Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression.
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.
Luan
J
J
Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Shattuck-Brandt
R
R
Haghnegahdar
H
H
Owen
J D
JD
Strieter
R
R
Burdick
M
M
Nirodi
C
C
Beauchamp
D
D
Johnson
K N
KN
Richmond
A
A
D000818:Animals; D054360:Chemokine CXCL1; D018925:Chemokines / Q000096:biosynthesis*; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis*; D018450:Disease Progression; D006133:Growth Substances / Q000096:biosynthesis*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D051379:Mice
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins