Objective:

To investigate the role of CFTR in adenoid cystic carcinoma and its potential as a tumor suppressor.

Approach:

• Gene Expression Analysis: Differential expression analysis of multiple transcriptomic cohorts identified CFTR as downregulated in adenoid cystic carcinoma.
• Functional Experiments: Ectopic expression and knockdown of CFTR were performed in SACC-83 and SACC-LM cell lines, alongside RNA sequencing and Western blot analyses.
• Pharmacological Inhibition: Hsp70 was inhibited using VER155008, and the heat shock response was activated by HSF1A to assess effects on cell viability and migration.
• Xenograft Experiments: Subcutaneous xenograft experiments in nude mice evaluated tumor growth following stable CFTR knockdown.

Key Findings:

• Low CFTR expression is associated with inferior overall survival in preliminary analyses.
• CFTR acts as a tumor suppressor, with its ectopic expression suppressing cell proliferation, migration, and invasion.
• CFTR knockdown enhances malignant phenotypes in cell lines.
• Pharmacological inhibition of Hsp70 mimics the effects of CFTR restoration, reducing cell viability and inducing apoptosis.
• Stable CFTR knockdown accelerates tumor growth in xenograft models.

Interpretation:

CFTR silencing in adenoid cystic carcinoma correlates with increased Hsp70 expression, suggesting a potential therapeutic target in Hsp70.

Limitations:

• The association of low CFTR expression with poor survival requires validation in larger cohorts.
• The study primarily relies on cell line models and xenografts, which may not fully replicate human disease.

Conclusion:

Targeting Hsp70 presents a preclinical rationale for further investigation in adenoid cystic carcinoma treatment.