Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Signal transducer and activator of transcription 3 (STAT3) is often viewed as oncogenic in lung cancer.
• Targeting STAT3 is a proposed therapeutic strategy for various malignancies.

Purpose of the Study:

• To investigate the role of STAT3 in KRAS-mutant lung adenocarcinoma (AC).
• To elucidate the underlying mechanisms of STAT3's function in this context.

Main Methods:

• Lung tissue-specific Stat3 inactivation in Kras(G12D) mutant mice.
• STAT3 knockdown in human AC xenograft models.
• Clinical correlation analysis of STAT3 expression with patient survival and tumor stage.
• Mechanistic studies involving NF-κB and IL-8 signaling pathways.

Main Results:

• STAT3 inactivation in mice accelerated Kras(G12D)-driven AC initiation, progression, and reduced survival.
• STAT3 knockdown in human AC xenografts increased tumor growth.
• Low STAT3 expression correlated with poor survival and advanced malignancy in human lung AC patients with smoking history (prone to KRAS mutations).
• KRAS mutant lung tumors showed reduced STAT3 levels.
• STAT3 was found to sequester NF-κB in the cytoplasm, inhibiting NF-κB-induced IL-8 expression, myeloid cell infiltration, and tumor vascularization.

Conclusions:

• STAT3 plays a tumor-suppressive role in KRAS-mutant lung adenocarcinoma, contrary to its general oncogenic role.
• A novel STAT3-NF-κB-IL-8 axis regulates tumor progression in KRAS-mutant AC.
• STAT3 has significant therapeutic and prognostic relevance for KRAS-mutant lung AC.