Role of STEAP2 protein in hepatocarcinogenesis

Our long-term goal is to uncover potential molecular mechanisms that contribute to the increased incidence of hepatocellular carcinoma (HCC) in the US. particularly South Texas Latino population. Towards this end. we performed whole genome RNA sequencing in paired adjacent non-tumor liver and HCC tumor tissue total RNA samples from South Texas Latino patients in our region. Analysis of the differentially expressed genes revealed significant upregulation of expression of Six Transmembrane Epithelial Antigen of Prostate (STEAP) family members. STEAP1 and STEAP2. in the tumors in comparison to adjacent non-tumor liver tissues of the Latino patients. Real time RT-PCR assays also showed more dramatic upregulation of STEAP2 expression in Latino patients than in non-Latino patients. These significant observations build the foundation for the proposed studies. It has been known that the STEAP family members contribute to the metal uptake. especially iron and copper. Some of the STEAP proteins are overexpressed in prostate cancer. Indeed. our preliminary experiments showed that knockdown of STEAP2 expression in human HCC cell lines significantly inhibited their viability. motility. and clonogenicity in soft agar. whereas overexpression of STEAP2 promoted the malignant features of HCC cells and increased cellular accumulation of iron and copper. Here. we propose to test the novel hypothesis. on the basis of our novel preliminary findings. that STEAP2 promotes HCC development and progression by acting as a metalloreductase to facilitate iron and copper uptake in HCC cells. In specific aim 1. the Sun lab at UTHSA will use currently available human HCC cell lines and newly established patient-derived HCC organoid cultures to determine whether altered expression of STEAP2 will affect the malignant properties of HCC tumor cells in vitro and in vivo. We will also study whether inducible expression of liver-specific STEAP2 in a mouse model of spontaneous HCC will accelerate HCC development and progression without or with high iron diet supplement. In specific aim 2. the Liu lab at UTSA will employ biochemical and biophysical approaches to determine whether STEAP2 possesses the metalloreductase catalytic activity and whether its intracellular N-terminal domain binds NADPH and its C-terminal transmembrane domains bind heme. We are proposing a new paradigm involving a unique pathway regulating metal ion homeostasis in promoting hepatocarcinogenesis. If successful. our research will begin to uncover a novel molecular mechanism contributing to HCC development and progression in Latinos as well as in non-Latino patients and to reveal potential new cancer targets for the development of innovative preventive and therapeutic strategies.
 
 Note: This is an R01 application led by Dr. LuZhe Sun of UT Health San Antonio. The UTSA portion led by Dr. Aimin Liu will be a Subaward/Consortium in the application package.