Abstracts 2
Professor Jinke Cheng: Protein SUMOylation and Tumorigenesis 2
Associate Professor Graham Mann: Confronting melanoma in its homeland: lessons for multidisciplinary cancer research 3
Associate Professor Christine Clarke: Endocrine signalling in normal and malignant breast 4
Professor Zeguang Han: Functional Genomics of Liver Cancer 5
Associate Professor Qihan Dong: Lipid modifying enzymes in prostate cancer 6
Professor Yingyan Yu: IPO-38 is identified as a novel serum biomarker of gastric cancer based on clinical proteomics technology 7
Professor Xia Pu: The role of sphingosine kinase 1 in cancer: oncogene or non-oncogene addiction? 8
Associate Professor Qian Zhao: Herb-derived active compounds-based chemical biology for leukemic cells 9
Professor Stephen Clarke: Inter-ethnic differences in chemotherapy 10
Professor Fengchun Zhang: Cancer Stem Cell and its regulation 11
Associate Professor Kewen Zhao: The ubiquitination of E3 ligase EFP involves in the degradation of transcriptional factor KLF5 14
Professor Des Richardson: Novel and selective anti-cancer agents that overcome resistance to established chemotherapy: the double punch 15
Associate Professor Zonghai Li: Phage display: a magic tool for cancer biology 16
Dr Diana Benn and Professor Bruce Robinson: Hereditary phaeochromocytoma / paraganglioma syndromes 18
Fei Yue: Identification of Novel Biomarkers Evaluating Lymph Node Metastasis in Colorectal Cancer 19
Dr Lyndee Scurr: p16INK4a-induced senescence is disabled by melanoma-associated mutations 20
Mingzhu Huang: Cancer stem cell and its microenviroment 21
Biographies 22
Shanghai Jiao Tong University School of Medicine speakers 22
Fei Yue (Ph.D. candidate) - 22
Professor Fengchun Zhang - 23
Professor Guoqiang Chen - 24
Professor Jing Yi - 24
Associate Professor Kewen Zhao - 25
Mingzhu Huang (Ph.D. candidate) 26
Associate Professor Qian Zhao - 27
Professor Yingyan Yu - 27
Professor Zeguang Han – 28
Associate Professor Zonghai Li - 30
University of Sydney speakers 30
Associate Professor Christine Clarke - 31
Professor Des Richardson - 32
Dr Diana Benn - 33
Associate Professor Graham Mann 33
Dr Lyndee Scurr - 34
Associate Professor Xia Pu - 37
Abstracts
Professor Jinke Cheng: Protein SUMOylation and Tumorigenesis
Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine
Post-translational modifiers of the small ubiquitin-like modifier protein (SUMO) family have emerged as key regulators of protein function and localization. SUMO modification is a dynamic process, catalyzed by SUMO-specific E1, E2, and E3s and reversed by a family of SUMO-specific proteases (SENPs). Although six human SENPs have been identified, each with different cellular locations and substrate specificities, the precise roles of SENPs in cellular processes involved has not been well-defined. We used used functional screen to identify HDAC1 as a target protein for SENP1 desumoylation in androgen-induced androgen receptor response. SENP1 specifically and markedly enhance androgen-induced androgen receptor activity and androgen can also increase SENP1 expression through androgen receptor-dependent manner. We further determined the role of SENP1 in prostate cancer development by using transgenic mice model. Using SENP1 knockout mice, we identified another SENP1 target HIF1 and found that SENP1 involves hypoxia-induced cellular process. Interestingly, hypoxia can induce SENP1 expression, which further enhance hypoxia response in a positive feedback loop. These findings indicates that SENP1 plays an important role in tumor genesis.
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Associate Professor Graham Mann: Confronting melanoma in its homeland: lessons for multidisciplinary cancer research
Westmead Millennium Institute – University of Sydney
[to come]
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Associate Professor Christine Clarke: Endocrine signalling in normal and malignant breast
NHMRC Research Fellow, Westmead Millennium Institute, University of Sydney
The ovarian hormones oestrogen and progesterone exert fundamental control over the female reproductive system by multiple independent and overlapping mechanisms. They also have non-reproductive functions in tissues such as brain and the vasculature. While aspects of their function are known through epidemiological studies and animal and cell line models, the mechanisms of their action in the human breast are poorly understood. This knowledge gap exists despite the known role of ovarian hormones in breast development and function, and in breast cancer. The causes of breast cancer are largely unknown, but the currently accepted view is that development of invasive breast cancer requires multiple genetic changes, with the original mutation occurring early in reproductive life, and additional mutations accumulating over decades until menopause, when most breast cancers are diagnosed. Although the initiating genetic mutations are largely unknown, the pivotal involvement of ovarian hormones has been known for over a century. Women without ovaries have a markedly reduced breast cancer incidence, with a risk that is analogous to the low risk of breast cancer observed in men. The underlying mechanisms by which ovarian hormones and the endocrine milieu contribute to development of breast cancer are not known.
The Westmead Institute of Cancer Research, based in the Westmead Milennium Institute at the University of Sydney Western Clinical School, focusses on research in breast cancer from several perspectives, including basic research and a translational research focus. It also houses the national headquarters of a Breast Cancer Tissue Bank, which supplies biospecimens for breast cancer research to researchers throughout Australia. The studies to be described in this presentation have used a variety of techniques, including expression profiling, live cell imaging and related approaches in human tissues to elucidate the cellular targets of progesterone and the mechanisms by which the nuclear progesterone receptor regulates transcription. The results of these studies demonstrate a critical relationship between nuclear organisation and transcriptional activity in the progesterone signalling axis, and point to mechanisms by which this is disrupted in cancers. Identification of such mechanisms may lead to further understanding of critical pathways and cellular vulnerabilities in the development of breast cancer.
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Professor Zeguang Han: Functional Genomics of Liver Cancer
Department of Functional Genomics, Shanghai Jiao Tong University
Human hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Genome-wide survey on pathological profiles of HCC will provide insights into hepatocellular carcinogenesis. In our work, we first figured out a comprehensive characterization of gene expression profiles of hepatitis B virus-positive HCC through the transcriptome approaches. Notably, the altered transcriptome profiles of HCC could be correlated to a number of chromosome regions with amplification or loss of heterozygosity (LOH)1. Subsequently, To investigate whether the genomic DNA copy number alterations may contribute to primary HCC, the cDNA microarray-based comparative genomic hybridization (CGH) analysis was performed in 41 primary HCC infected by hepatitis B virus and 12 HCC cell lines. The resulting data showed that gains involving chromosomes 1q, 6p, 8q and 9p were frequently observed in these cases; and whilst, losses involving 1p, 16q and 19p occurred in most patients. Interestingly, the genomic DNA copy number alterations of most genes appeared not to be in generally parallel with the corresponding transcriptional expression. However, the transcriptional deregulation of a few genes, such as osteopontin (SPP1), transgelin 2 (TAGLN2) and PEG10, could be ascribed partially to their genomic aberrations2. In addition, the dysregulation of the genomic imprinting genes is known to contribute to carcinogenesis. We here investigated the expression pattern of known imprinted genes on HCC. Interestingly, a maternal expressed gene, ARHI, was frequently down-regulated in HCC due to the DNA hypermethylation of its promoter, where exotic ARHI could significantly inhibit the cell growth and colony formation. However, delta-like 1 homolog (Drosophila) (DLK1), a paternally expressed gene, was found to be significantly up-regulated in majority of HCC specimens. The exogenous DLK1 can significantly promote the HCC cell proliferation, whereas the suppression of endogenetic DLK1 through RNA interference can markedly inhibit cell growth, colony formation and tumorigenicity of HCC cells3. Recently, we employed a genome-wide approach to screen out the epigenetically silenced tumor suppressor genes associated with HCC. Here we pay attention to these genes mapped onto chromosome 8p, the frequent LOH region in human HCC. A putative tumor suppressor gene, SFRP1 (the secreted frizzled-related protein 1), was significantly down-regulated in many HCC specimens, whereas the overexpression of SFRP1 can significantly inhibit the cell growth and colony formation of HCC cells. LOH of both microsatellite markers flanking the gene locus and DNA hypermethylation within SFRP1 promoter were found in some HCC specimens4.
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Associate Professor Qihan Dong: Lipid modifying enzymes in prostate cancer
Head, Cancer Biology Group; Central Clinical School, The University of Sydney
Scientific Director, Department of Endocrinology, Royal Prince Alfred Hospital
Previous studies support a role for eicosanoid products of the cyclooxygenase (COX) pathways in the proliferation of prostate cancer cells in culture and regulation of tumour vascularisation and metastasis in animal models. Pharmacological agents that block COX products effectively reduce the size of prostate cancer xenografts. However, COX-2 selective inhibitors can have thrombosis-related cardiovascular side effects. Since phospholipase A2 (PLA2) enzymes regulate the provision of arachidonic acid for the production of eicosanoids, we have investigated the role on PLA2 in prostate cancer. We have demonstrated an increase in the PLA2 levels/activity and a loss of the natural inhibitor of PLA2. Blocking PLA2 suppresses the growth of hormone refractory prostate cancer cells and experimental angiogenesis. The mechanism underlying the PLA2 effect is via PI3K/Akt pathways. As the activated Akt is associated with poor clinical outcome, identification of a novel regulator of Akt activity in prostate cancer cells has a potential to impact on clinical practice.
