Role of STEAP2 protein in hepatocarcinogenesis
STEAP2蛋白在肝癌发生中的作用
基本信息
- 批准号:10183205
- 负责人:
- 金额:$ 43.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAgarAutomobile DrivingBindingBinding SitesBiochemicalBiological AssayBiological ProcessBiophysicsC-terminalCancer Cell GrowthCancer EtiologyCellsCessation of lifeCodeCopperDNADNA DamageData SetDevelopmentDietElementsEngineeringFamilyFamily memberFlavinsGenesGoalsGrowthHeat shock proteinsHemeHemochromatosisHepaticHepatocarcinogenesisHepatolenticular DegenerationHomeostasisHumanHydrogen PeroxideHydroxyl RadicalIn VitroIncidenceIntakeIonsIronIron OverloadLipid PeroxidationLiverMAPK8 geneMalignant - descriptorMalignant Epithelial CellMalignant NeoplasmsMediatingMembraneMetalsMitogen-Activated Protein KinasesMolecularMutationN-terminalNADPNADPH OxidaseOncogenicOrganellesOrganoidsOxidation-ReductionOxidative StressOxidoreductasePathway interactionsPatientsPreventivePrimary carcinoma of the liver cellsProductionPropertyProtein FamilyProteinsPublishingRNAResearchReverse Transcriptase Polymerase Chain ReactionRisk FactorsRoleSamplingSiteStainsStressTestingThe Cancer Genome AtlasTherapeuticTimeTissuesTumor TissueUp-RegulationValidationWestern BlottingXenograft procedureadductbasecell growthcell motilitycuprous iondifferential expressionhepatocellular carcinoma cell linein vivoknock-downmouse modelneoplastic cellnoveloverexpressionp38 Mitogen Activated Protein Kinasesix transmembrane epithelial antigen of the prostate 2transcriptome sequencingtumortumorigenesistumorigenicwhole genome
项目摘要
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 whether its catalytic activity is
necessary for its tumor-promoting activity including cell growth and migration, and tumorigenic property in HCC
cells. In specific aim 3, we will determine whether altered expression of STEAP2 results in increased labile iron
and copper, oxidative stress, DNA damage, and protein adduct formation in HCC cells. We will investigate
whether STEAP2-stimulated oncogenic pathways is dependent on iron and copper accumulation. We will also
determine whether stress-activated MAP kinases mediate the HCC-promoting activities of STEAP2. We are
the first to show the upregulation and tumor-promoting functions of STEAP2 in HCC. Given its role in
promoting cancer cell growth and intracellular iron/copper accumulation leading to oxidative stress and
activation of oncogenic pathways, our proposed research promises to uncover a novel molecular mechanism
contributing to hepatocarcinogenesis and to reveal actionable targets for the development of novel preventive
and therapeutic strategies.
我们的长期目标是揭示导致发病率增加的分子机制
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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LUZHE SUN其他文献
LUZHE SUN的其他文献
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{{ truncateString('LUZHE SUN', 18)}}的其他基金
Aging-associated mammary cancer-initiating cells
与衰老相关的乳腺癌起始细胞
- 批准号:
10292285 - 财政年份:2021
- 资助金额:
$ 43.81万 - 项目类别:
Aging-associated mammary cancer-initiating cells
与衰老相关的乳腺癌起始细胞
- 批准号:
10490409 - 财政年份:2021
- 资助金额:
$ 43.81万 - 项目类别:
Aging-associated mammary cancer-initiating cells
与衰老相关的乳腺癌起始细胞
- 批准号:
10682483 - 财政年份:2021
- 资助金额:
$ 43.81万 - 项目类别:
Role of STEAP2 protein in hepatocarcinogenesis
STEAP2蛋白在肝癌发生中的作用
- 批准号:
10432061 - 财政年份:2020
- 资助金额:
$ 43.81万 - 项目类别:
Role of STEAP2 protein in hepatocarcinogenesis
STEAP2蛋白在肝癌发生中的作用
- 批准号:
10632092 - 财政年份:2020
- 资助金额:
$ 43.81万 - 项目类别:
Aging mammary stem cells and breast cancer prevention
衰老的乳腺干细胞与乳腺癌预防
- 批准号:
9536728 - 财政年份:2015
- 资助金额:
$ 43.81万 - 项目类别:
Aging mammary stem cells and breast cancer prevention
衰老的乳腺干细胞与乳腺癌预防
- 批准号:
9753963 - 财政年份:2015
- 资助金额:
$ 43.81万 - 项目类别:
Aging mammary stem cells and breast cancer prevention
衰老的乳腺干细胞与乳腺癌预防
- 批准号:
8963571 - 财政年份:2015
- 资助金额:
$ 43.81万 - 项目类别:
Effect of bisphenol A exposure on mammary stem cell function and transformation
双酚A暴露对乳腺干细胞功能和转化的影响
- 批准号:
8843434 - 财政年份:2012
- 资助金额:
$ 43.81万 - 项目类别:
Effect of bisphenol A exposure on mammary stem cell function and transformation
双酚A暴露对乳腺干细胞功能和转化的影响
- 批准号:
8535764 - 财政年份:2012
- 资助金额:
$ 43.81万 - 项目类别:
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