Publications by authors named "Yick Pang Ching"

66 Publications

TEC kinase stabilizes PLK4 to promote liver cancer metastasis.

Cancer Lett 2021 Oct 9. Epub 2021 Oct 9.

School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China; State Key Laboratory of Liver Research (The University of Hong Kong), The University of Hong Kong, Pokfulam, Hong Kong, China. Electronic address:

Aberrated PLK4 expression has been reported in different malignancies and causes centrosome amplification, aneuploidy, and genomic instability. However, the mechanism by which PLK4 is regulated in carcinogenesis remains not fully characterised. Here, we showed that PLK4 was overexpressed in human HCC and overexpression of PLK4 predicted poorer patient prognosis. Unexpectedly, we found that induced expression of PLK4 promotes, but knockdown of PLK4 inhibits, HCC cell migration and invasion. Mechanistically, we found that TEC tyrosine kinase, which also promotes HCC cell migration, stabilizes PLK4 by phosphorylation. TEC directly phosphorylates PLK4 at tyrosine 86 residue, which not only stabilizes the protein but also enhances PLK4-mediated HCC cell invasion. Further investigation by transcriptome sequencing indicated that PLK4 promotes the phosphorylation of focal adhesion kinase to regulate the focal adhesion pathway in HCC cell migration. Taken together, our results demonstrated that PLK4 plays an important role in HCC metastasis and revealed for the first time the mechanism by which PLK4 promotes HCC metastasis via TEC phosphorylation.
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http://dx.doi.org/10.1016/j.canlet.2021.08.038DOI Listing
October 2021

Centrosomal protein TAX1BP2 inhibits centrosome-microtubules aberrations induced by hepatitis B virus X oncoprotein.

Cancer Lett 2020 11 19;492:147-161. Epub 2020 Aug 19.

School of Biomedical Sciences, Hong Kong; State Key Laboratory of Liver Research (The University of Hong Kong), The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong. Electronic address:

Liver cancer (hepatocellular carcinoma, HCC) is one of the most prevalent cancers worldwide. Several etiological factors of HCC, including hepatitis B or hepatitis C virus infection, liver cirrhosis and aflatoxin B1 intake has been identified. HBx, which is an oncogenic protein encoded by the hepatitis B virus, is strongly associated with hepatocarcinogenesis. Using stable HBx-expressing cell, we showed that HBx induced chromosome gain, with amplification of centrosomes numbers and deregulation of centrosome ultrastructure. To dissect the mechanism for chromosome instability, our result revealed that HBx contributed to a hyperactive centrosome-microtubule dynamics by accelerating microtubule nucleation and polymerization. Further investigations suggested that HBx interacted with a centrosome linker protein TAX1BP2, which has previously been shown to function as an intrinsic block of centrosome amplification and a tumour suppressor in HCC. Restoring TAX1BP2 was able to block HBx-mediated centrosome amplification and abolish the HBx-mediated centrosome aberration, thereby suppressing chromosome instability. Thus, we demonstrate here a mechanism by which HBx deregulates centrosome-microtubule dynamics through interacting with TAX1BP2, which underlines the possibility of restoration of TAX1BP2 to rescue cells from chromosome instability.
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http://dx.doi.org/10.1016/j.canlet.2020.08.005DOI Listing
November 2020

PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation.

Cell Rep 2018 10;25(3):690-701.e8

School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China; State Key Laboratory for Liver Research, University of Hong Kong, Pokfulam, Hong Kong, China. Electronic address:

Arginine methylation is a post-translational modification that plays pivotal roles in signal transduction and gene transcription during cell fate determination. We found protein methyltransferase 6 (PRMT6) to be frequently downregulated in hepatocellular carcinoma (HCC) and its expression to negatively correlate with aggressive cancer features in HCC patients. Silencing of PRMT6 promoted the tumor-initiating, metastasis, and therapy resistance potential of HCC cell lines and patient-derived organoids. Consistently, loss of PRMT6 expression aggravated liver tumorigenesis in a chemical-induced HCC PRMT6 knockout (PRMT6) mouse model. Integrated transcriptome and protein-protein interaction studies revealed an enrichment of genes implicated in RAS signaling and showed that PRMT6 interacted with CRAF on arginine 100, which decreased its RAS binding potential and altered its downstream MEK/ERK signaling. Our work describes a critical repressive function for PRMT6 in maintenance of HCC cells by regulating RAS binding and MEK/ERK signaling via methylation of CRAF on arginine 100.
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http://dx.doi.org/10.1016/j.celrep.2018.09.053DOI Listing
October 2018

Aberrant cytokine secretion and zinc uptake in chronic cadmium-exposed lung epithelial cells.

Proteomics Clin Appl 2017 03 14;11(3-4). Epub 2016 Dec 14.

Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, P. R. China.

Purpose: Our previous results showed that cadmium (Cd)-adapted lung epithelial cells (LECs) developed resistance to apoptosis due to non-responsiveness of the c-Jun N-terminal kinase pathway and augmented expression of cytokeratin 8. Since cellular Cd entry is a prerequisite in order for Cd to elicit its cytotoxicity, therefore, we wonder if there are differential metal ion transport ability and also other phenotypic changes that occurred in these Cd-resistant LECs.

Experimental Design And Results: Here, we explored further and found that the zinc (Zn) importer Zip8 was stably abolished in these cells along with a marked decrease of Cd and Zn accumulation. Moreover, by cell migration assays and cytokine antibody array analysis, we found that Cd-adapted cells exhibit enhanced migratory ability possibly due to elevated secretions of vascular endothelial growth factor and macrophage inflammatory protein-3 alpha (MIP-3α).

