Deciphering the Molecular Mechanisms of Estrogen Signaling in Gastrointestinal Tumors

Colorectal and pancreatic cancers are predominant gastrointestinal (GI) tumors with estimated 90,970 deaths in the United Sates in 2016, representing ~ 60% of the total GI tumors related-mortalities. Several investigations, including meta-analysis, preclinical, and in vitro studies have established the protective role of estrogens and related receptors against GI tumors. The main estrogen nuclear receptor in the colon is estrogen receptor beta (ERβ/ESR2). During colon cancer progression, ERβ expression is considerably reduced. Re-expressing ERβ in colon cancer cell line (SW480) induces significant changes in miRnome. miR-205 is among the upregulated genes which directly targets the oncogene PROX1. In vivo studies demonstrated that both ERβ and miR-205 exert anti-metastatic effects. SW620, a highly metastasized human colorectal cancer cell line was used for further analysis. This cell line dose not express any ERα or ERβ, and ERβ was introduced using lentiviral. Here we show that 17β-estradiol (E2) has an ERβ-dependent as well as ERβ-independent effects suggesting possible role of alternative receptors in estrogen signaling in colonic epithelium such as G-protein coupled estrogen receptor 1 (GPER1). In response to E2 or GPER1-selective agonist G1 treatments, several oncogenic long non-coding RNAs (lncRNAs) show downregulation, including MALAT1, NEAT1, ZEB1-AS1 and HOTAIR. Several of these lncRNAs are involved in epithelial-to-mesenchymal transition (EMT) and tumor metastasis. Collectively, our data demonstrate that estrogen singling in the colon has anti-metastatic effects by modulating the expression of the cancer-related noncoding RNAs. EMT transition is frequently linked to a chemoresistance phenotype, which is a common phenomenon in pancreatic cancer. Genistein, a phytoestrogen, has a chemoenhancing effect when it combined with gemcitabine in pancreatic cancer cell lines (PANC1 and MiaPaCa2). Using RNA-seq, genistein induces expression of genes that are related to apoptosis, calcium signaling, and endoplasmic reticulum stress, which can all be linked to enhanced GPER1 activity. Genistein treatment also reduces the expression of several inflammation related genes including MUC1. We demonstrate that G1 treatment similarly reduces proliferation, but dose not fully mimic the apoptotic features of genistein. Collectively, these data indicate that using an estrogenic compound, such as genistein, may enhance the anti-proliferative and apoptotic effects of chemotherapeutic agents such as gemcitabine.