High mobility group box-1-inducible melanoma inhibitory activity is associated with nodal metastasis and lymphangiogenesis in oral squamous cell carcinoma.
Melanoma inhibitory activity (MIA) is an 11-kDa secretory protein isolated from malignant melanoma cells that is correlated with invasion and metastasis in various human malignancies. We examined MIA expression in 62 oral squamous cell carcinomas (OSCC) by immunohistochemistry. MIA expression was significantly associated with nodal metastasis (P = 0.00018). MIA expression was also associated with expression of high mobility group box-1 (HMGB1) (P < 0.0001) and lymph vessel density (P < 0.0001). Expression levels of MIA, HMGB1, nuclear factor kB (NFkB) p65 and HMGB1-NFkB p65 binding were significantly higher in a metastatic human OSCC cell line (HSC3) than those in a non-metastatic OSCC cell line (HSC4). Treatment with receptor for advanced glycation end products (RAGE) antisense or small interfering RNA and human recombinant HMGB1 (hrHMGB1) did not affect MIA expression, whereas HMGB1 antisense or siRNA treatment decreased MIA expression in HSC3 cells. Then HMGB1 enhanced MIA expression as an NFkB cofactor but not as a RAGE ligand. MIA neutralization by MIA antibodies increased extracellular signal-related kinase 1/2 phosphorylation, but decreased p38 phosphorylation and the expression of vascular epithelial growth factor (VEGF)-C and -D. Treatment with p38 inihibitor decreased VEGF-C and -D expression in HSC3 cells. These results suggest that MIA expression is enhanced by the interaction of intracellular HMGB1 and NFkBp65 and MIA is closely involved in tumor progression and nodal metastasis by the increments of VEGF-C and VEGF-D in OSCC.
Sasahira
Tomonori
T
Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara, Japan.
Kirita
Tadaaki
T
Oue
Naohide
N
Bhawal
Ujjal Kumar
UK
Yamamoto
Kazuhiko
K
Fujii
Kiyomu
K
Ohmori
Hitoshi
H
Luo
Yi
Y
Yasui
Wataru
W
Bosserhoff
Anja Katrin
AK
Kuniyasu
Hiroki
H
D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D024002:HMGB Proteins / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins; D051996:Transcription Factor RelA / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism
D016326:Extracellular Matrix Proteins; D024002:HMGB Proteins; D024243:HMGB1 Protein; C090059:MIA protein, human; D016328:NF-kappa B; D009363:Neoplasm Proteins; D051996:Transcription Factor RelA; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D