大腸直腸癌(colorectal cancer)發生率在全球排名第四，在台灣位居首位。雙酚A(bisphenol A; BPA)為一內分泌干擾物質，是塑膠容器製程中廣泛使用之塑化劑，人類藉由空氣、飲水和食物等途徑會暴露到BPA。BPA 結構類似雌激素，會與雌激素受體(estrogen receptor; ER)結合，已有研究指出ER 在大腸癌細胞具有抗癌作用，ER 功能失調會導致腫瘤生成，推測BPA 可能干擾ER 作用誘發大腸癌。然而，BPA 暴露可能誘發大腸細胞癌化的分子機制並不清楚，因此本研究利用基因網絡探究BPA 暴露是否影響基因表現而誘發大腸細胞癌化。
本研究從ArrayExpress 匯集206 個人類細胞暴露BPA 和599 個人類大腸癌組織之微陣列資料，探究BPA 暴露之差異表現基因(differentially expressed genes;DEGs)是否與大腸癌生成和轉移基因有關。微陣列資料以NetworkAnalyst 分析DEGs 並建立模組基因，進一步以Cytoscape 分析各模組基因之基因網絡，整合建構出BPA 暴露誘發大腸細胞癌化之可能基因網絡和路徑。基因網絡結果顯示BPA 暴露可能會影響ESRRA-TP53/MYC-PIK3CA/STAT3-IGF1R 路徑和CTNNB1-MYC/TP53-STAT3/PIK3CA-IGF1R 路徑中之基因表現來誘使大腸癌癌化。本研究亦利用人類大腸直腸腺癌SW480 細胞驗證基因網絡發現，SW480 細胞暴露BPA (10、103 和105 nM)會增加細胞複製及細胞移動和侵襲情形，轉染estrogen-related receptor alpha (ESRRA)基因siRNAs 則會降低細胞移動和侵襲能力。
此外，根據標靶治療在大腸癌之發展，本研究利用301 個臨床輔助化療藥物
之治療效果的微陣列資料，探究治療轉移性大腸癌之潛在基因網絡和目標基因，
建立大腸癌治療之可能基因路徑。結果發現大腸癌化療藥物Bevacizumab、
Cetuximab 、FOLFIRI 和FOLFOX 均會透過GRB2-CDKN1A-MYC-STAT3/PIK3CA-IGF1R 路徑來治療轉移性大腸癌。SW480細胞轉染GRB2 (growth factor receptor-bound protein 2)基因siRNAs 也會降低細胞移動和侵襲能力。
本研究藉由基因網絡分析和SW480 細胞驗證發現，BPA 暴露會促使
ESRRA-TP53/MYC-PIK3CA/STAT3-IGF1R 路徑中上游基因ESRRA 表現，增加
大腸細胞移動和侵襲之癌化能力。此外，GRB2-CDKN1A-MYC-STAT3/PIK3CA-IGF1R 路徑中上游基因GRB2 表現上升，會降低臨床藥物治療效果，下調GRB2 表現可降低大腸癌細胞轉移能力。因此ESRRA 和GRB2 可做為大腸癌癌化之目標基因。

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.

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