Conclusion And Clinical Relevance: Taken together, our results show that during chronic Cd exposure, lung cells antagonize excessive cellular Cd-influx by abolishing Zip8 expression to reduce Cd-toxicity; however, this also renders cells with a diminished Zn uptake. The imbalance of Zn homeostasis and elevation of angiogenic and epithelial-mesenchymal transition-promoting cytokines in Cd-adapted cells might thus likely promote Zn deficiency, angiogenesis, and cell invasion.
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http://dx.doi.org/10.1002/prca.201600059DOI Listing
March 2017

PAK4 Phosphorylates p53 at Serine 215 to Promote Liver Cancer Metastasis.

Cancer Res 2016 10 5;76(19):5732-5742. Epub 2016 Aug 5.

School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China. Cancer Research Center, The University of Hong Kong, Hong Kong, China.

PAK4 kinase contributes to signaling pathways controlling cancer cell transformation, invasion, and survival, but its clinicopathological impact has begun to emerge only recently. Here we report that PAK4 overexpression in hepatocellular carcinoma (HCC) conveys aggressive metastatic properties. A novel nuclear splice isoform of PAK4 lacking exon 2 sequences was isolated as part of our studies. By stably overexpressing or silencing PAK4 in HCC cells, we showed that it was critical for their migration. Mechanistic investigations in this setting revealed that PAK4 directly phosphorylated p53 at S215, which not only attenuated transcriptional transactivation activity but also inhibited p53-mediated suppression of HCC cell invasion. Taken together, our results showed how PAK4 overexpression in HCC promotes metastatic invasion by regulating p53 phosphorylation. Cancer Res; 76(19); 5732-42. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-3373DOI Listing
October 2016

C-terminal truncated hepatitis B virus X protein promotes hepatocellular carcinogenesis through induction of cancer and stem cell-like properties.

Oncotarget 2016 Apr;7(17):24005-17

School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.

Tumor relapse after chemotherapy typifies hepatocellular carcinoma (HCC) and is believed to be attributable to residual cancer stem cells (CSCs) that survive initial treatment. Chronic infection with hepatitis B virus (HBV) has long been linked to the development of HCC. Upon infection, random HBV genome integration can lead to truncation of hepatitis B virus X (HBx) protein at the C-terminus. The resulting C-terminal-truncated HBx (HBx-ΔC) was previously shown to confer enhanced invasiveness and diminished apoptotic response in HCC cells. Here, we found HBx-ΔC to promote the appearance of a CD133 liver CSC subset and confer cancer and stem cell-like features in HCC. HBx-ΔC was exclusively detected in HCC cell lines that were raised from patients presented with a HBV background with concomitant CD133 expression. Stable overexpression of the naturally occurring HBx-ΔC mutants, HBx-Δ14 or HBx-Δ35, in HCC cells Huh7 and immortalized normal liver cells MIHA resulted in a significant increase in the cells ability to self-renew, resist chemotherapy and targeted therapy, migrate and induce angiogenesis. MIHA cells with the mutants stably overexpressed also resulted in the induction of CD133, mediated through STAT3 activation. RNA sequencing profiling of MIHA cells with or without HBx-ΔC mutants stably overexpressed identified altered FXR activation. This, together with rescue experiments using a selective FXR inhibitor suggested that C-terminal truncated HBx can mediate cancer stemness via FXR activation. Collectively, we find C-terminal truncated HBx mutants to confer cancer and stem cell-like features in vitro and to play an important role in driving tumor relapse in HCC.
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http://dx.doi.org/10.18632/oncotarget.8209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029680PMC
April 2016

Proteome profiling of cadmium-induced apoptosis by antibody array analyses in human bronchial epithelial cells.

Oncotarget 2016 Feb;7(5):6146-58

Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, P. R. China.

Protein array technology is a powerful platform for the simultaneous determination of the expression levels of a number of proteins as well as post-translational modifications such as phosphorylation. Here, we screen and report for the first time, the dominant signaling cascades and apoptotic mediators during the course of cadmium (Cd)-induced cytotoxicity in human bronchial epithelial cells (BEAS-2B) by antibody array analyses. Proteins from control and Cd-treated cells were captured on Proteome Profiler™ Arrays for the parallel determination of the relative levels of protein phosphorylation and proteins associated with apoptosis. Our results indicated that the p38 MAPK- and JNK-related signal transduction pathways were dramatically activated by Cd treatment. Cd potently stimulates the phosphorylations of p38α (MAPK14), JNK1/2 (MAPK8/9), and JUN; while the phosphorylations of Akt1, ERK1/2 (MAPK3/1), GSK3β, and mTOR were suppressed. Moreover, there was an induction of proapoptotic protein BAX, release of cytochrome c (CYCS) from mitochondria, activation of caspase-3/9 (CASP3/9); as well as decreased expression of cell cycle checkpoint proteins (TP53, p21, and p27) and several inhibitors of apoptosis proteins (IAPs) [including cIAP-1/2 (BIRC2/3), XIAP (BIRC4), and survivin (BIRC5)]. Pretreatment of cells with the thiol antioxidant glutathione or p38 MAPK/JNK inhibitors before Cd treatment effectively abrogated ROS activation of p38 MAPK/JNK pathways and apoptosis-related proteins. Taken together, our results demonstrate that Cd causes oxidative stress-induced apoptosis; and the p38 MAPK/JNK and mitochondrial pathways are more importantly participated for signal transduction and the induction of apoptosis in Cd-exposed human lung cells.
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http://dx.doi.org/10.18632/oncotarget.6738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868746PMC
February 2016

Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin.

Proc Natl Acad Sci U S A 2014 Nov 20;111(44):15810-5. Epub 2014 Oct 20.

