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Published on: October 9, 2016
Differential roles of STAT3 in the initiation and growth of lung cancer
Jingjiao Zhou1,2, Zhaoxia Qu1,2, Shapei Yan1,2
1University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Abstract:
Signal transducer and activator of transcription 3 (STAT3) is linked to multiple cancers, including pulmonary adenocarcinoma. However, the role of STAT3 in lung cancer pathogenesis has not been determined. Using lung epithelial-specific inducible knockout strategies, we demonstrate that STAT3 has contrasting roles in the initiation and growth of both chemically and genetically induced lung cancers. Selective deletion of lung epithelial STAT3 in mice before cancer induction by the smoke carcinogen, urethane, resulted in increased lung tissue damage and inflammation, K-Ras oncogenic mutations and tumorigenesis. Deletion of lung epithelial STAT3 after establishment of lung cancer inhibited cancer cell proliferation. Simultaneous deletion of STAT3 and expression of oncogenic K-Ras in mouse lung elevated pulmonary injury, inflammation and tumorigenesis, but reduced tumor growth. These studies indicate that STAT3 prevents lung cancer initiation by maintaining pulmonary homeostasis under oncogenic stress, whereas it facilitates lung cancer progression by promoting cancer cell growth. These studies also provide a mechanistic basis for targeting STAT3 to lung cancer therapy.
Insights
Signal transducer and activator of transcription 3 (STAT3) plays a dual role in lung cancer. It prevents tumor initiation by maintaining homeostasis but promotes cancer growth once established, offering therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Pulmonary Medicine
Background:
- Signal transducer and activator of transcription 3 (STAT3) is implicated in various cancers, including lung adenocarcinoma.
- The precise role of STAT3 in lung cancer development and progression remains unclear.
Purpose of the Study:
- To elucidate the specific functions of STAT3 in lung cancer initiation and growth.
- To investigate the contrasting roles of STAT3 in different stages of lung cancer pathogenesis.
Main Methods:
- Utilized lung epithelial-specific inducible knockout mouse models.
- Induced lung cancer using chemical carcinogens (urethane) and genetic manipulations (oncogenic K-Ras).
- Assessed lung tissue damage, inflammation, oncogenic mutations, and tumor cell proliferation.
Main Results:
- Deleting STAT3 before cancer induction increased lung damage, inflammation, K-Ras mutations, and tumorigenesis.
- Deleting STAT3 after cancer establishment inhibited tumor cell proliferation.
- Simultaneous deletion of STAT3 and K-Ras expression led to increased injury, inflammation, and tumorigenesis, but reduced tumor growth.
Conclusions:
- STAT3 acts as a tumor suppressor in lung cancer initiation by preserving pulmonary homeostasis under stress.
- STAT3 functions as an oncogene in lung cancer progression by promoting cancer cell proliferation.
- These findings provide a mechanistic rationale for targeting STAT3 in lung cancer therapy.
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