Knockout of phospholipase Cε attenuates N-butyl-N-(4-hydroxybutyl) nitrosamine-induced bladder tumorigenesis

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.

PLCε promotes urinary bladder cancer cells proliferation through STAT3/LDHA pathway‑mediated glycolysis

“…Phospholipase Cε (PLCε) is a member of the phospholipase C family, which catalyzes polyphosphoinositol, such as phosphatidylinositol 4,5-diphosphate, and produces the second messenger, including 1,4,5-triphosphate and diacylglycerol (8). Our previous studies demonstrated that PLCε may serve an important role in UBC growth (9,10) and activation of the signal transducer and activator of transcription 3 (STAT3) pathway (11). STAT3 is involved in the development and progression of a variety of tumor types, including colon, gastric and liver cancer (12–14), which may be partially achieved by regulating anaerobic glycolysis (15).…”

Insights from animal models of bladder cancer: recent advances, challenges, and opportunities

“…The authors identified that SPARC restrains urothelial carcinogenesis, progression and metastasis through an effect on cancer cells inhibiting carcinogen-induced cell cycle deregulation and on stromal cell plasticity, inhibiting their acquisition of a pro-inflammatory cancer associated phenotype. In another study, utilizing Rgs6 −/− mice, the role for RGS6 as a tumor suppressor was reported as they displayed accelerated pathological lesions than Rgs6 +/+ mice [ 46 ]. The investigators identified RGS6 as a tumor suppressor modulating ATM/p53 and RASSF1A, the two critical signaling pathways that are often dysregulated in urothelial carcinoma.…”

“…BBN-induced rodent models were analyzed by genome-wide analysis of copy number aberrations in bladder lesions [ 47 ]. The tumor promoting effect of phospholipase Cε (PLCε) was also studied using BBN in PLCε knockout mice [ 46 ]. The tumor promoting effect of PLCε was demonstrated by a decreased incidence of ensuing urothelial lesions in PLCε knockout mice compared to their wildtypes as well as a significant downregulation of PLCε downstream targets such as VEGF-A and COX-2 [ 46 ].…”

“…The tumor promoting effect of phospholipase Cε (PLCε) was also studied using BBN in PLCε knockout mice [ 46 ]. The tumor promoting effect of PLCε was demonstrated by a decreased incidence of ensuing urothelial lesions in PLCε knockout mice compared to their wildtypes as well as a significant downregulation of PLCε downstream targets such as VEGF-A and COX-2 [ 46 ]. Array CGH revealed that several mouse chromosome regions, including the Cyp2a5 and Cyp2a22 loci on mouse chromosome 7qA3, were amplified in invasive bladder cancer.…”

“…BBN model can be also used to study the impact of conditional cell/tissue specific knockout/knockin of genes; for example, the effect of conditional knockout of estrogen receptor α and β [ 48 ] as well as androgen receptor [ 49 ]. Moreover, this model was used to evaluate the preventive and therapeutic efficacy of chemotherapeutics [ 46 , 50 – 52 ].…”