NF-κB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy

Jian Min Wu, Hongmiao Sheng, Romil Saxena, N. Skill, Poornima Bhat-Nakshatri, Menggang Yu, Harikrishna Nakshatri, Mary Maluccio

Research output: Contribution to journalArticle

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Abstract

Nuclear factor-kappaB (NF-κB) has been shown to play an important role in the development and progression of cancer. In this study, we systematically examined NF-κBp65 signaling pathway in both human hepatocellular carcinoma (HCC) tissue and HCC cell lines. NF-κBp65 signaling pathway is aberrantly expressed and activated in both human HCC tissue and HCC Hep3B cells. Inhibition of NF-κB activity significantly reduced proliferation and invasion of Hep3B cells as well as down-regulated the expression of invasion-related molecules including matrix metalloproteinase (MMP)-2, MMP-9, membrane type-1 MMP (MT1-MMP), urokinase plasminogen activator (uPA) and vascular endothelial growth factor (VEGF). Hep3B cells exhibited a dose-dependent increase in apoptosis after receiving sorafenib treatment. Inhibition of NF-κB activity strongly sensitized Hep3B cells to sorafenib-induced cell death. Mechanistically, combined treatment of sorafenib and NF-κB inhibition enhanced inhibition of MAPK signaling and down-regulation of anti-apoptotic protein Mcl-1 expression. These observations indicate that inhibition of NF-κB may be a potential antineoplastic therapy for HCC, especially the combination of NF-κB inhibition and sorafenib provides a novel therapeutic strategy for patients with advanced-stage HCC.

Original languageEnglish
Pages (from-to)145-155
Number of pages11
JournalCancer Letters
Volume278
Issue number2
DOIs
StatePublished - Jun 18 2009

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Hepatocellular Carcinoma
Matrix Metalloproteinase 14
Therapeutics
Apoptosis Regulatory Proteins
Plasminogen Activators
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Urokinase-Type Plasminogen Activator
Antineoplastic Agents
Vascular Endothelial Growth Factor A
sorafenib
Cell Death
Down-Regulation
Apoptosis
Cell Line
Neoplasms

Keywords

  • Hepatocellular carcinoma (HCC)
  • NF-κB
  • Sorafenib
  • Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

NF-κB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy. / Wu, Jian Min; Sheng, Hongmiao; Saxena, Romil; Skill, N.; Bhat-Nakshatri, Poornima; Yu, Menggang; Nakshatri, Harikrishna; Maluccio, Mary.

In: Cancer Letters, Vol. 278, No. 2, 18.06.2009, p. 145-155.

Research output: Contribution to journalArticle

Wu, Jian Min ; Sheng, Hongmiao ; Saxena, Romil ; Skill, N. ; Bhat-Nakshatri, Poornima ; Yu, Menggang ; Nakshatri, Harikrishna ; Maluccio, Mary. / NF-κB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy. In: Cancer Letters. 2009 ; Vol. 278, No. 2. pp. 145-155.
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