State Key Laboratory of Brain and Cognitive Science, Departments of Anatomy, Research Centre of Heart, Brain, Hormone and Healthy Ageing, Ophthalmology, Guangdong-Hong Kong-Macau Institute of CNS Regeneration and Guangdong Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou 510632, China

Adiponectin (ADN) is an adipocyte-secreted protein with insulin-sensitizing, antidiabetic, antiinflammatory, and antiatherogenic properties. Evidence is also accumulating that ADN has neuroprotective activities, yet the underlying mechanism remains elusive. Here we show that ADN could pass through the blood-brain barrier, and elevating its levels in the brain increased cell proliferation and decreased depression-like behaviors. ADN deficiency did not reduce the basal hippocampal neurogenesis or neuronal differentiation but diminished the effectiveness of exercise in increasing hippocampal neurogenesis. Furthermore, exercise-induced reduction in depression-like behaviors was abrogated in ADN-deficient mice, and this impairment in ADN-deficient mice was accompanied by defective running-induced phosphorylation of AMP-activated protein kinase (AMPK) in the hippocampal tissue. In vitro analyses indicated that ADN itself could increase cell proliferation of both hippocampal progenitor cells and Neuro2a neuroblastoma cells. The neurogenic effects of ADN were mediated by the ADN receptor 1 (ADNR1), because siRNA targeting ADNR1, but not ADNR2, inhibited the capacity of ADN to enhance cell proliferation. These data suggest that adiponectin may play a significant role in mediating the effects of exercise on hippocampal neurogenesis and depression, possibly by activation of the ADNR1/AMPK signaling pathways, and also raise the possibility that adiponectin and its agonists may represent a promising therapeutic treatment for depression.
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http://dx.doi.org/10.1073/pnas.1415219111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226125PMC
November 2014

The role of p21-activated kinases in hepatocellular carcinoma metastasis.

J Mol Signal 2014 1;9. Epub 2014 Aug 1.

Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China ; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.

The p21-activated kinases (PAKs) are downstream effectors of the Rho family small GTPases as well as a wide variety of mitogenic factors and have been implicated in cancer formation, development and metastasis. PAKs phosphorylate a wide spectrum of substrates to mediate extracellular signals and regulate cytoskeletal remodeling, cell motility and survival. In this review, we aim to summarize the findings regarding the oncogenic role and the underlying mechanisms of PAKs signaling in various cancers, and in particular highlight the prime importance of PAKs in hepatocellular carcinoma (HCC) progression and metastasis. Recent studies exploring the potential therapeutic application of PAK inhibitors will also be discussed.
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http://dx.doi.org/10.1186/1750-2187-9-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121300PMC
August 2014

Lycium barbarum polysaccharides therapeutically improve hepatic functions in non-alcoholic steatohepatitis rats and cellular steatosis model.

Sci Rep 2014 Jul 7;4:5587. Epub 2014 Jul 7.

1] Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China [2] Research Centre of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

This study aimed to investigate the possible therapeutic effects and active components of Lycium barbarum polysaccharides (LBP) on a high fat diet-induced NASH rat model. We induced NASH in a rat model by voluntary oral feeding with a high-fat diet ad libitum for 8 weeks. After 8 weeks, 1 mg/kg LBP was orally administered for another 4 weeks with a high-fat diet. When compared with NASH rats treated for 12 weeks, therapeutic LBP treatment for 4 weeks during 12 weeks of NASH induction showed ameliorative effects on: (1) increased body and wet liver weights; (2) insulin resistance and glucose metabolic dysfunction; (3) elevated level of serum aminotransferases; (4) fat accumulation in the liver and increased serum free fatty acid (FFA) level; (5) hepatic fibrosis; (6) hepatic oxidative stress; (7) hepatic inflammatory response; and (8) hepatic apoptosis. These improvements were partially through the modulation of transcription factor NF-κB, MAPK pathways and the autophagic process. In a palmitate acid-induced rat hepatocyte steatosis cell-based model, we also demonstrated that l-arabinose and β-carotene partially accounted for the beneficial effects of LBP on the hepatocytes. In conclusion, LBP possesses a variety of hepato-protective properties which make it a potent supplementary therapeutic agent against NASH in future clinical trials.
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http://dx.doi.org/10.1038/srep05587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083265PMC
July 2014

Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer.

Nat Genet 2014 Jun 11;46(6):573-82. Epub 2014 May 11.

Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.

Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy.
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http://dx.doi.org/10.1038/ng.2983DOI Listing
June 2014

IPA-3 inhibits the growth of liver cancer cells by suppressing PAK1 and NF-κB activation.

PLoS One 2013 19;8(7):e68843. Epub 2013 Jul 19.

Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is associated with poor prognosis due to the high incidences of metastasis and tumor recurrence. Our previous study showed that overexpression of p21-activated protein kinase 1 (PAK1) is frequently observed in HCC and is associated with a more aggressive tumor behavior, suggesting that PAK1 is a potential therapeutic target in HCC. In the current study, an allosteric small molecule PAK1 inhibitor, IPA-3, was evaluated for the potential in suppressing hepatocarcinogenesis. Consistent with other reports, inhibition of PAK1 activity was observed in several human HCC cell lines treated with various dosages of IPA-3. Using cell proliferation, colony formation and BrdU incorporation assays, we demonstrated that IPA-3 treatment significantly inhibited the growth of HCC cells. The mechanisms through which IPA-3 treatment suppresses HCC cell growth are enhancement of apoptosis and blockage of activation of NF-κB. Furthermore, our data suggested that IPA-3 not only inhibits the HCC cell growth, but also suppresses the metastatic potential of HCC cells. Nude mouse xenograft assay demonstrated that IPA-3 treatment significantly reduced the tumor growth rate and decreased tumor volume, indicating that IPA-3 can suppress the in vivo tumor growth of HCC cells. Taken together, our demonstration of the potential preclinical efficacy of IPA-3 in HCC provides the rationale for cancer therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0068843PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716906PMC
March 2014

Garlic-Derived S-Allylmercaptocysteine Ameliorates Nonalcoholic Fatty Liver Disease in a Rat Model through Inhibition of Apoptosis and Enhancing Autophagy.

Evid Based Complement Alternat Med 2013 19;2013:642920. Epub 2013 Jun 19.

Center for Gene and Cell Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China ; Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.

