Scientific Reports: STEAP2 promotes hepatocellular carcinoma progression via increased copper levels and stress-activated MAP kinase activity (Chen)

  • Carla Zeballos Torrez,
  • Acarizia Easley,
  • Hakim Bouamar,
  • Guixi Zheng,
  • Xiang Gu,
  • Junhua Yang,
  • Yu-Chiao Chiu,
  • Yidong Chen,
  • Glenn A. Halff,
  • Francisco G. Cigarroa
  • Lu-Zhe Sun

Abstract

Six Transmembrane Epithelial Antigen of Prostate 2 (STEAP2) belong to a family of metalloreductases, which indirectly aid in the uptake of iron and copper ions. Its role in hepatocellular carcinoma (HCC) remains to be characterized. Here, we report that STEAP2 expression was upregulated in HCC tumors compared with paired adjacent non-tumor tissues by RNA sequencing, RT-qPCR, Western blotting, and immunostaining. Public HCC datasets demonstrated upregulated STEAP2 expression in HCC and a positive association with tumor grade. Transient and stable knockdown (KD) of STEAP2 in HCC cell lines abrogated their malignant phenotypes in vitro and in vivo, while STEAP2 overexpression showed opposite effects. STEAP2 KD in HCC cells led to significant alteration of genes associated with extracellular matrix organization, cell adhesion/chemotaxis, negative enrichment of an invasiveness signature gene set, and cell migration/invasion inhibition. STEAP2 KD reduced intracellular copper levels and activation of stress-activated MAP kinases, including p38 and JNK. Treatment with copper rescued the reduced HCC cell migration due to STEAP2 KD and activated p38 and JNK. Furthermore, treatment with p38 or JNK inhibitors significantly inhibited copper-mediated cell migration. Thus, STEAP2 plays a malignant-promoting role in HCC cells by driving migration/invasion via increased copper levels and MAP kinase activities. Our study uncovered a novel molecular mechanism contributing to HCC malignancy and a potential therapeutic target for HCC treatment.

Read Full Text

Article Categories: Research Paper

Since 2004, UT Health San Antonio, Greehey Children’s Cancer Research Institute’s (Greehey CCRI) mission has been to advance scientific knowledge relevant to childhood cancer, contribute to understanding its causes, and accelerate the translation of knowledge into novel therapies. Greehey CCRI strives to have a national and global impact on childhood cancer by discovering, developing, and disseminating new scientific knowledge. Our mission consists of three key areas — research, clinical, and education.

Stay connected with the Greehey CCRI on Facebook, Twitter, LinkedIn, and Instagram.