Implication of VHL, ERK5, and HIF-1alpha in clear cell renal cell carcinoma: Molecular basis

Abstract

Objectives: To determine the expression status of several proteins related to VHL gene function and its relationship with common clinicopathological parameters.Material and methods: Observational, analytical, cross-sectional study with 50 patients diagnosed with clear cell renal cell carcinoma. The study analyzed VHL mutations and hypermethylation as well as protein expression of VHL, CA-IX, HIF-1alpha, VEGF, ERK1/2, and ERK5, relating them to clinical variables.A bivariate and multivariate descriptive logistical regression analysis was performed, using the presence of metastasis at diagnosis as dependent variable.Results: The study identified 13 (26%) VHL mutations related to nuclear grade (P ¼ 0.036). VHL hypermethylation was found in 20% of cases. VHL expression was associated with the presence of mutations (P ¼ 0.013), and the absence of expression was associated with nuclear grade and the presence of metastasis (P o 0.05). HIF-1alpha was negative in only 5 cases. Vascular endothelial growth factor (VEGF) was positive in 31 of 47 cases and was associated with Fuhrman nuclear grade, presence of metastasis, and stage (P o 0.05). ERK5 expression was increased in 58% of cases and associated with the presence of metastasis and more advanced stages (P o 0.05). In the logistic regression analysis, the only variable remaining in the model was VEGF expression (P ¼ 0.014).Conclusions: VEGF has prognostic value in clear cell renal cell carcinoma, and ERK5 may be a new prognostic marker in this type of tumor owing to its relationship with metastasis and more advanced stages. r

Impact of ERK5 on the Hallmarks of Cancer

“…Moreover, an association of high ERK5 expression with advanced tumor stage and the presence of lymph node metastases has been reported in a subset of patients, linking ERK5 to an invasive phenotype in this cancer [100]. Similarly, although a functional role of ERK5 has not been demonstrated, an observational study with 50 patients diagnosed with CCRC showed that ERK5 expression is increased in 58% of cases and is associated with the presence of metastasis and more advanced stages [101].…”

Effect of Extracellular Signal-Regulated Protein Kinase 5 Inhibition in Clear Cell Renal Cell Carcinoma

“…ERK5 positively regulates cell proliferation via p21 inhibition and cell survival via BCL2 expression in endothelial cells [ 25 , 26 , 27 , 28 , 29 ]. Several reports showed that strong ERK5 expression indicates worse prognoses in breast, prostate cancer, and ccRCC [ 12 , 13 , 30 , 31 ]. In addition, recent studies demonstrated ERK5 as a potential therapeutic target in leukemia, multiple myeloma, breast, liver, prostate, and pancreatic cancer [ 25 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ].…”

“…A recent study revealed that ERK5 is degraded through the ubiquitin–proteasome system in a process mediated by a VHL protein (pVHL) [ 11 ] because harboring an inactivation of pVHL, ccRCC should store ERK5. In fact, a previous report demonstrated that 60% of ccRCC patients had overexpression of ERK5 in their surgical specimens [ 12 , 13 ].…”

Bone and Extracellular Signal-Related Kinase 5 (ERK5)

“…Arias et al confirmed that increased ERK5 levels foster proliferation, invasion, and metastasis in clear cell renal cell carcinoma, with a positive correlation between ERK5 expression and the disease's invasiveness and metastasis in fresh human samples [81]. Another study identified a connection between ERK5 and enhanced metastasis and advanced disease stages [130]. A clinical investigation underscored ERK5's prognostic significance in renal cell carcinoma, where patients with elevated ERK5 expression experienced poorer outcomes [131].…”