Our previous study demonstrated that administration of garlic-derived antioxidant S-allylmercaptocysteine (SAMC) ameliorated hepatic injury in a nonalcoholic fatty liver disease (NAFLD) rat model. Our present study aimed to investigate the mechanism of SAMC on NAFLD-induced hepatic apoptosis and autophagy. Adult female rats were fed with a high-fat diet for 8 weeks to develop NAFLD with or without intraperitoneal injection of 200 mg/kg SAMC for three times per week. During NAFLD development, increased apoptotic cells and caspase-3 activation were observed in the liver. Increased apoptosis was modulated through both intrinsic and extrinsic apoptotic pathways. NAFLD treatment also enhanced the expression of key autophagic markers in the liver with reduced activity of LKB1/AMPK and PI3K/Akt pathways. Increased expression of proapoptotic regulator p53 and decreased activity of antiautophagic regulator mTOR were also observed. Administration of SAMC reduced the number of apoptotic cells through downregulation of both intrinsic and extrinsic apoptotic mechanisms. SAMC also counteracted the effects of NAFLD on LKB1/AMPK and PI3K/Akt pathways. Treatment with SAMC further enhanced hepatic autophagy by regulating autophagic markers and mTOR activity. In conclusion, administration of SAMC during NAFLD development in rats protects the liver from chronic injury by reducing apoptosis and enhancing autophagy.
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http://dx.doi.org/10.1155/2013/642920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703729PMC
July 2013

Group I p21-activated kinases facilitate Tax-mediated transcriptional activation of the human T-cell leukemia virus type 1 long terminal repeats.

Retrovirology 2013 Apr 26;10:47. Epub 2013 Apr 26.

Department of Biochemistry, The University of Hong Kong, 3/F Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong.

Background: Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and tropical spastic paraparesis. HTLV-1 encodes transactivator protein Tax that interacts with various cellular factors to modulate transcription and other biological functions. Additional cellular mediators of Tax-mediated transcriptional activation of HTLV-1 long terminal repeats (LTR) remain to be identified and characterized.

Results: In this study, we investigated the regulatory role of group I p21-activated kinases (Paks) in Tax-induced LTR activation. Both wild-type and kinase-dead mutants of Pak3 were capable of potentiating the activity of Tax to activate LTR transcription. The effect of Paks on the LTR was attributed to the N-terminal regulatory domain and required the action of CREB, CREB-regulating transcriptional coactivators (CRTCs) and p300/CREB-binding protein. Paks physically associated with Tax and CRTCs. Paks were recruited to the LTR in the presence of Tax. siRNAs against either Pak1 or Pak3 prevented the interaction of Tax with CRTC1 and the recruitment of Tax to the LTR. These siRNAs also inhibited LTR-dependent transcription in HTLV-1-transformed MT4 cells and in cells transfected with an infectious clone of HTLV-1.

Conclusion: Group I Paks augment Tax-mediated transcriptional activation of HTLV-1 LTR in a kinase-independent manner.
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http://dx.doi.org/10.1186/1742-4690-10-47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651266PMC
April 2013

LKB1 tumor suppressor and salt-inducible kinases negatively regulate human T-cell leukemia virus type 1 transcription.

Retrovirology 2013 Apr 11;10:40. Epub 2013 Apr 11.

Department of Biochemistry, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong.

Background: Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Treatment options are limited and prophylactic agents are not available. We have previously demonstrated an essential role for CREB-regulating transcriptional coactivators (CRTCs) in HTLV-1 transcription.

Results: In this study we report on the negative regulatory role of LKB1 tumor suppressor and salt-inducible kinases (SIKs) in the activation of HTLV-1 long terminal repeats (LTR) by the oncoprotein Tax. Activation of LKB1 and SIKs effectively blunted Tax activity in a phosphorylation-dependent manner, whereas compromising these kinases, but not AMP-dependent protein kinases, augmented Tax function. Activated LKB1 and SIKs associated with Tax and suppressed Tax-induced LTR activation by counteracting CRTCs and CREB. Enforced expression of LKB1 or SIK1 in cells transfected with HTLV-1 molecular clone pX1MT repressed proviral transcription. On the contrary, depletion of LKB1 in pX1MT-transfected cells and in HTLV-1-transformed T cells boosted the expression of Tax. Treatment of HTLV-1 transformed cells with metformin led to LKB1/SIK1 activation, reduction in Tax expression, and inhibition of cell proliferation.

Conclusions: Our findings revealed a new function of LKB1 and SIKs as negative regulators of HTLV-1 transcription. Pharmaceutical activation of LKB1 and SIKs might be considered as a new strategy in anti-HTLV-1 and anti-ATL therapy.
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http://dx.doi.org/10.1186/1742-4690-10-40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640950PMC
April 2013

CDK5RAP3 is a novel repressor of p14ARF in hepatocellular carcinoma cells.

PLoS One 2012 31;7(7):e42210. Epub 2012 Jul 31.

Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

CDK5 regulatory subunit associated protein 3 (CDK5RAP3) is a novel activator of PAK4 and processes important pro-metastatic function in hepatocarcinogenesis. However, it remains unclear if there are other mechanisms by which CDK5RAP3 promotes HCC metastasis. Here, we showed that in CDK5RAP3 stable knockdown SMMC-7721 HCC cells, p14(ARF) tumor suppressor was upregulated at protein and mRNA levels, and ectopic expression of CDK5RAP3 was found to repress the transcription of p14(ARF). Using chromatin immunoprecipitation assay, we demonstrated that CDK5RAP3 bound to p14(ARF) promoter in vivo. Furthermore, knockdown of p14(ARF) in CDK5RAP3 stable knockdown HCC cells reversed the suppression of HCC cell invasiveness mediated by knockdown of CDK5RAP3. Taken together, our findings provide the new evidence that overexpression of CDK5RAP3 promotes HCC metastasis via downregulation of p14(ARF).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042210PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409131PMC
January 2013

AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells.

Cancer Res 2012 Sep 22;72(17):4394-404. Epub 2012 Jun 22.

Departments of Anatomy and Pathology, Li Ka Shing Faculty of Medicine, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.

