Nitrilase 1 modulates lung tumor progression in vitro and in vivo

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Novel therapeutic targets for non-small cell lung cancer (NSCLC) are needed.
• Nitrogenase 1 (Nit1) has been implicated in suppressing chemically induced carcinogenesis in mouse models.
• The role of Nit1 in Kras-driven lung tumorigenesis remains unclear.

Purpose of the Study:

• To investigate the role of Nit1 in a transgenic mouse model of non-small cell lung cancer (NSCLC) driven by a Kras G12D mutation.
• To determine if Nit1 inactivation affects lung tumor development and response to chemotherapy.

Main Methods:

• Crossed Nit1 knockout mice (Nit1-/-) with KrasG12D/+ mice to generate a compound mutant model (Nit1-/-:KrasG12D/+).
• Assessed tumor volume using Micro-CT scans and gross measurements.
• Quantified Nit1 expression in human lung cancer tissues and cell lines.
• Utilized siRNA to knockdown Nit1 in lung cancer cells in vitro and evaluated cell survival.
• Assessed the in vitro and in vivo response to cisplatin in Nit1-deficient models.

Main Results:

• Lung tumorigenesis was significantly suppressed in Nit1-/-:KrasG12D/+ mice, with a 5-fold reduction in total tumor volume compared to Nit1+/+KrasG12D/+ mice (p<0.01).
• Nit1 is highly expressed in human lung cancer tissues and cell lines.
• Nit1 knockdown using siRNA decreased lung cancer cell survival in vitro.
• Nit1 deficiency enhanced sensitivity to cisplatin in both human lung cancer cells in vitro and in KrasG12D/+ mouse tumors in vivo.

Conclusions:

• Nit1 plays a supportive role in modulating lung tumorigenesis in a Kras-driven mouse model.
• Nit1 is upregulated in human lung cancer and contributes to cell survival.
• Nit1 represents a potential novel therapeutic target for non-small cell lung cancer (NSCLC) treatment, particularly in combination with chemotherapy like cisplatin.