RNA sequencing-based analysis of gallbladder cancer reveals the importance of the liver X receptor and lipid metabolism in gallbladder cancer

// Mingxin Zuo 1 , Asif Rashid 2 , Ying Wang 3 , Apurva Jain 1 , Donghui Li 1 , Anu Behari 4 , Vinay Kumar Kapoor 4 , Eugene J. Koay 5 , Ping Chang 1 , Jean Nicholas Vauthey 6 , Yanan Li 1 , Jaime A. Espinoza 7 , Juan Carlos Roa 8, Milind Javle 1 1 Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Department of Surgical Gastroenterology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, UP, India 5 Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 6 Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 7 SciLifeLab, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Stockholm, Sweden 8 Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), UC-Center for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile Correspondence to: Milind Javle, email: mjavle@mdanderson.org Keywords: RNA sequence, gallbladder cancer, liver X receptor, lipid metabolism pathways Received: February 12, 2016      Accepted: April 16, 2016      Published: May 5, 2016 ABSTRACT Gallbladder cancer (GBC) is an aggressive malignancy. Although surgical resection may be curable, most patients are diagnosed at an advanced unresectable disease stage. Cholelithiasis is the major risk factor; however the pathogenesis of the disease, from gallstone cholecystitis to cancer, is still not understood. To understand the molecular genetic underpinnings of this cancer and explore novel therapeutic targets for GBC, we examined the key genes and pathways involved in GBC using RNA sequencing. We performed gene expression analysis of 32 cases of surgically-resected GBC along with normal gallbladder tissue controls. We observed that 519 genes were differentially expressed between GBC and normal GB mucosal controls. The liver X receptor (LXR)/retinoid X receptor (RXR) and farnesoid X receptor (FXR) /RXR pathways were the top canonical pathways involved in GBC. Key genes in these pathways, including SERPINB3 and KLK1 , were overexpressed in GBC, especially in female GBC patients. Additionally, ApoA1 gene expression suppressed in GBC as compared with normal control tissues. LXR and FXR genes, known to be important in lipid metabolism also function as tumor suppressors and their down regulation appears to be critical for GBC pathogenesis. LXR agonists may have therapeutic value and as potential therapeutic targets.