AMP-activated protein kinase (AMPK), a biologic sensor for cellular energy status, has been shown to act upstream and downstream of known tumor suppressors. However, whether AMPK itself plays a tumor suppressor role in cancer remains unclear. Here, we found that the α2 catalytic subunit isoform of AMPK is significantly downregulated in hepatocellular carcinoma (HCC). Clinicopathologic analysis revealed that underexpression of AMPK-α2 was statistically associated with an undifferentiated cellular phenotype and poor patient prognosis. Loss of AMPK-α2 in HCC cells rendered them more tumorigenic than control cells both in vitro and in vivo. Mechanistically, ectopic expression of AMPK enhanced the acetylation and stability of p53 in HCC cells. The p53 deacetylase, SIRT1, was phosphorylated and inactivated by AMPK at Thr344, promoting p53 acetylation and apoptosis of HCC cells. Taken together, our findings suggest that underexpression of AMPK is frequently observed in HCC, and that inactivation of AMPK promotes hepatocarcinogenesis by destabilizing p53 in a SIRT1-dependent manner.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-0429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433393PMC
September 2012

The centrosomal protein Tax1 binding protein 2 is a novel tumor suppressor in hepatocellular carcinoma regulated by cyclin-dependent kinase 2.

Hepatology 2012 Nov 17;56(5):1770-81. Epub 2012 Sep 17.

Department of Anatomy, The University of Hong Kong, Hong Kong, China.

Unlabelled: Deregulation of cellular-signaling pathways by the inactivation of tumor-suppressor genes is one of the major causes of hepatocellular carcinoma (HCC). In this study, we identified Tax1 binding protein 2 (TAX1BP2) as a novel tumor-suppressor gene in HCC. TAX1BP2 transcript was frequently underexpressed (42.2% with T/NT <0.5; P < 0.03) in HCCs, and underexpression of TAX1BP2 was associated with poorer overall survival rates in patients after surgical resection. An effector domain (ED) for TAX1BP2 tumor-suppressor activity was mapped to the amino-acid residues 267-756. Transient or stable expression of either full-length or ED of TAX1BP2 significantly suppressed HCC cell tumorigenicity through the activation of the p38/p53/p21 pathway. In contrast, silencing of TAX1BP2 by short interfering RNA remarkably suppressed the activation of the p38/p53/p21 pathway. Finally, phosphorylation of TAX1BP2 at serine-763 by cyclin-dependent kinase (CDK)2 abolished the TAX1BP2-mediated p38 activation and tumor-suppressive activity, indicating that TAX1BP2 can adapt CDK2 signaling to the p38/p53/p21 pathway.

Conclusion: Taken together, our data provide the first evidence that TAX1BP2 is a CDK2-regulated tumor-suppressor gene in HCC and is a novel activator of the p38/p53/p21 pathway.
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http://dx.doi.org/10.1002/hep.25851DOI Listing
November 2012

Garlic-derived S-allylmercaptocysteine is a hepato-protective agent in non-alcoholic fatty liver disease in vivo animal model.

Eur J Nutr 2013 Feb 26;52(1):179-91. Epub 2012 Jan 26.

Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, L1-41, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong, SAR.

Purpose: To investigate the hepato-protective properties and underlying mechanisms of SAMC in a non-alcoholic fatty liver disease (NAFLD) rat model.

Methods: Female rats were fed with a diet comprising highly unsaturated fat diet (30% fish oil) for 8 weeks to develop NAFLD with or without an intraperitoneal injection of 200 mg/kg SAMC three times per week. After euthanasia, blood and liver samples of rats were collected for histological and biochemical analyses.

Results: Co-treatment of SAMC attenuated NAFLD-induced liver injury, fat accumulation, collagen formation and free fatty acids (FFAs). At the molecular level, SAMC decreased the lipogenesis marker and restored the lipolysis marker. SAMC also reduced the expression levels of pro-fibrogenic factors and diminished liver oxidative stress partly through the inhibition in the activity of cytochrome P450 2E1-dependent pathway. NAFLD-induced inflammation was also partially mitigated by SAMC treatment via reduction in the pro-inflammatory mediators, chemokines and suppressor of cytokine signaling. The protective effect of SAMC is also shown partly through the restoration of altered phosphorylation status of FFAs-dependent MAP kinase pathways and diminished in the nuclear transcription factors (NF-κB and AP-1) activity during NAFLD development.

Conclusions: SAMC is a novel hepato-protective agent against NAFLD caused by abnormal liver functions. Garlic or garlic derivatives could be considered as a potent food supplement in the prevention of fatty liver disease.
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http://dx.doi.org/10.1007/s00394-012-0301-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549410PMC
February 2013

Lycium barbarum polysaccharides protect mice liver from carbon tetrachloride-induced oxidative stress and necroinflammation.

J Ethnopharmacol 2012 Jan 26;139(2):462-70. Epub 2011 Nov 26.

Department of Anatomy, The University of Hong Kong, Hong Kong Special Administrative Region.

Ethnopharmacological Relevance: Lycium barbarum has been used as a traditional Chinese medicine to nourish liver, kidneys and the eyes.

Aim Of The Study: We investigated the protective mechanisms of Wolfberry, Lycium barbarum polysaccharides (LBP) in carbon tetrachloride (CCl(4))-induced acute liver injury.

Materials And Methods: Mice were intraperitoneally injected with a 50 μl/kg CCl(4) to induce acute hepatotoxicity (8h) and were orally fed with LBP 2 h before the CCl(4) injection. There were six experimental groups of mice (n=7-8 per group), namely: control mice (vehicle only; 1 mg/kg LBP or 10 mg/kg LBP), CCl(4)-treated mice and CCl(4)+LBP treated mice (1 mg/kg LBP or 10 mg/kg LBP).

