Expression of proangiogenic chemokine Gro 1 in low and high metastatic variants of Pam murine squamous cell carcinoma is differentially regulated by IL-1alpha, EGF and TGF-beta1 through NF-kappaB dependent and independent mechanisms

Int J Cancer. 2001 Dec 1;94(5):637-44. doi: 10.1002/ijc.1514.


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-kappaB (NF-kappaB), leading to accelerated tumor growth, angiogenesis and metastasis in vivo. In our study, we investigated the effect of the regulatory cytokines, IL-1alpha, EGF and TGF-beta1 on activation of NF-kappaB and Gro1 in primary and metastatic sublines of the murine SCC Pam 212. We found that Gro 1 expression could be induced by IL-1alpha 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-1alpha 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-beta1 suppressed constitutive as well as IL-1alpha and EGF-inducible Gro 1 production in both Pam 212 and LY-2 cells. IL-1alpha and EGF, but not TGF-beta1, were found to activate NF-kappaB in Pam 212, whereas none of the stimulants showed a significant effect on constitutive activation of NF-kappaB in LY-2 cells. Overexpression of a super repressor IkappaBalphaM in Pam 212 inhibited NF-kappaB binding activity, which led to impaired Gro 1 induction by IL-1alpha and EGF. These results demonstrate that IL-1alpha, EGF, and TGF-beta1 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-kappaB activation. Published 2001 Wiley-Liss, Inc.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Chemokine CXCL1
  • Chemokines, CXC*
  • Chemotactic Factors / genetics*
  • DNA-Binding Proteins / physiology
  • Epidermal Growth Factor / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Growth Substances / genetics*
  • I-kappa B Proteins*
  • Intercellular Signaling Peptides and Proteins*
  • Interleukin-1 / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / physiology*
  • Neoplasm Metastasis
  • Neovascularization, Pathologic / etiology
  • RNA, Messenger / analysis
  • Transforming Growth Factor beta / pharmacology


  • Chemokine CXCL1
  • Chemokines, CXC
  • Chemotactic Factors
  • Cxcl1 protein, mouse
  • DNA-Binding Proteins
  • Growth Substances
  • I-kappa B Proteins
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-1
  • NF-kappa B
  • Nfkbia protein, mouse
  • RNA, Messenger
  • Transforming Growth Factor beta
  • NF-KappaB Inhibitor alpha
  • Epidermal Growth Factor