The prognostic significance of DAPK1 in bladder cancer.

Bladder cancer is one of the leading causes of cancer-related death in men, however, there was only limited effective treatment for invasive bladder cancer. DAPK1 has been shown to play important role in apoptosis and autophagy to suppress cancer progression. Previous results have shown that DAPK1 promoter was hypermethylated in the majority of bladder cancer specimens, however, the prognostic significance of DAPK1 in bladder cancer has yet to be demonstrated. In the present study, we found that DAPK1 expression was negatively associated with tumor stage and a low level expression of DAPK1 in bladder cancer specimens were associated with shorter survival in bladder cancer patients in 3 independent bladder cancer datasets (n = 462). Further investigation showed that FGFR3 knockdown resulted in downregulation of DAPK1 in bladder cancer cell line, suggesting that FGFR3 may be an upstream factor of DAPK1. Further analysis of the 3 independent bladder cancer datasets have identified ACOX1, UPK2, TRAK1, PLEKHG6 and MT1X genes had their expression significantly correlated with that of DAPK1. Knockdown of DAPK1 in bladder cancer T24 cells resulted in downregulation of ACOX1, UPK2 and TRAK1. Interestingly, TRAK1, by itself, was a favorable prognostic marker in the 3 independent bladder cancer datasets. Importantly, by using connectivity mapping with DAPK1-associated gene signature, we found that vemurafenib and trametinib could possibly reverse DAPK1-associated gene signature, suggesting that inhibition of Raf/MEK pathway may be a potential therapeutic approach for bladder cancer. Indeed, treatment of vemurafenib in T24 bladder cancer cells resulted in upregulation of DAPK1 confirming our connectivity mapping, while knockdown of DAPK1 resulted in reduced sensitivity towards inhibition of Braf signaling by vemurafenib. Together, our results suggest that DAPK1 is an important prognostic marker and therapeutic target for bladder cancer and have identified possible therapeutic agents for future testing in bladder cancer models with low DAPK1 expression.

Expression of CRM1 and CDK5 shows high prognostic accuracy for gastric cancer.

AIM: To evaluate the predictive value of the expression of chromosomal maintenance (CRM)1 and cyclin-dependent kinase (CDK)5 in gastric cancer (GC) patients after gastrectomy. METHODS: A total of 240 GC patients who received standard gastrectomy were enrolled in the study. The expression level of CRM1 and CDK5 was detected by immunohistochemistry. The correlations between CRM1 and CDK5 expression and clinicopathological factors were explored. Univariate and multivariate survival analyses were used to identify prognostic factors for GC. Receiver operating characteristic analysis was used to compare the accuracy of the prediction of clinical outcome by the parameters. RESULTS: The expression of CRM1 was significantly related to size of primary tumor (P = 0.005), Borrmann type (P = 0.006), degree of differentiation (P = 0.004), depth of invasion (P = 0.008), lymph node metastasis (P = 0.013), TNM stage (P = 0.002) and distant metastasis (P = 0.015). The expression of CDK5 was significantly related to sex (P = 0.048) and Lauren's classification (P = 0.011). Multivariate Cox regression analysis identified that CRM1 and CDK5 co-expression status was an independent prognostic factor for overall survival (OS) of patients with GC. Integration of CRM1 and CDK5 expression could provide additional prognostic value for OS compared with CRM1 or CDK5 expression alone (P = 0.001). CONCLUSION: CRM1 and CDK5 co-expression was an independent prognostic factors for GC. Combined CRM1 and CDK5 expression could provide a prognostic model for OS of GC.

Digitoxin synergizes with sorafenib to inhibit hepatocelluar carcinoma cell growth without inhibiting cell migration.

Sorafenib is a chemotherapeutic agent approved for the treatment of hepatocellular carcinoma (HCC) in China. Digitoxin is a cardiotonic drug, which has been demonstrated to exhibit anticancer effects in a number of cancers, but not in HCC. The aim of the present study was to evaluate the combinational effect of sorafenib and digitoxin on the treatment of HCC and to investigate the relevant molecular mechanisms of action that underlie these effects. The proliferation, cell death and migration of HCC cell lines, HepG2 and BEL­7402, were examined using MTT, acridine orange/ethidium bromide staining and scratch wound healing assays, respectively. In addition, alterations in the expression of phosphorylated-extracellular signal-regulated kinase (ERK), hypoxia­inducible factor 1­α (HIF­1α), hypoxia­inducible factor 2­α (HIF­2α) and vascular endothelial growth factor (VEGF) were measured prior to and following drug application using western blot analysis. Digitoxin and sorafenib synergistically inhibited cell viability, but did not inhibit migration, which was potentially mediated by suppression of ERK and hypoxia signaling. In downstream signaling pathways, the activity of ERK was synergistically suppressed by combinatorial treatment of HepG2 and BEL­7402 cells with sorafenib and digitoxin. In addition, the expression of HIF­1α, HIF­2α and VEGF was synergistically downregulated by combinational treatment.

