Abstract
The incidence of colorectal cancer (CRC) is rated fourth in the world, and first in Taiwan. Bisphenol A (BPA) is one of endocrine disruptor compounds (EDCs) used as a common plasticizer for manufacturing polycarbonate plastics. Human may expose BPA through air, drinking water and food uptake. BPA is similar in structure to estrogen, and can bind to estrogen receptors (ERs). ERs have been found playing anti‐tumorigenic roles in CRC cells that dysregulated ER function would induce development of CRC. It suggested that BPA exposure may affect ER function to lead to tumorigenesis of CRC. However, the effects of BPA exposure on the progression of CRC development is not clearly known. Thus, this study performed a meta‐analysis of gene networks to investigate whether BPA exposure affected gene expression to induce CRC carcinogenesis. This study collected the microarray samples of 206 human cells exposure to BPA and 599 human CRC tissues from ArrayExpress to identify the differentially expressed genes (DEGs) for BPA exposure corresponding with CRC progression and metastasis. The module genes of DEGs conducted from NetworkAnalyst were further illustrated by Cytoscape to explore regulatory pathways in the integrated gene network of BPA‐induced CRC carcinogenesis. The results of gene-network analysis showed that BPA exposure could induce CRC carcinogenesis through altered gene expression in ESRRA‐TP53/MYC‐PIK3CA/STAT3‐IGF1R pathway and CTNNB1‐MYC/TP53‐STAT3/PIK3CA‐IGF1R pathway. Furthermore, the result of gene‐network analysis was validated in human colon adenocarcinoma SW480 cells that BPA exposure (10, 103 and 105 nM) promoted cell proliferation, migration and invasion, which can be attenuated by knockdown of upstream gene ESRRA with siESRRA. Regarding to the development of targeted therapy in CRC, 301 microarray samples of human CRC tissues relevant to prognosis with adjuvant chemotherapy were used to explore the gene networks and target genes potentially for the therapy of metastatic CRC (mCRC). According to the results of gene‐network analysis, GRB2‐CDKN1A‐MYC‐STAT3/PIK3CA‐IGF1R pathway was the target of adjuvant chemotherapy, Bevacizumab, Cetuximab, FOLFIRI and FOLFOX, for curing mCRC, and the capability of cell migration and invasion in SW480 cells was attenuated after knockdown of upstream gene GRB2 expression with siGRB2. The findings of gene‐network analysis and validation in SW480 cells revealed that BPA exposure induced the expression of upstream gene ESRRA in ESRRA‐TP53/MYC‐PIK3CA/STAT3‐IGF1R pathway to trigger cell migration and invasion potentially for CRC carcinogenesis. Overexpressed GRB2 in GRB2‐CDKN1A‐MYC‐STAT3/PIK3CA‐IGF1R pathway reduced adjuvant chemotherapy efficacy, and attenuation of GRB2 suppressed capability of CRC cell metastasis. Therefore, ESRRA and GRB2 could serve as target genes for CRC carcinogenesis.