Caspase 9b Drives Cellular Transformation, Lung Inflammation, and Lung Tumorigenesis

Area of Science:

• Molecular Biology
• Cancer Research
• Immunology

Background:

• Caspase 9 alternative splicing yields proapoptotic Caspase 9a and pro-survival Caspase 9b (C9b).
• C9b is prevalent in non-small cell lung cancer and activates the NF-κB pathway.
• The in vivo roles of C9b in inflammation, immunity, and tumorigenesis require elucidation.

Purpose of the Study:

• To investigate the in vivo function of C9b in lung inflammation and immune responses.
• To determine the role of C9b in lung tumorigenesis.
• To examine C9b's cooperation with oncogenic factors in cell transformation.

Main Methods:

• Generation of a transgenic mouse model expressing human C9b in lung pneumocytes.
• Analysis of NF-κB pathway activation, lung inflammation, and immune cell infiltration.
• Assessment of spontaneous lung tumor development and cooperation with oncogenic KRAS and p53 downregulation in cell transformation models.

Main Results:

• C9b transgenic mice exhibited inflammatory lung lesions, elevated NF-κB activity, and increased immunosuppressive myeloid-derived suppressor cells.
• Facial dermatitis, dermal changes, and elevated serum IL6 were observed in C9b mice.
• C9b expression promoted spontaneous lung tumor formation and cooperated with oncogenic KRAS and p53 loss in driving cell transformation.

Conclusions:

• C9b directly activates the NF-κB pathway in vivo, modulating lung inflammation, immune responses, and peripheral immunity.
• C9b is a critical factor in driving cell transformation and promoting lung tumorigenesis.
• C9b's pro-survival function and pathway activation highlight its significance in lung cancer progression.