behaviors. If the signaling system loses its balance, it will cause a cell to lose control of its cell proliferation and gain the malignant behaviors. EGFR and HER-2 is the member of the erb B family of receptor tyrosine kinase protein, they undergoes dimerization or autophosphorylation and than trigger downstream signaling cascades, such as phosphatidylinositol-3-kinase/AKT and MAPK activation. When they overexpressed or abnormal activity, the phosphoinosite 3-kinase(PI3K)/AKT pathway will be activated to regulate the proliferation, metastasis and invasion of tumor cells. Phosphatase and tensin homologue deleted on chromosome 10(PTEN), best known as a lipid phosphatase, negatively regulates cell proliferation and survival through antagonizing the phosphatidylinositol 3-kinase(PI3K) signaling. It always frequentlymutated or deleted in a wide variety of human tumors. Recently investigations have demonstrated that EGFR/PI3K/AKT/m TOR pathway play an important role in many human cancers, such as breast cancer, prostate cancer and colon cancer. Furthermore, our lab has found that loss of PTEN expression was predominantly found in human solid salivary adenoid cystic carcinomas, and the PI3K/Akt/m TOR signaling pathways has been activated. However, little data have been investigated the relationship of EGFR, HER-2 and PTEN/PI3K/ Akt/m TOR pathway in salivary adenoid cystic carcinoma.Objective:This research aims to investigate the expression of EGFR, HER-2 in PTEN-deficient solid pattern of salivary adenoid cystic carcinoma. Analyzing the relationship between EGFR 与 HER-2 and PTEN in salivary adenoid cystic carcinoma. It is expected to search more specific and clinical application of molecular treatment in salivary adenoid cystic carcinoma.Methods:Immunohistochemistry was used to detect the protein expression of EGFR, HER-2 in PTEN-deficient solid pattern of salivary adenoid cystic carcinoma and their surrounding normal tissues. The 18 cases of PTEN-deficient and 10 cases PTEN-positive salivary adenoid cystic carcinoma were from Dalian medical university hospital and Shanghai ninth people’s hospital.Using real-time quantitative RT-PCR to measure m RNA expression of EGFR, HER-2 in normal salivary cell lines HSG, high-(SACC-LM) and low-lung-metastatic(SACC-83) cell lines. The data was analyzed using the SPSS 19.0 for windows, p<0.05 as the standard of having statistically significant difference.Results:(1)The m RNA expression of EGFR, HER-2 in HSG,SACC-83 and SACC-LM cell lines in vitro.1) Compared with SACC-83 and SACC-LM, The m RNA levels of EGFR increased in HSG. There were statistically significant differences between HSG and SACC-83; HSG and SACC-LM(p<0.05).2) Compared with SACC-83 and SACC-LM, The m RNA levels of HER-2 decreased inHSG. There were statistically differences between HSG and SACC-LM(p<0.05). But there were no statistically significant differences between HSG and SACC-83.(2)The location and protein expression pattern of EGFR, HER-2 in surrounding normal salivary gland tissues of salivary adenoid cystic carcinoma.EGFR and HER-2 positive expression located at the cytoplasm of duct cells. Both were not observed in acinus.(3)The protein expression of EGFR, HER-2 in human salivary adenoid cystic carcinoma.1) In cribriform and tubular pattern of salivary adenoid cystic carcinoma, EGFR protein was not observed or only weak expression; almost all these cases showed high level of HER-2 staining.2) In PTEN-deficient solid pattern of salivary adenoid cystic carcinoma, the positive rate of EGFR is only 27.8%(5/18); However, HER-2 was overexpressed in 100% of SACC patients(18/18)(p<0.05).3) Statistical analysis shown that there was no correlation between PTEN and EGFR, while immunoexpression of PTEN to be inversely correlated with upstream HER-2(p<0.05).Conclusion:The weak positive expression of EGFR in PTEN-deficient solid pattern of salivary adenoid cystic carcinoma suggests that EGFR may not play the main roles in the progressive of solid pattern of salivary adenoid cystic carcinoma. HER-2 overexpression correlated with the loss of PTEN expression indicates that HER-2 may participate in the regulation of PTEN/PI3K/Akt/m TOR signaling pathway to regulate the relentless progressive of salivary adenoid cystic carcinoma.