• Flavio Nguyen posted an update 1 week, 1 day ago

    Although PROX1 mRNA was slightly down-regulated in pancreatic carcinomas, immunofluorescence revealed variable PROX1 Fulvestrant protein expression in pancreatic carcinomas. Another study of liver tumor found that PROX1 mRNA expression was highly variable among samples of normal, cirrhotic, HCC and cholangiocellular carcinoma human liver specimens, specifically showing that expression was decreased in HCC and CCC liver samples relative to normal controls, and was stably elevated in HCC cell lines. As is the case during development, the role of PROX1 in a variety of human cancer types also appears to be tissue dependent and reflect both oncogenic and tumor-suppressive potential. In the present communication, we demonstrated that, although PROX1 expression in RCC tissue was lower than that in adjacent normal tissue, high expression was correlated with poor patient survival. These results imply that down-regulation of PROX1 expression may promote the early stage of RCC progression. We speculate that, by eliminating PROX1-mediated regulation of cell differentiation, down-regulation of PROX1 may be an important phenomenon in the progression from normal to precancerous cells or in situ establishment of early cancer status. However, upregulation of PROX1 expression during the transition from localized to advanced cancer stages may imply altered promotion of cell proliferative and invasive functions at this stage of disease progression, strengthening the opinion that PROX1 exerts its function in a context-dependent manner. However, a clearer understanding of the underlying mechanisms through which PROX1 acts in different stages of tumor development will require further investigation. One of key processes in the development of metastatic disease is the loss of cellular adhesion. E-cadherin, a member of the cadherin family of adhesion molecules, is responsible for maintaining interactions of epithelial cells. Our research on HCC has detected that the expression of E-cadherin was downregulated in PROX1-overexpressing cell and up-regulated in PROX1-knockdown cells, and the expression of vimentin was reversely related with the change of E-cadherin. In accord with our findings, Lu and colleagues found that forced expression of PROX1 in colon cancer cells also down-regulated E-cadherin expression and attenuated cell adhesion; conversely, knockdown of PROX1 restored E-cadherin expression and reduced invasiveness. In the case of squamous cell carcinoma, E-cadherinmediated cell-cell adhesion was found to induce epidermal growth factor receptor activation, which triggers the ERK/ MAPK signaling module and further blocks down-regulation of the anti-apoptotic protein Bcl-2, promoting tumor cell survival. Given the role of PROX1 in down-regulating the E-cadherin tumor-suppressor protein, it is likely that E-cadherin is involved in PROX1-stimulated proliferation and migration of tumor cells. It is well known that vimentin is a prominent member of the intermediate filament family of proteins whose overexpression in cancer correlates well with increased tumor growth, invasion, and poor prognosis. In prostate cancer, abrogating the expression of vimentin significantly decreases tumor cell invasiveness, an effect that has been attributed to its ability to regulate the Ecadherin/ b-catenin complex via c-Src regulation. Utilizing oligonucleotide microarrays and gene set enrichment analyses, Chen D et al. showed that down-regulation of E-cadherin and low vimentin levels were correlated with RCC metastasis and poor prognosis, providing strong evidence that epithelial-mesenchymal transition occurs in RCC. Our in vitro experiments revealed that PROX1-overexpressing 786-O cells showed a more aggressive phenotype in association with reduced E-cadherin and enhanced vimentin expression, whereas PROX1 down-regulated ACHN cells showed a less aggressive phenotype accompanied by enhanced E-cadherin and reduced vimentin expression. Given that both E-cadherin and vimentin are generally regarded as critical markers of EMT, these data indicate that expression of PROX1 may contribute to the development of an invasive phenotype in conjunction with E-cadherin and vimentin during the process of EMT in RCC. To date, no specific biomarker of renal cell carcinoma has been developed for use in clinical diagnosis and prediction of prognosis. Many of the oncogenes and tumor-suppressor genes whose mutation leads to dysregulation of cellular pathways in RCC remain to be elucidated. To our knowledge, this is the first study to evaluate the possibility of using PROX1 as a potential clinical indicator of disease progression, as well as a prognostic marker for patient survival in RCC. Although PROX1 does not appear to be a specific RCC marker, its significance in predicting tumor progression and prognosis suggest that it could benefit RCC patients. Hepatocellular carcinoma is the third most common cause of cancer-related death worldwide.. Moreover, several studies have shown that 5% to 30% of patients with HCC lack a readily identifiable risk factor for their cancer. Most of these ‘‘cryptogenic’’ HCC might be attributed to Non-Alcoholic Fatty Liver Disease and the concomitant metabolic syndrome, nevertheless it is not yet clear what predisposes to the progression of the disease. On this regard, NAFLD is a major health problem that integrates several liver conditions ranging from simple fatty liver to Non-Alcoholic Steatohepatitis, which is associated with fibrosis that may evolve into cirrhosis and results into HCC. How HCC develops from NASH livers is still obscure. Some hypotheses suggest that obesity, insulin resistance, release of inflammatory cytokines and autophagy can contribute to the carcinogenic potential in NASH liver, where HCC can occur in 65% of patients without an over cirrhosis in the background liver.