Results: Pre-treatment with LBP effectively reduced the hepatic necrosis and the serum ALT level induced by CCl(4) intoxication. LBP remarkably inhibited cytochrome P450 2E1 expression and restored the expression levels of antioxidant enzymes. It also decreased the level of nitric oxide metabolism and lipid peroxidation induced by CCl(4). LBP attenuated hepatic inflammation via down-regulation of proinflammatory mediators and chemokines. Furthermore, LBP promoted liver regeneration after CCl(4) treatment. The protective effects of LBP against hepatotoxicity were partly through the down-regulation of nuclear factor kappa-B activity.

Conclusion: LBP is effective in reducing necroinflammation and oxidative stress induced by a chemical toxin, thus it has a great potential use as a food supplement in the prevention of hepatic diseases.
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http://dx.doi.org/10.1016/j.jep.2011.11.033DOI Listing
January 2012

Hippocampal neurogenesis and dendritic plasticity support running-improved spatial learning and depression-like behaviour in stressed rats.

PLoS One 2011 15;6(9):e24263. Epub 2011 Sep 15.

Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

Exercise promotes hippocampal neurogenesis and dendritic plasticity while stress shows the opposite effects, suggesting a possible mechanism for exercise to counteract stress. Changes in hippocampal neurogenesis and dendritic modification occur simultaneously in rats with stress or exercise; however, it is unclear whether neurogenesis or dendritic remodeling has a greater impact on mediating the effect of exercise on stress since they have been separately examined. Here we examined hippocampal cell proliferation in runners treated with different doses (low: 30 mg/kg; moderate: 40 mg/kg; high: 50 mg/kg) of corticosterone (CORT) for 14 days. Water maze task and forced swim tests were applied to assess hippocampal-dependent learning and depression-like behaviour respectively the day after the treatment. Repeated CORT treatment resulted in a graded increase in depression-like behaviour and impaired spatial learning that is associated with decreased hippocampal cell proliferation and BDNF levels. Running reversed these effects in rats treated with low or moderate, but not high doses of CORT. Using 40 mg/kg CORT-treated rats, we further studied the role of neurogenesis and dendritic remodeling in mediating the effects of exercise on stress. Co-labelling with BrdU (thymidine analog) /doublecortin (immature neuronal marker) showed that running increased neuronal differentiation in vehicle- and CORT-treated rats. Running also increased dendritic length and spine density in CA3 pyramidal neurons in 40 mg/kg CORT-treated rats. Ablation of neurogenesis with Ara-c infusion diminished the effect of running on restoring spatial learning and decreasing depression-like behaviour in 40 mg/kg CORT-treated animals in spite of dendritic and spine enhancement. but not normal runners with enhanced dendritic length. The results indicate that both restored hippocampal neurogenesis and dendritic remodelling within the hippocampus are essential for running to counteract stress.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024263PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174166PMC
February 2012

Differential regulation of RNF8-mediated Lys48- and Lys63-based poly-ubiquitylation.

Nucleic Acids Res 2012 Jan 12;40(1):196-205. Epub 2011 Sep 12.

Genome Stability Research Laboratory, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong SAR.

Pairing of a given E3 ubiquitin ligase with different E2s allows synthesis of ubiquitin conjugates of different topologies. While this phenomenon contributes to functional diversity, it remains largely unknown how a single E3 ubiquitin ligase recognizes multiple E2s, and whether identical structural requirements determine their respective interactions. The E3 ubiquitin ligase RNF8 that plays a critically important role in transducing DNA damage signals, interacts with E2s UBCH8 and UBC13, and catalyzes both K48- and K63-linked ubiquitin chains. Interestingly, we report here that a single-point mutation (I405A) on the RNF8 polypeptide uncouples its ability in catalyzing K48- and K63-linked ubiquitin chain formation. Accordingly, while RNF8 interacted with E2s UBCH8 and UBC13, its I405A mutation selectively disrupted its functional interaction with UBCH8, and impaired K48-based poly-ubiquitylation reactions. In contrast, RNF8 I405A preserved its interaction with UBC13, synthesized K63-linked ubiquitin chains, and assembled BRCA1 and 53BP1 at sites of DNA breaks. Together, our data suggest that RNF8 regulates K48- and K63-linked poly-ubiquitylation via differential RING-dependent interactions with its E2s UBCH8 and UBC13, respectively.
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http://dx.doi.org/10.1093/nar/gkr655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245915PMC
January 2012

Multiple pathways were involved in tubeimoside-1-induced cytotoxicity of HeLa cells.

J Proteomics 2011 Dec 28;75(2):491-501. Epub 2011 Aug 28.

School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361005, China.

The Bolbostemma paniculatum (Maxim.) Franquet (Cucurbitaceae) is a Chinese herb with anticancer potential. Its main active component tubeimoside-1 (TBMS1), a triterpenoid saponin, was previously proved as a potent anticancer chemotherapeutic agent; however, the molecular basis for its activities is still elusive. In the present study, subcellular proteomic study in the cytoplasm and membrane protein fractions extracted from HeLa cells revealed that proteins act as mediators of ROS generation and Ca(2+) regulation were substantially altered in expression upon TBMS1 stimuli. We also found that TBMS1 induced cell cycle arrest at G2/M phase accompanied by a decrease in G0/G1 phase in HeLa cells. Further biochemical studies showed that TBMS1 inhibited the levels of cyclinB1, Cdc2 and Cdc25C, but enhanced Chk2 phosphorylation. In addition, the cytoplasm sequestration of Cdc25C, Cip1/p21 induction and tubulin dyspolymerization also contributed to the TBMS1-mediated cell cycle arrest on the G2/M phase.
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http://dx.doi.org/10.1016/j.jprot.2011.08.014DOI Listing
December 2011

TSPYL2 is important for G1 checkpoint maintenance upon DNA damage.

PLoS One 2011 27;6(6):e21602. Epub 2011 Jun 27.

