Journal Article

Hepatocyte growth factor-activated NF-κB regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines

L. Tacchini, C. De Ponti, E. Matteucci, R. Follis and M.A. Desiderio

in Carcinogenesis

Volume 25, issue 11, pages 2089-2100
Published in print November 2004 | ISSN: 0143-3334
Published online November 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh227
Hepatocyte growth factor-activated NF-κB regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics

GO

Show Summary Details

Preview

Hepatocyte growth factor (HGF)-stimulated Met signaling influences tumor survival, growth and progression, all processes involving the transcription factor NF-κB. NF-κB plays a complex role in the control of survival due to the influence of cellular factors acting downstream. We undertook a comparative investigation of two human breast carcinoma cells with different grades of malignancy and HepG2 hepatoma cells, which present a biphasic response to HGF (proliferation followed by apoptosis). We found evidence that HGF induced gene patterns characteristic of survival rather than apoptosis depending on the cell type. The ability of NF-κB to regulate expression of hypoxia-inducible factor-1α (HIF-1α), a survival/anti-apoptotic gene in cancer, seemed to be critical. In the HepG2 and MCF-7 (low invasive breast carcinoma) cell lines increased transcription and translation were responsible for HIF-1α induction after HGF. The regulation by NF-κB was mainly at the level of the 5′-UTR of the HIF-1α message. HIF-1 (α/β heterodimer) was likely to transactivate Mcl-1, another anti-apoptotic gene. Opposite results were observed in MDA-MB-231 cells (highly invasive breast carcinoma), which have high NF-κB activity, further inducible by HGF, because HIF-1α mRNA expression and HIF-1 transactivating capacity were HGF-insensitive while the α subunit seemed to be degraded after HGF. However, ornithine decarboxylase (ODC) and heme oxygenase mRNA expression persistently increased. By transiently transfecting two ODC gene reporters we demonstrated that ODC is a target gene of NF-κB in HGF-treated tumor cells. By regulating HIF-1 activity and specific gene expression downstream, NF-κB may influence the survival threshold, with an impact on the fate of carcinoma cells after prolonged HGF treatment.

Keywords: FBS, fetal bovine serum; HGF, hepatocyte growth factor; HIF-1, hypoxia-inducible factor-1; HO-1, heme oxygenase-1; HRE, hypoxia responsive elements; MEM, minimal essential medium; NF-κB, nuclear factor κB; ODC, ornithine decarboxylase; PBS, phosphate-buffered saline; PI3K, phosphatidylinositol 3-kinase; ssNF-κB, NF-κB super-repressor; TdT, terminal-dUTP-transferase; 5′-UTR, 5′-untranslated region.

Journal Article.  8664 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.