hMENA isoforms impact NSCLC patient outcome through fibronectin/β1 integrin axis

Area of Science:

• Molecular Biology
• Cell Biology
• Cancer Research

Background:

• The actin regulator hMENA exists in two isoforms, hMENA^11a and hMENAΔv6, with opposing roles in cell invasiveness.
• The precise mechanisms by which these isoforms influence cell behavior and signaling pathways remain largely unelucidated.

Purpose of the Study:

• To elucidate the functional mechanisms of hMENA^11a and hMENAΔv6.
• To investigate the regulation of β1 integrin by hMENA isoforms.
• To explore the clinical relevance of hMENA isoforms in non-small cell lung cancer (NSCLC).

Main Methods:

• Depletion of total hMENA to assess its effect on nuclear localization of myocardin-related transcription factor 1 (MRTF-A) and β1 integrin expression.
• Analysis of the G-actin/F-actin ratio to understand MRTF-A localization and serum response factor (SRF) activity.
• Exogenous expression of hMENA isoforms in cancer cells to evaluate their impact on β1 integrin activation, extracellular matrix (ECM) component secretion, and fibronectin production.
• Correlation analysis of hMENA^11a expression with stromal fibronectin and clinical outcomes in NSCLC patients.

Main Results:

• hMENA depletion reduces nuclear MRTF-A, increases the G-actin/F-actin ratio, inhibits SRF activity, and decreases β1 integrin expression.
• hMENA^11a suppresses β1 integrin activation and ECM secretion, while hMENAΔv6 promotes β1 integrin activation and fibronectin production.
• High hMENA^11a expression correlates with low stromal fibronectin and favorable outcomes in early-stage, node-negative NSCLC patients.

Conclusions:

• hMENA isoforms differentially regulate the β1 integrin-ECM signaling axis, impacting cancer cell invasiveness.
• These findings provide mechanistic insights into hMENA's role in cancer progression.
• The study identifies hMENA isoforms as potential biomarkers for risk stratification and therapeutic guidance in NSCLC patients.