Enhancement of pituitary adenoma cell invasion and adhesion is mediated by discoidin domain receptor-1.
The discoidin domain receptor-1 (DDR1) tyrosine kinases are a family of cell surface receptors that bind to several types of collagen and facilitate cell adhesion that is known association with several cancers. However, no previous study has examined the expression and function of DDR1 in pituitary adenoma. Tissue microarray analysis of DDR1 expression levels in 52 pituitary adenoma tissues revealed that DDR1 expression was significantly related to hormonal background (Kruskal-Wallis test; P < 0.0001). To further elucidate the function of DDR1 in pituitary adenoma, we developed DDR1 over- and under-expressing cell lines using DDR1 clone transfection and short interfering ribonucleic acids (siRNA)-based DDR1 gene silencing, respectively, in a human pituitary adenoma cell line (HP-75). Real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting confirmed that expression of both DDR1 isoforms (DDR1a and DDR1b) was elevated by clone transfection and diminished by siRNA. Matrigel invasion assays revealed that cell invasion was increased in HP-75 cells over-expressing DDR1 and decreased in cells under-expressing DDR1. Consistent with this, zymography revealed that the activation levels of matrix metalloproteinase (MMP)-2 and -9 were increased and decreased in cells over- and under-expressing DDR1, respectively. Examination of in vitro cell adhesion to collagen types I, II, III, and IV with respect to MMP-2 and -9 expression revealed that DDR1 regulated cell adhesion to collagen type I, which was responsible for accelerating secretion of MMP-2 and -9 in DDR1 over-expressing cells. Taken together, these results strongly suggest that DDR1 mediates cell invasion-related signaling between collagen type I and MMP-2 and -9 in pituitary adenoma cells.
Yoshida
Daizo
D
Department of Neurosurgery, Nippon Medical School, 1-1-5, Sendagi, Tokyo, Japan. dyoshida@nms.ac.jp
Teramoto
Akira
A
D000236:Adenoma / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D002448:Cell Adhesion / Q000502:physiology*; D024042:Collagen Type I / Q000378:metabolism*; D000070818:Discoidin Domain Receptors; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010911:Pituitary Neoplasms / Q000378:metabolism / Q000473:pathology*; D040081:Protein Array Analysis; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured
D024042:Collagen Type I; D012333:RNA, Messenger; D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9