Effect of Hypoxia on DDR1 Expression in Pituitary Adenomas

Abstract

BackgroundPituitary 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.Material/MethodsA 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.ResultsDDR1 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.ConclusionsHypoxia 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.

Role of matrix Metalloproteinases in pituitary adenoma invasion

“…They revealed that PA invasion is enhanced by the binding of DDR1-collagen I which elevates the cellular secretion of MMP-2 and MMP-9. A further research demonstrated that hypoxia increases the expression of DDR1 at mRNA and protein levels [42]. It is also confirmed that hypoxia-associated overexpression of DDR1 enhances the secretion of MMP-2 and MMP-9 and promotes PA invasion [42].…”

Genome-Wide Analysis and Function Prediction of Long Noncoding RNAs in Sheep Pituitary Gland Associated with Sexual Maturation

“…Up-regulated gene CLOCK [60], NUMB [61] and down-regulated gene JAK1 [62] were found to be involved in pituitary development, CLOCK played a key regulatory role in gonadotropin release of pituitary, as well [63]. Down-regulated gene DDR1 was investigated that promoting pituitary adenoma cell proliferation and invasion by reason of increasing expression of DDR1 in hypoxia condition [64]. Sox family of transcription factors can regulate the embryonic development and the determination of cell fate, such as SOX2 and SOX3 were pivotal in pituitary function exertion [12].…”

Effect of selective small molecule inhibitors on MMP-9 and VEGFR-1 expression in p16-positive and -negative squamous cell carcinoma

“…The mechanism of decreased MMP-9 expression following treatment with nilotinib and dasatinib remain to be elucidated. A recent study demonstrated that MMP-9 expression may be decreased in pituitary adenomas, suggesting that nilotinib exerts its inhibitory effects through the inhibition of the tyrosine kinase receptor, epithelial discoidin domain-containing receptor 1 (DDR1) (55). The present study hypothesizes that DDR1 may be associated with the regulation of MMPs, including MMP-2 and MMP-9, and therefore, may be associated with the mechanism of decreased MMP-9 levels in HNSCC, although DDR1 expression patterns in HNSCC remain to be elucidated.…”