# Role of STEAP2 protein in hepatocarcinogenesis

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $449,583

## Abstract

Our long-term goal is to uncover molecular mechanisms that contribute to the increased incidence of
hepatocellular carcinoma (HCC) in the US. In order to understand potential molecular mechanisms that may
drive HCC development and progression, we performed whole genome RNA sequencing using total RNA
samples from paired adjacent non-tumor liver and HCC tumor tissues of local HCC patients. Analysis of the
differentially expressed genes between the paired tissues revealed significant alterations of Biological
Processes and Molecular Pathways associated with oxidation reduction, which involves a gene coding for Six
Transmembrane Epithelial Antigen of Prostate 2 (STEAP2) protein. We found that STEAP2 was also
significantly upregulated in the tumors in comparison to adjacent non-tumor liver tissues of the patients in The
Cancer Genome Atlas (TCGA) dataset as well as in two recently published RNA-seq datasets. STEAP2
belongs to a family of proteins involved in the reduction and transport of iron and copper ions across
membranes of a cell and various cellular organelles. The reduced forms of iron and copper ions are not only
essential elements needed for uncontrolled tumor cell growth, but also known to mediate the production of
hydroxyl radicals from hydrogen peroxide, which cause DNA and protein damage and lipid peroxidation.
Consistent with these functions of STEAP2, we found total levels of copper were significantly higher in the
HCC tissues than in the adjacent non-tumor tissues. Knockdown of STEAP2 expression in human HCC cell
lines significantly inhibited their viability, motility, clonogenicity in soft agar, and xenograft growth in vivo along
with decreased stress-activated MAP kinase activity and intracellular iron and copper levels, whereas STEAP2
overexpression showed opposite effects. Furthermore, a high iron diet significantly increased HCC incidence in
a mouse model. Although hepatic copper or iron overload associated with Wilson's disease and
hemochromatosis respectively is a known risk factor for HCC, whether dysregulation of copper and iron
homeostasis due to STEAP2 overexpression may contribute to hepatocarcinogenesis has not been explored.
On the basis of our novel preliminary findings, we hypothesize that STEAP2 upregulation can drive HCC
development and progression via increased supply of ferrous and cuprous ions, oxidative stress, and lipid
peroxidation resulting in the activation of stress-activated pathways. In specific aim 1, we will use newly
established patient-derived HCC organoid cultures and a spontaneous mouse model of HCC to determine
whether altered expression of STEAP2 will affect their malignant properties in vitro and in vivo. In specific aim
2, we will first determine whether STEAP2 possesses metalloreductase catalytic activity and whether its N-
terminal domain has a well-defined NADPH binding site and its C-terminal domain binds heme in HCC cells.
We will then engineer site-directed mutations of STEAP2 to determine ...

## Key facts

- **NIH application ID:** 10072613
- **Project number:** 1R01CA247379-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** LUZHE SUN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $449,583
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072613

## Citation

> US National Institutes of Health, RePORTER application 10072613, Role of STEAP2 protein in hepatocarcinogenesis (1R01CA247379-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10072613. Licensed CC0.

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