Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression

J Leukoc Biol. 1997 Nov;62(5):588-97. doi: 10.1002/jlb.62.5.588.

Abstract

By reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry, MGSA-alpha, -beta, -gamma, and CXCR2 mRNA expression and proteins are detected in 7 out of 10 human melanoma lesions. The biological consequence of constitutive expression of the MGSA/GRO chemokine in immortalized melanocytes was tested in SCID and nude mouse models. Continuous expression of MGSA/GRO-alpha, -beta, or -gamma in immortalized melan-a mouse melanocytes results in nearly 100% tumor formation for each of the clones tested, whereas clones expressing only the neomycin resistance vector form tumors <10% of the time. Moreover, antibodies to the MGSA/GRO proteins slow or inhibit the formation of tumors in the SCID mouse model and block the angiogenic response to conditioned medium from the tumor-producing clones. Transcription of the MGSA/GRO chemokines is regulated by an enhancesome-like complex comprised of the nuclear factor-kappaB (NF-kappaB), HMG(I)Y, IUR, and Sp1 elements. In Hs294T melanoma cells the half life of the IKB protein is shortened in comparison to normal retinal epithelial cells, facilitating the endogenous nuclear localization of NF-kappaB. We propose that this endogenous nuclear NF-kappaB, working in concert with the 115-kDa IUR-binding factor, promotes constitutive expression of MGSA/GRO genes.

Publication types

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

MeSH terms

  • Animals
  • Chemokine CXCL1
  • Chemokines / biosynthesis*
  • Chemokines, CXC*
  • Chemotactic Factors / biosynthesis*
  • Disease Progression
  • Growth Substances / biosynthesis*
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Melanoma / metabolism*
  • Melanoma / pathology*
  • Mice

Substances

  • CXCL1 protein, human
  • Chemokine CXCL1
  • Chemokines
  • Chemokines, CXC
  • Chemotactic Factors
  • Cxcl1 protein, mouse
  • Growth Substances
  • Intercellular Signaling Peptides and Proteins