Abstract 2424: Hepatocellular carcinoma in the South Texas Latino population: Implications of STEAP2

Abstract

Abstract Introduction: Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults and the third most common cause of cancer death worldwide; while incidence and mortality rates are two times higher in Latinos, incidence rates are the highest among Latinos in the South Texas region. The genetic and epigenetic events associated with the increased incidence of HCC in this population are largely unknown. We performed whole genome RNA sequencing in paired HCC tumor and adjacent non-tumor tissue total RNA from nine South Texas Latino patients. Analysis of differentially expressed genes revealed significant alterations in pathways associated with oxidative stress; most importantly, we found that the expression of STEAP2 (Six Transmembrane Epithelial Antigen of the Prostate 2) is increased five-fold in HCC tumor tissue compared to adjacent non-tumor tissue. In comparison to a non-Latino population, this finding was unique to South Texas Latinos. STEAP2 is a metalloreductase of iron and copper; reduced iron and copper ions can mediate the production of hydroxyl radicals resulting in increased oxidative stress, which can cause DNA damage and lipid peroxidation. We aim to prove that STEAP2 through regulation of iron and copper homeostasis, and an increase in oxidative stress, will lead to malignant transformation of hepatocytes resulting in tumor progression of HCC, including in obese hosts. Material and Methods: Latino paired HCC and adjacent non-tumor tissues were collected for RNA sequencing, metal ion measurement and oxidative stress markers. STEAP2 RNA and protein expression levels in Latino and Caucasian samples were evaluated by RT-PCR, Western blot, and immunohistochemistry. HCC cell lines (SNU398 and HUH7) with knockdown (KD) and overexpression (OE) of STEAP2 were created to examine the proliferation, migration, anchorage independent growth, and oxidative stress in vitro. Results: Analysis of RNA sequencing data demonstrated the overexpression of STEAP2 in HCC tumors in Latino patients, which were validated by RT-PCR and Western blot data. Lipid peroxidation product, 4-hydroxynonenal, and copper levels were higher in HCC tumor vs. adjacent tissue. KD of STEAP2 in the HCC cell lines decreased proliferation, migration and anchorage independent growth, while OE of STEAP2 increase migration and anchorage independent growth but not proliferation. Conclusions: STEAP2 is specifically overexpressed in HCC tumors in Latinos in comparison to HCC tumors in non-Latino whites and appears to play a malignant-promoting role in HCC cells. Further studies on the role of STEAP2 as a novel 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 Latinos and potential therapeutic targets. Citation Format: Carla Zeballos, Hakim Bouamar, Guixi Zheng, Xiang Gu, Yidong Chen, Francisco G. Cigarroa, Lu-Zhe Sun. Hepatocellular carcinoma in the South Texas Latino population: Implications of STEAP2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2424.