Reactive oxygen species-mediated PKC and integrin signaling promotes tumor progression of human hepatoma HepG2

Chi Tan Hu, Jia Ru Wu, Chuan Chu Cheng, Sindy Wang, Hsiao Ting Wang, Ming Che Lee, Ling Jung Wang, Siou Mei Pan, Tsu Yao Chang, Wen Sheng Wu

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

The poor prognosis and recurrence of HCC are majorly caused by intrahepatic metastasis. Delineating the molecular pathways mediating these processes may benefit developing effective targeting therapies. Using human hepatoma HepG2 as a model, we have found reactive oxygen species (ROS) may cooperate with protein kinase C (PKC) for sustained ERK phosphorylation and migration of HepG2 induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA). We further investigated whether integrin signaling is involved. Various antagonists of integrin signaling prevented TPA-induced activation of ERK and PKC, ROS generation and migration of HepG2. On the other hand, TPA-induced phosphorylation of integrin signaling components including focal adhesion kinase (FAK), Src (Tyr416) and paxillin (Tyr31 and Ser178) can be prevented by PKC inhibitor Bisindolylmaleimides (BIS) and antioxidant dithiotheritol (DTT). HepG2 overexpressing PKCα contained elevated phosphorylated paxillin. Also, ROS generator phenazine methosulfate and tert-Butyl hydroperoxide may induce phosphorylation of paxillin and activation of PKC. Taken together, ROS mediated cross talk of PKC and integrin for migration of HepG2 induced by TPA. Furthermore, TPA induced intrahepatic metastasis of HepG2 in SCID mice, which was prevented by BIS or (BIS plus DTT). Elevated phosphorylation of paxillin was observed in tumor of mice treated with TPA as compared with those co-treated with TPA/BIS. In summary, the signal pathways for tumor progression of hepatoma induced by TPA can be established both in vitro and in vivo.

Original languageEnglish
Pages (from-to)851-863
Number of pages13
JournalClinical and Experimental Metastasis
Volume28
Issue number8
DOIs
Publication statusPublished - Dec 2011
Externally publishedYes

Keywords

  • ERK
  • Integrin
  • Intrahepatic metastasis
  • Migration
  • Paxillin
  • PKC
  • ROS

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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