Expression of proangiogenic chemokine Gro 1 in low and high metastatic variants of Pam murine squamous cell carcinoma is differentially regulated by IL-1?, EGF and TGF-?1 through NF-?B dependent and independent mechanisms

Abstract

We previously reported that chemokine Growth Regulated Oncogene 1 (Gro 1) is over‐expressed in murine squamous cell carcinoma (SCC) with metastatic tumor progression. The enhanced expression of Gro‐1 gene by SCC is regulated by activation of nuclear factor‐κB (NF‐κB), leading to accelerated tumor growth, angiogenesis and metastasis in vivo. In our study, we investigated the effect of the regulatory cytokines, IL‐1α, EGF and TGF‐β1 on activation of NF‐κB and Gro1 in primary and metastatic sublines of the murine SCC Pam 212. We found that Gro 1 expression could be induced by IL‐1α or EGF in the low cytokine producing Pam 212 cells, but no significant induction was observed in high cytokine producing and metastatic LY‐2 cells. Conditioned medium from LY‐2 containing functional IL‐1α induced Gro 1 expression in Pam 212 cells, which can be blocked by IL‐1 receptor antagonist (IL‐1RA). IL‐1RA, however, had a minimal effect on constitutive Gro 1 production by LY‐2 cells. TGF‐β1 suppressed constitutive as well as IL‐1α and EGF‐inducible Gro 1 production in both Pam 212 and LY‐2 cells. IL‐1α and EGF, but not TGF‐β1, were found to activate NF‐κB in Pam 212, whereas none of the stimulants showed a significant effect on constitutive activation of NF‐κB in LY‐2 cells. Overexpression of a super repressor IκBαM in Pam 212 inhibited NF‐κB binding activity, which led to impaired Gro 1 induction by IL‐1α and EGF. These results demonstrate that IL‐1α, EGF, and TGF‐β1 are important modulators of Gro 1 expression in SCC. Different responses to these modulators observed along with SCC metastatic progression may suggest a transition mechanism(s) for Gro 1 expression from host factor dependent to an independent stage involving NF‐κB activation. Published 2001 Wiley‐Liss, Inc.