Tid1 negatively regulates the migratory potential of cancer cells by inhibiting the production of interleukin-8.
Tid1 is the human homologue of the Drosophila tumor suppressor, Tid56. Reducing the expression of Tid1 in MDA-MB231 breast cancer cells enhanced their migration without affecting their survival or growth rate. From microarray screening, we discovered that after Tid1 depletion, the mRNA level of interleukin-8 (IL-8) was significantly increased in these cancer cells, which consequently increased secretion of IL-8 protein by 3.5-fold. The enhanced migration of these Tid1-knockdown cells was blocked by reducing the IL-8 expression or by adding an IL-8 neutralizing antibody to the culture medium, suggesting that enhancement of cell motility in these Tid1-deficient cells is dependent on the de novo synthesis of IL-8. Subsequently, we found that abrogating the nuclear factor kappaB binding site in the IL-8 promoter completely blocked the Tid1 depletion-induced IL-8 expression in the breast cancer cells. As increased IL-8 levels are known to promote tumor metastasis, we tested the effect of Tid1 knockdown on tumor metastasis and found that Tid1 depletion enhanced the metastasis of breast cancer cells in animals. Together, these results indicate that Tid1 negatively regulates the motility and metastasis of breast cancer cells, most likely through attenuation of nuclear factor kappaB activity on the promoter of the IL8 gene.
Kim
Sung-Woo
SW
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Hayashi
Masaaki
M
Lo
Jeng-Fan
JF
Fearns
Colleen
C
Xiang
Rong
R
Lazennec
Gwendal
G
Yang
Young
Y
Lee
Jiing-Dwan
JD
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D005167:Factor VII / Q000494:pharmacology; D015942:Factor VIIa; D050956:HSP40 Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation
C120664:DNAJA3 protein, human; D050956:HSP40 Heat-Shock Proteins; D016209:Interleukin-8; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa