title: Effect of NR5A2 inhibition on pancreatic cancer stem cell (CSC) properties and epithelial-mesenchymal transition (EMT) markers.
abstract: NR5A2 (aka LRH-1) has been identified as a pancreatic cancer susceptibility gene with missing biological link. This study aims to demonstrate expression and potential role of NR5A2 in pancreatic cancer. NR5A2 expression was quantified in resected pancreatic ductal adenocarcinomas and the normal adjacent tissues of 134 patients by immunohistochemistry. The intensity and extent of NR5A2 staining was quantified and analyzed in association with overall survival (OS). The impact of NR5A2 knockdown on pancreatic cancer stem cell (CSC) properties and epithelial-mesenchymal transition (EMT) markers was examined in cancer cells using RT-PCR and Western Blot. NR5A2 was overexpressed in pancreatic tumors, the IHC-staining H score (mean ± SE) was 96.4 ± 8.3 in normal versus 137.9 ± 8.2 in tumor tissues (P < 0.0001). Patients with a higher NR5A2 expression had a median survival time 18.4 months compared to 23.7 months for those with low IHC H scores (P = 0.019). The hazard ratio of death (95% confidence interval) was 1.60 (1.07-2.41) after adjusting for disease stage and tumor grade (P = 0.023). NR5A2 was highly expressed in pancreatic cancer sphere forming cells. NR5A2-inhibition by siRNA was associated with reduced sphere formation and decreased levels of CSCs markers NANOG, OCT4, LIN28B, and NOTCH1. NR5A2 knockdown also resulted in reduced expression of FGB, MMP2, MMP3, MMMP9, SNAIL, and TWIST, increased expression of epithelial markers E-cadherin and β-catenin, and a lower expression of mesenchymal marker Vimentin. Taken together, our findings suggest that NR5A2 could play a role in CSC stemness and EMT in pancreatic cancer, which may contribute to the worse clinical outcome.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhaofan
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mingxin
authors.initials: M
authors.lastname: Zuo
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.forename: Weihua
authors.initials: W
authors.lastname: Tian
authors.affiliation: Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dong
authors.initials: D
authors.lastname: Yan
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Donghui
authors.initials: D
authors.lastname: Li
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C082631:NR5A2 protein, human; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear
keywords: EMT; expression; stem cell-like cancer cell; survival