Expression Of ER And Its Coregulators In Human Colorectal Cancer

OBJECTIVE:Estrogen receptors (ER) have been implicated in colorectal tumorigenesis, according to increasing number of related studies in recent years. However, the exact roles and mechanisms which ERs are involved in are not clear now. In our study, we evaluated the changes in the expression of ERβ and related coregulators including forhead box A1 (FOXA1), nuclear receptor coactivator 3 (NCOA3/AIB1), nuclear receptor coactivator 2 (NCOA2/TIF2) and Proline-, glutamic acid-, and leucine-rich protein 1(PELP1) in colorectal cancer (CRC) tissues by quantitative real-time PCR (qRT-PCR) and immunohistochemistry, respectively. We evaluated the association between the target genes and their clinicopathological parameters to explain potential role in tumor progression.METHODS:A total of 200 CRC patients, who underwent intestinal enterectomy for histopathologically confirmed colorectal carcinoma in the First Affiliated Hospital of the Guangxi Medical University between March 2014 and November 2014, were selected for the current study. The expression profiles of ERβ and its coregulators (FOXA1, AIB1, TIF2 and PELP1) in colorectal cancer and corresponding adjacent normal epithelium from 80 and 120 Chinese colorectal cancer patients were evaluated by quantitative real-time PCR (qRT-PCR) and immunohistochemistry, respectively. Statistical significance between two groups (cancer and normal tissues) was analyzed by Student’s t test. The expression profile of the five receptors was compared and their associations with clinicopathological characteristics were assessed by using Chi-square test. ROC curves were generated to evaluate the diagnostic value distinguishing CRC from noncancerous colorectal tissues.RESULTS:The mRNA and protein expression levels of the ERβ were decreased in malignant tissues (P<0.001,P<0.001). The selective loss of FOXA1 were also found in cancer tissues (P=0.032, P< 0.001), so were the AIB1 (mRNA P<0.001, protein P<0.001). The mRNA expression levels of the PELP1 was significantly imcreased in malignant tissues while the protein expression levels was significantly decreased in malignant tissues. Significant correlations among the five receptors were revealed in three couples (ERβ and AIB1、ERβ and PELP1、PELP1 and AIB1) in our analysis. Additionally, ERβ, AIB1, TIF2 and PELP1 have the diagnostic role in CRC progression according to ROC curve (P<0.001、P<0.001、P=0.011、P=0.009, respectivly). The expression of ERβ, AIB1、FOXA1、TIF2 and PELP1 in patients were associated with poor prognosis including larger tumor size, T classification (tumor invasion), N classification (lymph node invasion), clinical stages, neural invasion and vascular invasion.CONCLUSIONS:ERP, FOXA1、AIB1、TIF2 and PELP1 might be involved in the colorectal carcinogenesis. The data reviewed above suggest that ERβ, FOXA1、AIB1 and PELP1 might mainly exerts a protective effect against CRC carcinogenesis and TIF2 might accelerate colorectal tumorigenesis. The association among ERβ, AIB1 and PELP1 might be more close. AIB1 and PELP1 interacted with ERβ in a ligand-dependent manner and might assemble in a multi-protein complex. More experimental studies are still needed to figure out the exact role of ER signaling pathway.