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

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.

Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA

“…As STEAP3 is a metalloreductase responsible for reducing cellular Fe 3+ to Fe 2+ [ 53 ], increased expression of STEAP3 preserved cellular Fe 2+ concentrations to phosphorylate and inactivate GSK3β, thus activating Wnt/β-catenin signaling to favor CRC progression. In fact, the oncogenic roles of STEAP3 have already been found in HCC and glioblastoma [ 40 , 54 ], which could partially strengthen our conclusion that STEAP3-AS1 positively correlated with STEAP3 to promote CRC progression.…”

“…STEAP3 is a well-documented metalloreductase involved in reducing Fe 3+ to Fe 2+ , thus playing an essential role in cancer progression [ 38 – 40 ]. Given the role of Fe 2+ on phosphorylating and inactivating GSK3β [ 41 – 44 ], we therefore speculated that STEAP3-AS1 activated Wnt/β-catenin signaling might be related to STEAP3-mediated Fe 2+ generation.…”

“…and are representative of at least 3 independent experiments. (** P < 0.01 and *** P < 0.001, NS, not significant) in cancer progression [38][39][40]. Given the role of Fe 2+ on phosphorylating and inactivating GSK3β [41][42][43][44], we therefore speculated that STEAP3-AS1 activated Wnt/βcatenin signaling might be related to STEAP3-mediated Fe 2+ generation.…”

A‑kinase interacting protein 1 regulates the cell proliferation, invasion, migration and angiogenesis of clear cell renal cell carcinoma cells and affects the ERK/c‑Myc signaling pathway by binding to Rac1

“…Rac1 activates the ERK signaling pathway in hepatocellular carcinoma and colon cancer to regulate the proliferation, invasion and migration of cancer cells ( 25 , 26 ). Zhao et al ( 27 ) reported that the slit guidance ligand 2/roundabout guidance receptor 1 axis promotes the malignant progression of osteosarcoma cells via activation of the proto-oncogene tyrosine protein kinase Src/ERK/c-Myc/6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 signaling pathway.…”

STEAP Family Members and Gastric Cancer: Expression Profile and Prognostic Values

“…In colorectal cancer, STEAP3 mRNA levels are increased and sustain tumor growth under low-iron settings [52]. Wang et al [53] discovered that STEAP3 was abnormally overexpressed in the nucleus of HCC cells. Nuclear STEAP3 expression boosted stemness phenotype and cell cycle progression via the RAC1-ERK STAT3 and RAC1-JNK-STAT6 signaling pathways, which greatly increased HCC cell proliferation.…”