AKR7A3 suppresses tumorigenicity and chemoresistance in hepatocellular carcinoma through attenuation of ERK, c-Jun and NF-κB signaling pathways

// Raymond Kwok Kei Chow 1, 2, 3, * , Sarah Tsz-Kwan Sin 1, 2, 3, * , Ming Liu 4 , Yan Li 5 , Tim Hon Man Chan 6 , Yangyang Song 6 , Leilei Chen 6 , Dora Lai-Wan Kwong 1, 2 and Xin-Yuan Guan 1, 2, 3 1 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong 2 Centre for Cancer Research, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong 3 State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong 4 School of Basic Sciences, Guangzhou Medical University, Guangzhou, China 5 Department of Biology, South University of Science and Technology of China, Shenzhen, China 6 Cancer Science Institute of Singapore, National University of Singapore, Singapore * These authors contributed equally to this work Correspondence to: Xin-Yuan Guan, email: xyguan@hku.hk Dora Lai-Wan Kwong, email: dlwkwong@hku.hk Keywords: AKR7A3, HCC, tumor suppressor, methylation, chemoresistance Received: August 12, 2016 Accepted: October 04, 2016 Published: October 18, 2016 ABSTRACT Hepatocellular carcinoma (HCC), which accounts for 85–90% of primary liver cancer, is now the second leading cause of cancer-related mortality worldwide. Here we reported that Aldo-Keto Reductase family 7A isoform 3 (AKR7A3) is frequently down-regulated in HCC, associating with poor overall survival rate, elevated serum α-fetoprotein (AFP) and poor differentiation of HCC. The promoter region of AKR7A3 was detected to be hypermethylated. Loss of heterozygosity (LOH) was also detected in AKR7A3. Functional assays on both AKR7A3 overexpressed and knockdown cells, including foci formation, colony formation in soft agar, migration, invasion and tumor formation in nude mice, demonstrated the strong tumor suppressive functions of AKR7A3. In addition, treatment of chemotherapy drug cisplatin showed that AKR7A3 sensitizes tumor cells to apoptosis. Mechanistically, western blot analysis showed that overexpression of AKR7A3 inhibits the activation of ERK, c-Jun and NF-κB. In summary, we found that AKR7A3 functions as a tumor suppressor gene in HCC through attenuating c-Jun, ERK and NF-κB signaling pathways.