There was no significant difference in stage at presentation of renal cancer diagnosed in 1973 to 1985 compared with that diagnosed in 1986 to 1998. While the lack of a decrease in distant disease despite the increased detection of regional and localized renal cancer implies that a proportion of innocuous renal cancer cases may be detected by increased abdominal imaging, the increased incidence of renal cancer in all 3 categories indicates that other factors may also be contributing to the increasing incidence of renal cancer.
Cancer cells undergo epithelial-mesenchymal transition (EMT) as a program of increased invasion and metastasis during cancer progression. Here, we report that a novel regulator of EMT in cancer cells is protein kinase D1 (PKD1), which is downregulated in advanced prostate, breast, and gastric cancers. Ectopic reexpression of PKD1 in metastatic prostate cancer cells reversibly suppressed expression of mesenchyme-specific genes and increased epithelial markers such as E-cadherin, whereas small interfering RNA-mediated knockdown of PKD1 increased expression of mesenchyme markers. Further, PKD1 inhibited tumor growth and metastasis in a tumor xenograft model. PKD1 phosphorylates Ser 11 (S11) on transcription factor Snail, a master EMT regulator and repressor of E-cadherin expression, triggering nuclear export of Snail via 14-3-3σ binding. Snail S11 mutation causes acquisition of mesenchymal traits and expression of stem cell markers. Together, our results suggest that PKD1 functions as a tumor and metastasis suppressor, at least partly by regulating Snail-mediated EMT, and that loss of PKD1 may contribute to acquisition of an aggressive malignant phenotype.
The incidence of upper tract recurrence following radical cystectomy is low (3%). However, the incidence of bilateral tumors (31.3%) and locally advanced stage at the time of operation (58%) is higher than expected for upper tract tumors in the general population. Survival of patients with upper tract recurrence is poor, with a median of 10 months.
Serum neutrophil/lymphocyte ratio and hypoalbuminemia predict overall and cancer-specific survival in patients undergoing radical cystectomy for muscle-invasive bladder cancer. These parameters also predict risk for extravesical disease. These could be combined with other established preoperative parameters to improve risk stratification and preoperative counseling.
B-Catenin is essential for E-cadherin-mediated cell adhesion in epithelial cells and also acts as a key cofactor for transcription activity. We previously showed that protein kinase D1 (PKD1), founding member of the PKD family of signal transduction proteins, is down-regulated in advanced prostate cancer and interacts with E-cadherin. This study provides evidence that PKD1 interacts with and phosphorylates B-catenin at Thr 112 and Thr 120 residues in vitro and in vivo; mutation of Thr 112 and Thr 120 results in increased nuclear localization of B-catenin and is associated with altered B-catenin-mediated transcription activity. It is known that mutation of Thr 120 residue abolishes binding of B-catenin to A-catenin, which links to cytoskeleton, suggesting that PKD1 phosphorylation of Thr 120 could be critical for cell-cell adhesion. Overexpression of PKD1 represses B-catenin-mediated transcriptional activity and cell proliferation. Epistatic studies suggest that PKD1 and E-cadherin are within the same signaling pathway. Understanding the molecular basis of PKD1-B-catenin interaction provides a novel strategy to target B-catenin function in cells including prostate cancer.
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