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ADAM15 targets MMP9 activity to promote lung cancer cell invasion
Dan-Dan Dong1, Hui Zhou2, Gao Li3
1Department of Pathology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
Abstract:
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.
Insights
High expression of ADAM15 (a disintegrin and metalloproteinase) correlates with poor survival in non-small cell lung cancer (NSCLC). ADAM15 promotes cancer cell invasion by activating MMP9 via the MEK-ERK pathway.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- ADAM15 (a disintegrin and metalloproteinase) is implicated in cancer metastasis.
- Its role in non-small cell lung cancer (NSCLC) remains unclear.
Purpose of the Study:
- To investigate the function and mechanism of ADAM15 in NSCLC progression.
- To determine the association between ADAM15 expression and patient survival.
Main Methods:
- Analysis of ADAM15 expression in NSCLC patient cohorts.
- shRNA-mediated knockdown of ADAM15 in lung cancer cell lines.
- Investigation of the MEK-ERK pathway and MMP9 activation.
- In vitro and in vivo studies of ADAM15-MMP9 interaction.
Main Results:
- High ADAM15 expression is linked to decreased overall survival (OS) and disease-free survival (DFS) in NSCLC patients.
- ADAM15 knockdown reduces cancer cell migration and invasion.
- ADAM15 activates MMP9 expression and activity via the MEK-ERK pathway, promoting invasion.
Conclusions:
- ADAM15 plays a pro-metastatic role in NSCLC.
- ADAM15 promotes lung cancer cell invasion by directly activating MMP9.
