Expression of proangiogenic chemokine Gro 1 in low and high metastatic variants of Pam murine squamous cell carcinoma is differentially regulated by IL-1α, EGF and TGF-β1 through NF-κB dependent and independent mechanisms

✍ Scribed by Elena Loukinova; Zhong Chen; Carter Van Waes; Gang Dong

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: French
• Weight: 186 KB
• Volume: 94
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.1514

✦ Synopsis

We previously reported that chemokine Growth Regu

lated 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-B (NF-B), leading to accelerated tumor growth, angiogenesis and metastasis in vivo. In our study, we investigated the effect of the regulatory cytokines, IL-1␣, EGF and TGF-␤1 on activation of NF-B and Gro1 in primary and metastatic sublines of the murine SCC Pam 212. We found that Gro 1 expression could be induced by IL-1␣ 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-1␣ 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-␤1 suppressed constitutive as well as IL-1␣ and EGFinducible Gro 1 production in both Pam 212 and LY-2 cells. IL-1␣ and EGF, but not TGF-␤1, were found to activate NF-B in Pam 212, whereas none of the stimulants showed a significant effect on constitutive activation of NF-B in LY-2 cells. Overexpression of a super repressor IB␣M in Pam 212 inhibited NF-B binding activity, which led to impaired Gro 1 induction by IL-1␣ and EGF. These results demonstrate that IL-1␣, EGF, and TGF-␤1 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-B activation.