Introduction: The incidence of hepatocellular carcinoma (HCC) in Hispanics is three times higher than non-Hispanic whites, and even higher in South Texas (STX) Hispanics. This is attributed to a higher prevalence of hepatitis C, diabetes, obesity and perhaps genetic and epigenetic alterations. Knowledge regarding genetic alterations in Hispanics is sparse as demonstrated by the lack of Hispanics with HCC in The Cancer Genome Atlas (TCGA). Therefore, our group sequenced paired adjacent liver and HCC tumor samples from STX Hispanics, which highlighted a gene over-expressed in tumors of Hispanics, called the Six Transmembrane Epithelial Antigen of the Prostate 2 (STEAP2). STEAP2 is a metalloreductase of iron and copper and is implicated in increased iron and reactive oxygen species in the liver which can lead to the progression of inflammation and cirrhosis. STEAP2 may play an important oncogenic role in HCC, especially in the setting of obesity. We propose to test the hypothesis that overexpression of STEAP2 will lead to malignant property in HCC cells resulting in enhanced proliferation, survival, invasiveness, and eventually development of HCC, especially in obese hosts.
Methods: Hispanic paired tissue continues to be collected from our institution for RNA sequencing and establishment of Hispanic HCC cell lines. STEAP2 RNA and protein expression levels in Hispanic paired samples versus Caucasian paired samples were evaluated by RT-PCR, Western blot, and immunohistochemistry. Knockdown and overexpression of STEAP2 were established in HCC cell lines and in primary Hispanic HCC cell lines to examine the effects on iron levels, oxidative stress, proliferation, invasiveness, apoptosis and cell cycle in vitro.
Results: Hispanic HCC RNA sequencing data compared to TCGA HCC RNA sequencing data (no Hispanics) demonstrated the overexpression of STEAP2 in HCC tumors in Hispanic patients, which were validated by RT-PCR data and Western blot data. Lipid peroxidation product, 4-hydroxynonenal, and copper levels were higher in HCC tumor versus adjacent tissue. Iron levels were higher in adjacent tissue versus tumor tissue in Hispanics. Knockdown of STEAP2 in SNU398 cells decreased proliferation and migration, while in HUH7 cells STEAP2 knockdown only decreased migration.
Conclusions: STEAP2 is specifically overexpressed in HCC tumors in Hispanics in comparison to HCC tumors in non-Hispanic whites and appears to play a malignant-promoting role in HCC cells. Further studies to establish the role of STEAP2 as a tumor promoter in HCC and the mechanisms by which it promotes carcinogenesis are underway. The proposed studies will likely yield mechanistic insights into the molecular mechanisms that drive HCC development and progression in South Texas Hispanics and potential therapeutic targets involving STEAP2-mediated metal ion metabolism and oxidative stress.
Citation Format: Carla R. Zeballos, Hakim Bouamar, Xiang Gu, Yidong Chen, Francisco G. Cigarroa, LuZhe Sun. The role of six transmembrane epithelial antigen of the prostate 2 in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5425. doi:10.1158/1538-7445.AM2017-5425