Department of Paediatrics and Adolescent Medicine, Center of Reproduction, Development and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Nucleosome assembly proteins play important roles in chromatin remodeling, which determines gene expression, cell proliferation and terminal differentiation. Testis specific protein, Y-encoded-like 2 (TSPYL2) is a nucleosome assembly protein expressed in neuronal precursors and mature neurons. Previous studies have shown that TSPYL2 binds cyclin B and inhibits cell proliferation in cultured cells suggesting a role in cell cycle regulation. To investigate the physiological significance of TSPYL2 in the control of cell cycle, we generated mice with targeted disruption of Tspyl2. These mutant mice appear grossly normal, have normal life span and do not exhibit increased tumor incidence. To define the role of TSPYL2 in DNA repair, checkpoint arrest and apoptosis, primary embryonic fibroblasts and thymocytes from Tspyl2 deficient mice were isolated and examined under unperturbed and stressed conditions. We show that mutant fibroblasts are impaired in G1 arrest under the situation of DNA damage induced by gamma irradiation. This is mainly attributed to the defective activation of p21 transcription despite proper p53 protein accumulation, suggesting that TSPYL2 is additionally required for p21 induction. TSPYL2 serves a biological role in maintaining the G1 checkpoint under stress condition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0021602PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124543PMC
December 2011

S-allylmercaptocysteine reduces carbon tetrachloride-induced hepatic oxidative stress and necroinflammation via nuclear factor kappa B-dependent pathways in mice.

Eur J Nutr 2012 Apr 18;51(3):323-33. Epub 2011 Jun 18.

Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, L1-41, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China.

Purpose: To study the protective effects and underlying molecular mechanisms of SAMC on carbon tetrachloride (CCl4)-induced acute hepatotoxicity in the mouse model.

Methods: Mice were intraperitoneally injected with CCl4 (50 μl/kg; single dose) to induce acute hepatotoxicity with or without a 2-h pre-treatment of SAMC intraperitoneal injection (200 mg/kg; single dose). After 8 h, the blood serum and liver samples of mice were collected and subjected to measurements of histological and molecular parameters of hepatotoxicity.

Results: SAMC reduced CCl4-triggered cellular necrosis and inflammation in the liver under histological analysis. Since co-treatment of SAMC and CCl4 enhanced the expressions of antioxidant enzymes, reduced the nitric oxide (NO)-dependent oxidative stress, and inhibited lipid peroxidation induced by CCl4. SAMC played an essential antioxidative role during CCl4-induced hepatotoxicity. Administration of SAMC also ameliorated hepatic inflammation induced by CCl4 via inhibiting the activity of NF-κB subunits p50 and p65, thus reducing the expressions of pro-inflammatory cytokines, mediators, and chemokines, as well as promoting pro-regenerative factors at both transcriptional and translational levels.

Conclusions: Our results indicate that SAMC mitigates cellular damage, oxidative stress, and inflammation in CCl4-induced acute hepatotoxicity mouse model through regulation of NF-κB. Garlic or garlic derivatives may therefore be a potential food supplement in the prevention of liver damage.
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http://dx.doi.org/10.1007/s00394-011-0217-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313023PMC
April 2012

Overexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasis.

Cancer Res 2011 Apr 8;71(8):2949-58. Epub 2011 Mar 8.

Departments of Anatomy and Pathology, Li Ka Shing Faculty of Medicine, and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.

The CDK5 kinase regulatory subunit-associated protein 3 (CDK5RAP3 or C53/LZAP) regulates apoptosis induced by genotoxic stress. Although CDK5RAP3 has been implicated in cancer progression, its exact role in carcinogenesis is not well established. In this article, we report that CDK5RAP3 has an important prometastatic function in hepatocarcinogenesis. An examination of human hepatocellular carcinoma (HCC) samples revealed at least twofold overexpression of CDK5RAP3 transcripts in 58% (39/67) of HCC specimens when compared with corresponding nontumorous livers. CDK5RAP3 overexpression was associated with more aggressive biological behavior. In HCC cell lines, stable overexpression of CDK5RAP3 promoted, and small interfering RNA-mediated knockdown inhibited, tumorigenic activity and metastatic potential. We found that overexpression of CDK5RAP3 and p21-activated protein kinase 4 (PAK4) correlated in human HCCs, and that CDK5RAP3 was a novel binding partner of PAK4, and this binding enhanced PAK4 activity. siRNA-mediated knockdown of PAK4 in CDK5RAP3-expressing HCC cells reversed the enhanced cell invasiveness mediated by CDK5RAP3 overexpression, implying that PAK4 is essential for CDK5RAP3 function. Taken together, our findings reveal that CDK5RAP3 is widely overexpressed in HCC and that overexpression of CDK5RAP3 promotes HCC metastasis through PAK4 activation.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-4046DOI Listing
April 2011

Effect of corticosterone and paroxetine on masculine mating behavior: possible involvement of neurogenesis.

J Sex Med 2011 May 18;8(5):1390-403. Epub 2010 Oct 18.

Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.

Introduction: Corticosterone inhibits male rodent sexual behavior while the mechanism remains obscured. Recent studies have disclosed that neurogenesis in the subventricular zone (SVZ) can be increased by pheromone exposure from the opposite sex, and neurogenesis is essential for normal mating behavior of female mice. Together with the neurogenesis-inhibiting effect of corticosterone, we hypothesize that cell proliferation in the olfactory system is essential for male rodent sexual functioning.

Aim: The current study explored the relationship between cell proliferation in the olfactory system and male sexual behavior.

Main Outcome Measures: Sexual behavior performance, proliferative cell counts, and c-fos-expressing cell counts.

Methods: Adult male rats were treated with corticosterone and/or paroxetine, an antidepressant, for 2 weeks. These two drugs were shown to suppress and enhance hippocampus and SVZ cell proliferation, respectively. Mating behavior was assessed after the treatment, and proliferation of new cells and c-fos-expressing cells, activated neurons in the mating-related regions in the brain, were analyzed. To further confirm the necessity of cell proliferation in mating, inhibition of cell proliferation was performed by intracerebroventricular infusion of cytostatic cytosine arabinose (Ara-c).

