Effect of Hypoxia on DDR1 Expression in Pituitary Adenomas.
BACKGROUND
Pituitary adenoma is a common intracranial tumor in neurosurgery. Some pituitary adenomas have the characteristics of invasive growth make them unable to be removed completely by surgery leading to easy relapse. Discoidin domain receptor l (DDR1) is a new kind of tyrosine kinase receptor on the cell surface. DDR1 can be activated by tumor microenvironment signal in tumorigenesis, increasing MMP-2/9 expression and promoting the invasive ability of tumor cells. Anoxia can promote tumor growth and metastasis. This study investigated the impact of anoxic environment DDR1 expression in pituitary adenoma.


METHODS
A primary hypoxia pituitary adenoma cell model was established and treated with DDR1 inhibitor nilotinib. Real-time PCR and Western blot were used to detect DDR1 mRNA and protein expression. ELISA was used to detect MMP-2/9 changes. MTT method was used to detect pituitary adenoma cell proliferation. We used a transwell chamber to determine pituitary adenoma cell invasion ability.


RESULTS
DDR1 mRNA and protein were significantly overexpressed under hypoxia (P<0.05). MMP-2 and MMP-9 expression was obviously increased in supernatant (P<0.05). Pituitary adenoma cell proliferation and invasive ability improved markedly under hypoxia (P<0.05). Nilotinib could reduce DDR1 expression, decrease MMP-2 and MMP-9 expression, and inhibit pituitary adenoma cells proliferation and invasion.


CONCLUSIONS
Hypoxia can increase DDR1 expression in pituitary adenoma cells, leading to improved MMP-2 and MMP-9 secretion, and promoting pituitary adenoma cell proliferation and invasion.
Department of Neurosurgery, First Affiliated Hospital of Chinese PLA General Hospital, Bejing, China (mainland).
Shouchun
S
Li
Department of Neurosurgery, First Affiliated Hospital of Chinese PLA General Hospital, Bejing, China (mainland).
Zhiwen
Z
Zhang
Department of Neurosurgery, First Affiliated Hospital of Chinese PLA General Hospital, Bejing, China (mainland).
Jinghui
J
Xue
Department of Neurosurgery, First Affiliated Hospital of Chinese PLA General Hospital, Bejing, China (mainland).
Xiaoming
X
Guo
Department of Neurosurgery, First Affiliated Hospital of Chinese PLA General Hospital, Bejing, China (mainland).
Shuli
S
Liang
Department of Neurosurgery, First Affiliated Hospital of Chinese PLA General Hospital, Bejing, China (mainland).
Aijun
A
Liu
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology; D015687:Cell Hypoxia / Q000235:genetics* / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D000070819:Discoidin Domain Receptor 1; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C498826:nilotinib