2. Academic Validation
  3. STEAP3 promotes cancer cell proliferation by facilitating nuclear trafficking of EGFR to enhance RAC1-ERK-STAT3 signaling in hepatocellular carcinoma

STEAP3 promotes cancer cell proliferation by facilitating nuclear trafficking of EGFR to enhance RAC1-ERK-STAT3 signaling in hepatocellular carcinoma

  • Cell Death Dis. 2021 Nov 5;12(11):1052. doi: 10.1038/s41419-021-04329-9.
Li-Li Wang  # 1,  Jie Luo  # 1,  Zhang-Hai He 2,  Ye-Qing Liu 2,  Hai-Gang Li 2,  Dan Xie 3 4,  Mu-Yan Cai 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.
  • 2 Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 3 State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China. xiedan@sysucc.org.cn.
  • 4 Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China. xiedan@sysucc.org.cn.
  • 5 Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China. caimy@sysucc.org.cn.
  • # Contributed equally.
PMID: 34741044 DOI: 10.1038/s41419-021-04329-9
Abstract

STEAP3 (Six-transmembrane epithelial antigen of the prostate 3, TSAP6, dudulin-2) has been reported to be involved in tumor progression in human malignancies. Nevertheless, how it participates in the progression of human cancers, especially HCC, is still unknown. In the present study, we found that STEAP3 was aberrantly overexpressed in the nuclei of HCC cells. In a large cohort of clinical HCC tissues, high expression level of nuclear STEAP3 was positively associated with tumor differentiation and poor prognosis (p < 0.001), and it was an independent prognostic factor for HCC patients. In HCC cell lines, nuclear expression of STEAP3 significantly promoted HCC cells proliferation by promoting stemness phenotype and cell cycle progression via RAC1-ERK-STAT3 and RAC1-JNK-STAT6 signaling axes. Through upregulating the expression and nuclear trafficking of EGFR, STEAP3 participated in regulating EGFR-mediated STAT3 transactivity in a manner of positive feedback. In summary, our findings support that nuclear expression of STEAP3 plays a critical oncogenic role in the progression of HCC via modulation on EGFR and intracellular signaling, and it could be a candidate for prognostic marker and therapeutic target in HCC.

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