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Professor Yingyan Yu: IPO-38 is identified as a novel serum biomarker of gastric cancer based on clinical proteomics technology
Shanghai Institute of Digestive Surgery, Shanghai Jiao Tong University
Gastric cancer is one of the most common malignancies in China. So far, there are few reliable serum biomarkers for early diagnosis and prognostic prediction. The available biomarkers of CEA, CA19-9 and CA72-4 are not sufficiently sensitive and specific for gastric cancer. In this study, a high density antibody microarray was used for identifying new biomarkers from serum samples of gastric cancer. Serum samples from colorectal cancer, pancreatic cancer, hepatocellular cancer and breast cancer were also screened for comparative study. As result, some candidate biomarkers including 45 up-regulated and 6 down-regulated in serum sample of gastric cancer were found out. IPO-38, one of up-regulated serum proteins in gastric cancer was selected for subsequent validation including serum IPO-38 expression by ELISA, IPO-38 protein expressing status by immunohistochemical localization. The immunoprecipitation by IPO-38 for gastric cancer cell line and MALDI–TOF/TOF mass spectrometer suggested that pull-down of IPO-38 belongs to H2B histone, which was supported by co-localization study of laser scanning confocal microscope. Follow-up study showed that survival rate of IPO-38 negative group was better than that in IPO-38 positive group. The study firstly clarified the property of IPO-38 proliferating marker, and proposed that IPO-38 protein is a promising serum biomarker both for diagnosis and for predicting prognosis of gastric cancer.
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Professor Xia Pu: The role of sphingosine kinase 1 in cancer: oncogene or non-oncogene addiction?
Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney
Since we for the first time reported an oncogenic potential of sphingosine kinase-1 (SphK1) (Xia, et al. Current Biology, 2000), an increasing body of evidence has suggested a critical pathogenic role for SphK1 in a variety of human cancers. Upon activation, SphK1 catalyses the formation of sphingosine 1-phosphate (S1P) that serves as important signaling molecule in regulating cell survival, proliferation, differentiation, cellular motility and evasion of apoptosis, all key cellular processes in cancer development and progression. Over the past decade, our group has focused on understanding the activation mechanism of SphK1 and its role in cancer. We have demonstrated that the oncogenic activity of SphK1 entirely relies on its phosphorylation-dependent translocation to the plasma membrane beyond the enzymatic activity (Pitson, et al. JEM, 2005), and that this pathway can be activated by a wide variety of oncogenes or oncogenic factors. For instance, the steroid hormone estrogen has long been recognized as a key risk factor for the pathogenesis of breast cancer. We found that estrogen is a strong activator of SphK1 and that SphK1 is capable of transmitting estrogen signals to its mitogenic activity in human breast cancer cells (Sukocheva, et al. Mol. Endocrinol, 2003). Furthermore, SphK1 plays a central role to mediate the GPCR-EGFR transactivation in response to estrogen stimulation, revealing a new signaling mechanism whereby SphK1 couples three individual ligand/receptor systems, leading to activation of multiple mitogenic signal pathways in a coordinative manner to promote neoplastic cell growth (Sukocheva, et al. J. Cell Biol. 2006). More recently, our work shows that inhibition of the SphK1 pathway by either genetic means or chemical inhibitors resulted in not only arrest of cell growth, but also sensitizing the breast cancer cells to the antiestrogen therapy, leading to cell death. Interestingly, blocking of the SphK1/S1P pathway is also capable of restoring sensitivity of the resistant cells to the drug killing effect, revealing a new way to overcoming endocrine resistance in breast cancer. Thus, further elucidating the details of SphK1/S1P signaling, especially in clinical relevant settings, could provide a potential interventional target for the management of various cancers, such as breast cancer.
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Associate Professor Qian Zhao: Herb-derived active compounds-based chemical biology for leukemic cells
Department of Pathophysiology, Shanghai Jiao Tong University
Cumulative evidence indicates that traditional Chinese Medicine (TCM) is an important resource for discoveries of drugs against cancers. In the past year, we screened some small molecular compounds frm TCM herbs for leukemic cell differentiation. We found that SSMU55, a small molecular compound isolated from Isodon forrestii in Lijiang, China, can potentiate the differentiation-inducing effect of low-dose（10-8M）all- trans retinoic acid (ATRA) in acute myloid leukemic(AML) cell lines NB4 and U937 cells. Furthermore, the differentiation-inducing effect of these two reagents is not limited to ATRA-sensitive NB4 cells, the combination of these two reagents can also induce the differentiation of NB4-LR1 and NB4-MR2 cells, which are subtypes of NB4 cells resistant to ATRA-induced differentiation. More intriguingly, the treatment of NB4 and U937 cells with SSMU55 alone or with the combination of SSMU55 and ATRA obviously upregulate the RARa and PML-RARa protein. The up-regulation of these two protein are also appeared in the ATRA-resistant NB4-LR1，NB4-LR2 and NB4-MR2 cells after the same treatment. Moreover, SSMU55 dose not change the mRNA level of RARa in these cells, while the half-life of RARa protein appeared to be far longer, suggesting that the up-regulation of RARa protein is caused by the decreased degradation of this protein. Taken together, our results suggest that SSMU55 is a potential agent for the treatment of AML, especially in the ATRA-resistant AML cells.