RhoE/ROCK signaling modulates chemoresistance in HCC through IL6/JAK2/STAT3 pathways

Conference Theme: New Horizons in Cancer Research Conference: Harnessing Breakthroughs - Targeting CuresPoster Session B: Tumor Biology: no. B40Liver cancer (hepatocellular carcinoma, HCC) is a major malignancy worldwide and the second commonest fatal cancer in Southeast Asia and China including Hong Kong, due to the high prevalence of hepatitis B viral infection. HCC is highly chemoresistant, limiting treatment options to patients. There is an urgent need to delineate the underlying molecular mechanism of HCC chemoresistance so as to identify novel therapeutic targets for this aggressive cancer. Deregulation of Rho GTPase pathway is demonstrated to play important roles in HCC tumorigenesis. RhoE/Rnd3 belongs to the Rnd subfamily of the Rho GTPase which lacks the intrinsic GTPase activity. In our previous study, we have shown that RhoE is frequently downregulated in human HCCs and acts as a metastasis suppressor, whereas ROCK2 is upregulated in human HCCs. In this study, we aimed to investigate whether RhoE is also involved in the regulation of chemoresistance in HCC. Using short-hairpin RNA and ...published_or_final_versio

Tie-2 regulates the stemness and metastatic properties of prostate cancer cells.

Ample evidence supports that prostate tumor metastasis originates from a rare population of cancer cells, known as cancer stem cells (CSCs). Unfortunately, little is known about the identity of these cells, making it difficult to target the metastatic prostate tumor. Here, for the first time, we report the identification of a rare population of prostate cancer cells that express the Tie-2 protein. We found that this Tie-2High population exists mainly in prostate cancer cell lines that are capable of metastasizing to the bone. These cells not only express a higher level of CSC markers but also demonstrate enhanced resistance to the chemotherapeutic drug Cabazitaxel. In addition, knockdown of the expression of the Tie-2 ligand angiopoietin (Ang-1) led to suppression of CSC markers, suggesting that the Ang-1/Tie-2 signaling pathway functions as an autocrine loop for the maintenance of prostate CSCs. More importantly, we found that Tie-2High prostate cancer cells are more adhesive than the Tie-2Low population to both osteoblasts and endothelial cells. Moreover, only the Tie-2High, but not the Tie-2Low cells developed tumor metastasis in vivo when injected at a low number. Taken together, our data suggest that Tie-2 may play an important role during the development of prostate tumor metastasis.published_or_final_versio

Regulatory role of miR-142-3p on the functional hepatic cancer stem cell marker CD133

Tumor relapse after therapy typifies hepatocellular carcinoma (HCC) and is believed to be attributable to residual cancer stem cells (CSCs) that survive treatment. We have previously identified a CSC population derived from HCC that is characterized by CD133. Despite our growing knowledge of the importance of this subset of cells in driving HCC, the regulatory mechanism of CD133 is not known. Epigenetic changes are believed to be essential in the control of cancer and stem cells. Here, we report the epigenetic regulation of CD133 by miR-142-3p. The interaction between CD133 and miR-142-3p was identified by in silico prediction and substantiated by luciferase reporter analysis. Expression of CD133 was found to be inversely correlated with miR-142-3p in HCC clinical samples as well as in cell lines. Importantly, lower miR-142-3p expression in HCC was significantly associated with worst survival. Functional studies with miR-142-3p stably transduced in HCC cells demonstrated a diminished ability to self-renew, initiate tumor growth, invade, migrate, induce angiogenesis and resist chemotherapy. Rescue experiments whereby CD133 and miR-142-3p is simultaneously overexpressed compensated the deregulated ability of the cells to confer these features. Thus, miR-142-3p directly targets CD133 to regulate its ability to confer cancer and stem cell-like features in HCC.published_or_final_versio

A novel, rapid method to compare the therapeutic windows of oral anticoagulants using the Hill coefficient

