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TMPRSS4 regulates levels of integrin α5 in NSCLC through miR-205 activity to promote metastasis
L Larzabal1, A L de Aberasturi2, M Redrado1
1Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Background:
TMPRSS4 is a membrane-anchored protease involved in cell migration and invasion in different cancer types including lung cancer. TMPRSS4 expression is increased in NSCLC and its inhibition through shRNA reduces lung metastasis. However, molecular mechanisms leading to the protumorigenic regulation of TMPRSS4 in lung cancer are unknown.
Methods:
miR-205 was identified as an overexpressed gene upon TMPRSS4 downregulation through microarray analysis. Cell migration and invasion assays and in vivo lung primary tumour and metastasis models were used for functional analysis of miR-205 overexpression in H2170 and H441 cell lines. Luciferase assays were used to identify a new miR-205 direct target in NSCLC.
Results:
miR-205 overexpression promoted an epithelial phenotype with increased E-cadherin and reduced fibronectin. Furthermore, miR-205 expression caused a G0/G1 cell cycle arrest and inhibition of cell growth, migration, attachment to fibronectin, primary tumour growth and metastasis formation in vivo. Integrin α5 (a proinvasive protein) was identified as a new miR-205 direct target in NSCLC. Integrin α5 downregulation in lung cancer cells resulted in complete abrogation of cell migration, a decreased capacity to adhere to fibronectin and reduced in vivo tumour growth, compared with control cells. TMPRSS4 silencing resulted in a concomitant reduction of integrin α5 levels.
Conclusion:
We have demonstrated for the first time a new molecular pathway that connects TMPRSS4 and integrin α5 through miR-205 to regulate cancer cell invasion and metastasis. Our results will help designing new therapeutic strategies to inhibit this novel pathway in NSCLC.
Insights
We discovered a new pathway where miR-205 links TMPRSS4 to integrin α5, inhibiting lung cancer cell invasion and metastasis. This finding offers new therapeutic targets for non-small cell lung cancer (NSCLC).
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- TMPRSS4 protease activity drives cell migration and invasion in lung cancer.
- Elevated TMPRSS4 expression correlates with increased metastasis in non-small cell lung cancer (NSCLC).
- The regulatory mechanisms of TMPRSS4 in lung cancer remain largely unknown.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying TMPRSS4's protumorigenic role in NSCLC.
- To identify novel therapeutic targets for inhibiting lung cancer progression and metastasis.
Main Methods:
- Microarray analysis identified miR-205 as upregulated upon TMPRSS4 inhibition.
- Functional assays (migration, invasion, in vivo models) assessed miR-205's role.
- Luciferase assays identified direct targets of miR-205 in NSCLC cells.
Main Results:
- miR-205 overexpression induced an epithelial phenotype, cell cycle arrest, and inhibited growth and metastasis.
- Integrin α5 was identified as a direct miR-205 target, crucial for cell migration and invasion.
- TMPRSS4 silencing led to decreased integrin α5 levels, confirming the pathway.
Conclusions:
- A novel molecular pathway involving TMPRSS4, miR-205, and integrin α5 in regulating NSCLC invasion and metastasis was elucidated.
- This pathway represents a potential therapeutic target for novel anti-cancer strategies in NSCLC.
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