Activation of matrix metalloproteinase-9 (MMP-9) by neurotensin promotes cell invasion and migration through ERK pathway in gastric cancer

• DOI: 10.1007/s13277-015-3282-9
• Publication Date: 2015-02-27T10:16:51Z
• Authors: Hafeza Akter; Min Park; Oh-Seung Kwon; Eun Joo Song; Won-Sang Park; Min-Jung Kang
• Keywords: Adult; Aged, 80 and over; Male; Transcriptional Activation; 0301 basic medicine; MAP Kinase Signaling System; Middle Aged; 3. Good health; Gene Expression Regulation, Neoplastic; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Matrix Metalloproteinase 9; Cell Movement; Stomach Neoplasms; Cell Line, Tumor; Quinolines; Humans; Matrix Metalloproteinase 2; Pyrazoles; Female; Neoplasm Invasiveness; Neurotensin; Aged

Neurotensin (NT) is distributed throughout the brain and gastrointestinal tract. Although the relationship between NT and matrix metalloproteinase-9 (MMP-9) activity in gastric cancer has not been reported, the elevation of MMP-9 and NT is reported in the breast, lung, prostate, and gastric cancer. The aim of our study is to investigate the relationship between NT and MMP-9 activity and the underlying signaling mechanism in gastric cancer cell lines. Commercial ELISA kits were used for estimation of NT and MMP-9 expression, and fluorescence resonance energy transfer (FRET) assay was used for measurement of MMP-9 activity. Cell migration and invasion were determined by wound healing and transwell assay. The expression of signaling proteins was measured by Western blotting. Our study reveals a positive correlation between increased plasma NT and MMP-9 activity in both of patient's serum and gastric cancer cell lines. A dose-dependent elevation of MMP-9 activity was observed by NT treatment in gastric cancer cells (MKN-1 and MKN-45) compared to untreated gastric cancer and normal epithelial cell (HFE-145). Moreover, NT-mediated migration and invasion were observed in gastric cancer cells unlike in normal cell. The signaling mechanism of NT in gastric cancer cells was confirmed in protein kinase C (PKC), extracellular-signal regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K) pathway. In addition, pretreatment of gastric cancer cells with NTR1 inhibitor SR48692 was shown to significantly inhibit the NT-mediated MMP-9 activity, cell invasion, and migration. Our finding illustrated NTR1 could be a possible therapeutic target for gastric cancer.