Drug Repurposing in Anticancer Reagent Development.

BACKGROUND: Cancer is a complex disease and a huge threat to human health. The prognosis for some cancer types such as breast cancer has improved dramatically over the past 50 years due to rapid development of surgery, chemotherapy and radiotherapy technologies. However, for many patients bearing unresectable cancers, the prognosis remained poor. For this reason, there is always high demand for newer and better therapeutic reagents in cancer field. But the development of anticancer drugs is risky, lengthy and costly. Not many new anticancer reagents come into market every year. OBJECTIVE: This review focuses on the latest progress of chemotherapy drug repurposing in cancer research. CONCLUSION: It is clear from the review of that drug repurposing is faster and cheaper than conventional drug development process. The anticancer efficacy of numerous non-cancer drugs are being tested now. However, not many of them have obtained enough evidence to go into clinical trials for cancer treatment. How to filter the right candidate and narrow the gap between bench and bed remains a hurdle for both conventional and repurposing drug development.

Low Expression of CDK5 and p27 Are Associated with Poor Prognosis in Patients with Gastric Cancer.

Several previous studies have demonstrated that CDK5 or p27 expression in gastric cancer are associated with overall survival. We have previously reported that tumor suppressive function of CDK5 is related to p27. The aim of this study was to investigate correlation between the clinicopathological parameters and overall survival with different CDK5/p27 expression statuses in 244 gastric cancer patients using immunohistochemistry. Low CDK5 expression was detected in 93 cases (38.11%) and low p27 in 157 cases (64.34%). The expression of CDK5 was significantly related to sex (P = 0.034) and Lauren's classification (P = 0.013). The expression of p27 was significantly related to sex (P = 0.012), differentiation (P = 0.003), TNM stage (P = 0.013) and lymph node metastasis (P = 0.001). Based on the combined expression of CDK5 and p27, we classified the patients into four subtypes: CDK5 Low/p27 Low (n = 69), CDK5 High/p27 Low (n = 88), CDK5 Low/p27 High (n = 24) and CDK5 High/p27 High (n = 63). The CDK5 Low/p27 Low expression was closely related to female (P = 0.026), diffuse type (P = 0.027) and lymph node metastasis (P = 0.010). The CDK5 Low/p27 Low patients displayed poorer survival in comparison with the rest of the patients in Kaplan-Meier analysis. No significant overall survival difference was observed among the patients with CDK5 High and/or p27 High expression. In the multivariate analysis, CDK5 and p27 co-expression status was identified as an independent prognostic factor for patients with gastric cancer.

Evaluation of the prognostic value and functional roles of CD44v6 in gastric cancer.

PURPOSE: Tumor stem cell surface marker CD44v6, a member of the CD44 protein family, is causally involved in the metastasis of cancer. Little is known about the functions of CD44v6 in gastric cancer. The aim of this study was to evaluate the prognostic value of CD44v6 and investigate its functional roles. METHODS: The expression of CD44v6 in 208 primary gastric adenocarcinoma patient samples was examined using immunohistochemistry and its correlation with clinicopathological parameters, and 5-year patient survival was assessed. Two pairs of MGC-803 stable cells with either CD44v6 overexpression or knockdown were created. The effect of CD44v6 on cell proliferation, colony formation, migration and apoptosis was investigated using these two pairs of cells. RESULTS: Overexpression of CD44v6 was observed in all cancer cell lines. The 5-year survival rate of patients with positive CD44v6 expression is significantly worse compared to those with negative expression (38.8 vs. 73.6 %). CD44v6 and TNM stage are two independent prognostic factors of primary gastric adenocarcinoma. The risk factors for the positive CD44v6 expression are location of tumor, depth of invasion, lymph node metastasis, Lauren classification and TNM stage. In MGC-803 cells, CD44 stimulated proliferation and colony formation, antagonized oxaliplatin-induced apoptosis, but did not affect migration. CONCLUSION: CD44v6 is an important prognosis marker in gastric cancer. Tissue specificity may affect the functions of CD44v6, and further work is needed to elucidate its regulation.

How to improve skin notation. Position paper from a workshop.

The ICOH Scientific Committee on Occupational and Environmental Dermatoses organized an International Workshop on "Dermal risk assessment at workplace" with the aim of focussing on the different ways of approaching the concept of skin notation (S) for chemicals. The Workshop participants presented their ideas on several aspects of S such as the problems related to the absorption through the compromised skin, the different approaches to S and models that can be used as alternatives to S. Participants agreed to produce a position paper with the goal of exploring the actions needed to improve the S system towards international harmonization. They consider that further discussions are needed to obtain an international consensus, but at the same time they believe that by improving and harmonizing systems for setting S we can make an important contribution to improving health of people with potential dermal exposure to chemicals at work.