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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.

carcinogenesis

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