A central challenge in designing and administering effective anticoagulants is achieving the proper therapeutic window and dosage for each patient. The Hill coefficient, nH, which measures the steepness of a dose-response relationship, may be a useful gauge of this therapeutic window. We sought to measure the Hill coefficient of available anticoagulants to gain insight into their therapeutic windows. We used a simple fluorometric in vitro assay to determine clotting activity in platelet poor plasma after exposure to various concentrations of anticoagulants. The Hill coefficient for argatroban was the lowest, at 1.7±0.2 (95% confidence interval, CI), and the Hill coefficient for fondaparinux was the highest, at 4.5±1.3 (95% CI). Thus, doubling the dose of fondaparinux from its IC50 would decrease coagulation activity by nearly a half, whereas doubling the dose of argatroban from its IC50 would decrease coagulation activity by merely one quarter. These results show a significant variation among the Hill coefficients, suggesting a similar variation in therapeutic windows among anticoagulants in our assay

Using spatial analysis to demonstrate the heterogeneity of the cardiovascular drug-prescribing pattern in Taiwan

<p>Abstract</p> <p>Background</p> <p>Geographic Information Systems (GIS) combined with spatial analytical methods could be helpful in examining patterns of drug use. Little attention has been paid to geographic variation of cardiovascular prescription use in Taiwan. The main objective was to use local spatial association statistics to test whether or not the cardiovascular medication-prescribing pattern is homogenous across 352 townships in Taiwan.</p> <p>Methods</p> <p>The statistical methods used were the global measures of Moran's <it>I </it>and Local Indicators of Spatial Association (LISA). While Moran's <it>I </it>provides information on the overall spatial distribution of the data, LISA provides information on types of spatial association at the local level. LISA statistics can also be used to identify influential locations in spatial association analysis. The major classes of prescription cardiovascular drugs were taken from Taiwan's National Health Insurance Research Database (NHIRD), which has a coverage rate of over 97%. The dosage of each prescription was converted into defined daily doses to measure the consumption of each class of drugs. Data were analyzed with ArcGIS and GeoDa at the township level.</p> <p>Results</p> <p>The LISA statistics showed an unusual use of cardiovascular medications in the southern townships with high local variation. Patterns of drug use also showed more low-low spatial clusters (cold spots) than high-high spatial clusters (hot spots), and those low-low associations were clustered in the rural areas.</p> <p>Conclusions</p> <p>The cardiovascular drug prescribing patterns were heterogeneous across Taiwan. In particular, a clear pattern of north-south disparity exists. Such spatial clustering helps prioritize the target areas that require better education concerning drug use.</p

Cancer stem cells in hepatocellular carcinoma — from origin to clinical implications

Title in author's file: Cancer stem cells in hepatocellular carcinoma: A review from origin to clinical implications202308 bckwAccepted ManuscriptRGCOthersHealth@InnoHK Program, Innovation and Technology CommissionPublishe

Variability in response to clopidogrel: How important are pharmacogenetics and drug interactions?

Clopidogrel is a pro-drug which is converted to an active metabolite that selectively blocks ADP-dependent platelet activation and aggregation. The main enzyme responsible for activating clopidogrel is the cytochrome P450 (CYP) isoenzyme CYP2C19, which is polymorphic. There is a growing body of literature showing that carriers of variant CYP2C19 alleles have impaired ability to metabolize clopidogrel (i.e. poor metabolizers), which is associated with decreased inhibition of platelet aggregation and increased cardiovascular risk. Some proton pump inhibitors are also metabolized by the CYP2C19 enzyme and often given together with clopidogrel to reduce gastrointestinal side effects. In particular, omeprazole has been shown to inhibit the CYP-mediated metabolism of clopidogrel, and some studies have shown that the combination was associated with a higher incidence of cardiovascular adverse reactions than clopidogrel given alone. However, a recent randomized controlled trial demonstrated no significant difference in adverse cardiovascular events for patients on the combination of clopidogrel and omeprazole compared with clopidogrel alone. This current review aims to summarize the role of pharmacogenetics and drug interactions in determining variability in response to clopidogrel. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.link_to_OA_fulltex