RNA sequencing-based analysis of gallbladder cancer reveals the importance of the liver X receptor and lipid metabolism in gallbladder cancer
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Mingxin Zuo1, Asif Rashid2, Ying Wang3, Apurva Jain1, Donghui Li1, Anu Behari4, Vinay Kumar Kapoor4, Eugene J. Koay5, Ping Chang1, Jean Nicholas Vauthey6, Yanan Li1, Jaime A. Espinoza7, Juan Carlos Roa8, Milind Javle1
1Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
4Department of Surgical Gastroenterology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, UP, India
5Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
6Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
7SciLifeLab, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Stockholm, Sweden
8Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), UC-Center for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Milind Javle, email: [email protected]
Keywords: RNA sequence, gallbladder cancer, liver X receptor, lipid metabolism pathways
Received: February 12, 2016 Accepted: April 16, 2016 Published: May 5, 2016
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.
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