ADAM15 targets MMP9 activity to promote lung cancer cell invasion.
ADAM15 is a membrane-associated proteinase belonging to a disintegrin and metalloproteinase (ADAM) family. Recent studies suggested that ADAM15 is overexpressed in several types of cancer and is involved in metastatic tumor progression. However, the function of ADAM15 in non-small cell lung cancer (NSCLC) is currently unknown. In the present study, we found that high expression of ADAM15 was associated with decreased overall survival (OS) and disease-free survival (DFS) in NSCLC patients. Furthermore, shRNA-mediated knockdown of ADAM15 attenuated cell migration and invasion. Mechanistic study demonstrated that ADAM15 upregulated MMP9 expression in lung cancer cells via activation of the MEK-ERK pathway. Moreover, ADAM15 proteolytically cleaved and activated pro-MMP9 in vitro and interacted with MMP9 in vivo. Overexpression of ADAM15 in A549 cells promoted cell invasion, while knocking down MMP9 attenuated cell invasive ability. Therefore, our data not only support a pro-metastatic role of ADAM15 in lung cancer progression, but also reveal a novel mechanism of ADAM15 in promoting cancer cell invasion through directly targeting MMP9 activation.
Department of Pathology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
Dan-Dan
DD
Dong
Department of Thoracic Medicine, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China.
Hui
H
Zhou
Department of Thoracic Surgery, Hainan General Hospital, Haikou, Hainan 570311, P.R. China.
Gao
G
Li
D051722:ADAM Proteins / Q000502:physiology*; D000230:Adenocarcinoma / Q000201:enzymology* / Q000401:mortality / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000401:mortality / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D018572:Disease-Free Survival; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology*; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models
D008565:Membrane Proteins; D051722:ADAM Proteins; C098660:ADAM15 protein, human; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9