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Published on: October 30, 2013
Knockout of phospholipase Cε attenuates N-butyl-N-(4-hydroxybutyl) nitrosamine-induced bladder tumorigenesis
Taimao Jiang1, Tao Liu1, Lin Li2
1Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
Abstract:
Bladder cancer frequently shows mutational activation of the oncogene Ras, which is associated with bladder carcinogenesis. However, the signaling pathway downstream of Ras remains to be fully elucidated. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) is able to induce bladder cancer by driving the clonal expansion of initiated cells carrying the activated form of Ras. Phospholipase Cε (PLCε) is the main target of BBN, while the tumor promoting role of PLCε remains controversial. The present study examined the role of PLCε in BBN‑induced bladder carcinogenesis of mice with genetically inactivated PLCε. Using light and electron microscopy, the present study demonstrated that PLCε(‑/‑) mice were resistant to BBN‑induced bladder carcinogenesis. Furthermore, it was demonstrated that cyclooxygenase 2 and vascular endothelial growth factor‑A were affected by the PLCε background of the mice, suggesting that the role of PLCε in tumor promotion may be ascribed to augmentation of inflammatory responses and angiogenesis. These results indicated that PLCε is crucial for BBN‑induced bladder carcinogenesis as well as signaling downstream of Ras, and that PLCε is a candidate molecular target for the development of anti-cancer drugs.
Insights
Phospholipase Cε (PLCε) is crucial for bladder cancer development initiated by Ras mutations. Mice lacking PLCε resisted N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer, indicating PLCε as a potential anti-cancer drug target.
Area of Science:
- Oncology
- Molecular Biology
- Carcinogenesis
Background:
- Ras oncogene mutations are common in bladder cancer.
- The downstream signaling pathways of Ras are not fully understood.
- N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) induces bladder cancer via Ras activation.
Purpose of the Study:
- To investigate the role of Phospholipase Cε (PLCε) in N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder carcinogenesis.
- To determine if PLCε is essential for tumor promotion in bladder cancer.
Main Methods:
- Utilized genetically modified mice lacking PLCε (PLCε(‑/‑)).
- Administered N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to induce bladder cancer.
- Employed light and electron microscopy for histological analysis.
- Assessed levels of cyclooxygenase 2 and vascular endothelial growth factor-A.
Main Results:
- PLCε(‑/‑) mice exhibited resistance to BBN-induced bladder carcinogenesis.
- PLCε deficiency affected cyclooxygenase 2 and vascular endothelial growth factor-A expression.
- Findings suggest PLCε promotes tumors by enhancing inflammation and angiogenesis.
Conclusions:
- Phospholipase Cε (PLCε) is essential for bladder cancer development.
- PLCε plays a critical role in signaling downstream of Ras.
- PLCε is a potential molecular target for anti-bladder cancer drug development.