Results: Corticosterone treatment, which inhibited cell proliferation in both the SVZ and olfactory epithelium, led to inhibited male sexual performance. In contrast, paroxetine increased cell proliferation and improved the performance in corticosterone-treated animals. When cell proliferation in the brain was inhibited by Ara-c, a suppressed sexual performance was found. However, cell proliferation in olfactory epithelium was not inhibited by Ara-c and thus the sexual inhibition is unlikely to be linked to this region. Furthermore, a decrease in c-fos expression in the mating-related regions upon female pheromone stimulation was found.

Conclusions: These results suggest that cell proliferation in the SVZ and hippocampus may be involved in the reproduction of the male rodents, and pharmacological treatments may affect sexual functioning through alteration of neurogenesis.
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http://dx.doi.org/10.1111/j.1743-6109.2010.02081.xDOI Listing
May 2011

Deleted in liver cancer 2 suppresses cell growth via the regulation of the Raf-1-ERK1/2-p70S6K signalling pathway.

Liver Int 2010 Oct;30(9):1315-23

Department of Pathology, The University of Hong Kong, Hong Kong, China.

Background: Deleted in liver cancer 2 (DLC2) gene, a putative tumour suppressor gene, encodes a Rho GTPase-activating protein (RhoGAP) with GAP activity specific for RhoA. It exhibits tumour suppressor functions and inhibits tumour cell proliferation, migration as well as transformation.

Aims: In this study, we aimed to investigate the underlying mechanisms of the DLC2 gene in suppressing cell migration and cell growth. HepG2 hepatoma cells were stably transfected with the DLC2γ isoform, which contains the RhoGAP domain.

Methods And Results: On performing immunofluorescence staining and Western blot analysis, the expression of the focal adhesion protein paxillin was found to be much reduced in DLC2γ-stable clones. Upon flow cytometric analysis of the cell cycle profiles, the DLC2γ-stable clones were shown to have a higher population of cells arrested at the G1 phase than the EGFP vector-stable clone, suggesting that downregulation of RhoA activity in DLC2γ-stable clones inhibited cell cycle progression. In the DLC2γ-stable clone, the levels of Raf-1 and extracellular signal-regulated kinase (ERK) 1/2 were decreased as compared with those of the parental HepG2, EGFP vector and DLC2γ-GAP defective mutant-stable clones. Furthermore, the ribosomal kinase p70S6K, a downstream target of ERK1/2, was suppressed in the DLC2-stable clones. On the contrary, when DLC2 was knocked down by siRNA in HepG2 cells, the expression levels of phospho-p70S6K and phospho-ERK1/2 were upregulated.

Conclusion: Our data show that DLC2 inhibits the activity of Raf-1-ERK1/2-p70S6K via its RhoGAP function, resulting in the suppression of cell growth. Further studies on the molecular signalling between DLC2 and p70S6K may provide an insight into its growth suppressor function.
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http://dx.doi.org/10.1111/j.1478-3231.2010.02307.xDOI Listing
October 2010

Gamma-tocotrienol as an effective agent in targeting prostate cancer stem cell-like population.

Int J Cancer 2011 May;128(9):2182-91

Department of Anatomy, Faculty of Medicine, University of Hong Kong, Hong Kong, SAR, China.

Emerging evidence supports that prostate cancer originates from a rare subpopulation of cells, namely prostate cancer stem cells (CSCs). Conventional therapies for prostate cancer are believed to mainly target the majority of differentiated tumor cells but spare CSCs, which may account for the subsequent disease relapse after treatment. Therefore, successful elimination of CSCs may be an effective strategy to achieve complete remission from this disease. Gamma-tocotrienols (γ-T3) is one of the vitamin-E constituents, which have been shown to have anticancer effects against a wide range of human cancers. Recently, we have reported that γ-T3 treatment not only inhibits prostate cancer cell invasion but also sensitizes the cells to docetaxel-induced apoptosis, suggesting that γ-T3 may be an effective therapeutic agent against advanced stage prostate cancer. Here, we demonstrate for the first time that γ-T3 can downregulate the expression of prostate CSC markers (CD133/CD44) in androgen-independent prostate cancer cell lines (PC-3 and DU145), as evident from Western blotting analysis. Meanwhile, the spheroid formation ability of the prostate cancer cells was significantly hampered by γ-T3 treatment. In addition, pretreatment of PC-3 cells with γ-T3 was found to suppress tumor initiation ability of the cells. More importantly, although CD133-enriched PC-3 cells were highly resistant to docetaxel treatment, these cells were as sensitive to γ-T3 treatment as the CD133-depleted population. Our data suggest that γ-T3 may be an effective agent in targeting prostate CSCs, which may account for its anticancer and chemosensitizing effects reported in previous studies.
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http://dx.doi.org/10.1002/ijc.25546DOI Listing
May 2011

SON is a spliceosome-associated factor required for mitotic progression.

Cell Cycle 2010 Jul;9(13):2679-85

Genome Stability Research Laboratory, The University of Hong Kong, Hong Kong, SAR.

The eukaryotic RNA splicing machinery is dedicated to the daunting task of excising intronic sequences on the many nascent RNA transcripts in a cell, and in doing so facilitates proper translation of its transcriptome. Notably, emerging evidence suggests that RNA splicing may also play direct roles in maintaining genome stability. Here we report the identification of the RNA/DNA-binding protein SON as a component of spliceosome that plays pleiotropic roles during mitotic progression. We found that SON is essential for cell proliferation, and that its inactivation triggers a MAD2-dependent mitotic delay. Moreover, SON deficiency is accompanied by defective chromosome congression, compromised chromosome segregation and cytokinesis, which in turn contributes to cellular aneuploidy and cell death. In summary, our study uncovers a specific link between SON and mitosis, and highlights the potential of RNA processing as additional regulatory mechanisms that govern cell proliferation and division.
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http://dx.doi.org/10.4161/cc.9.13.12151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040851PMC
July 2010
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