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

Mingxin Zuo,Vinay Kumar Kapoor,Yanan Li,Ying Wang,Eugene J Koay,Juan Carlos Roa,Milind Javle,Apurva Jain,Asif Rashid,Jean Nicholas Vauthey,Jaime A Espinoza,Ping Chang,Anu Behari,Donghui Li

doi:10.18632/oncotarget.9181

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.

Highlights

Gallbladder cancer (GBC) is an aggressive but uncommon malignancy affecting about 5000 individuals in the United States annually
liver X receptor (LXR) and farnesoid X receptor (FXR) genes, known to be important in lipid metabolism function as tumor suppressors and their down regulation appears to be critical for GBC pathogenesis
We investigated the genetic variants in GBCs and compared them with in normal gallbladder tissue using the powerful RNA sequencing (RNA-seq) technology to better understand the pathogenesis of this disease and define targets for its therapy

Summary

Introduction

GBC is an aggressive but uncommon malignancy affecting about 5000 individuals in the United States annually. The incidence of this disease is decreasing in the Western Hemisphere, it continues to pose a challenge in certain geographic locations such as in Latin America and Asia. [1, 2] Gallstone is a known risk factor for this cancer. The actual incidence of GBC in patients with gallstones is very low and 10-15% of adults in the western world have gallstones. Other risk factors include Salmonella typhi infection, primary sclerosing www.impactjournals.com/oncotarget cholangitis, obesity, and gallbladder polyps. Still unknown is why certain ethnic groups have a higher predisposition to GBC than others. Molecular characterization of this cancer has been very limited far. We investigated the genetic variants in GBCs and compared them with in normal gallbladder tissue using the powerful RNA sequencing (RNA-seq) technology to better understand the pathogenesis of this disease and define targets for its therapy

Methods

Results

Conclusion