STAT3 can serve as a hit in the process of malignant transformation of primary cells

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Signal transducer and activator of transcription 3 (STAT3) is a transcription factor crucial for many pro-oncogenic signals.
• STAT3 is constitutively active in numerous tumors and plays a key role in inflammation-driven tumorigenesis, often activated by IL-6.
• Constitutively active STAT3 (STAT3C) in mouse embryonic fibroblasts (MEFs) leads to transformed cell phenotypes.

Purpose of the Study:

• To investigate if pre-existing constitutively active STAT3 is sufficient to initiate malignant transformation in primary MEFs.
• To determine the STAT3-dependent mechanisms underlying this transformation.
• To explore the role of hypoxia-inducible factor 1-alpha (HIF-1α) in STAT3-mediated oncogenesis.

Main Methods:

• Utilized mouse embryonic fibroblasts (MEFs) from STAT3C knock-in mice expressing active STAT3.
• Assessed cellular transformation hallmarks including proliferation, apoptosis resistance, senescence, and aerobic glycolysis.
• Measured STAT3 dependency, anti-apoptotic gene expression, and HIF-1α levels.

Main Results:

• Pre-existing constitutively active STAT3 primes primary MEFs for malignant transformation upon spontaneous immortalization.
• Transformation is strictly dependent on STAT3 activity and associated with high apoptosis resistance and increased pro-survival gene expression.
• Hypoxia inducible factor (HIF)-1α levels increased twofold, contributing to STAT3's oncogenic activity by promoting aerobic glycolysis.

Conclusions:

• Constitutively active STAT3 can act as an initial oncogenic hit, predisposing cells to malignant transformation.
• This finding is particularly relevant in chronically inflamed tissues, known pro-oncogenic microenvironments.
• STAT3's role extends beyond tumor progression to initiating carcinogenesis, highlighting its significance in early cancer development.