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Ng Ho-Keung 吳浩強 The State Key Laboratory of Oncology in South China

PDAM is frequently downregulated in oligodendroglial tumors and its knockdown by siRNA induces cisplatin resistance. Ng Ho-Keung 吳浩強 The State Key Laboratory of Oncology in South China Department of Anatomical and Cellular Pathology The Chinese University of Hong Kong.

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Ng Ho-Keung 吳浩強 The State Key Laboratory of Oncology in South China

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  1. PDAM is frequently downregulated in oligodendroglial tumors and its knockdown by siRNA induces cisplatin resistance Ng Ho-Keung吳浩強 The State Key Laboratory of Oncology in South China Department of Anatomical and Cellular Pathology The Chinese University of Hong Kong

  2. 1p/19q co-deletion is a genetic hallmark of oligodendroglial tumors (OTs) • Frequency of 1p/19q codeletion 60-70% Bigner et al., Am J Pathol, 1999

  3. Significance of chromosome 1p/19q co-deletion • Frequent 1p/19q co-deletion suggests the presence of tumor suppressor genes • 1p/19q co-deletion is correlated with oligodendrogliomas with ‘classic’ histology - an adjunct marker in OT diagnosis • 1p/19q co-deletion or 1p deletion alone is also associated with better survival and chemosensitivity in OT patients - first molecular marker in neuro-oncology for prognosis and chemosensitivity • Investigation into the mechanism of 1p loss would provide insights into - molecular pathogenesis of OTs - mechanism underlying chemosensitivity

  4. Deletion mapping on chromosome 1p in 52 OTs 1p loss frequency : 61% Dong et al., Br J Cancer 2004

  5. Candidate genes within the minimally deleted region on 1p36.3 ~1.2 Mb

  6. RT-PCR analysis of candidate genes in microdissected tumors 7/12 (58%) • / KIAA0495 CCDC27 LOC100133612 LOC284661 No detectable transcripts In all samples examined • Pang et al., Brain Pathol , in press

  7. PDAM is downregulated in OTs • p=0.01 64% (37 of 58) tumors showed reduced PDAM expression by >2-fold compared to normal brain, with 51% showing >10-fold decreased level

  8. Mechanisms responsible for PDAM downregulation Allelic deletion - 24 of 37 tumors with reduced PDAM expression showed chr 1p loss (p=0.01) Epigenetic modifications

  9. PDAM promoter is hypermethylated Reduced PDAM expression was associated with promoter hypermethylation (p=0.004)

  10. PDAM expression is regulated by epigenetic modifications * * * * * P<0.05 * * * * *

  11. Mechanisms responsible for PDAM downregulation Of 37 cases with reduced PDAM expression: - 20 (54%) exhibited both chr 1p loss and promoter hypermethylation - 10 (27%) showed promoter hypermethylation but intact chr 1p - 3 (8%) showed 1p deletion only - 4 (11%) -- other mechanisms? Hemizygous 1p deletion and epigenetic modifications are the major mechanisms contributing to PDAM downregulation

  12. Chr 1p loss is associated with chemosensitivity Would knockdown of PDAM render glioma cells sensitive to chemotherapeutic drugs?

  13. Chemosensitivity assay

  14. A172 U87MG PDAM knockdown induces cisplatin resistance p53 WT WT Mut Mut Mut

  15. cisplatin resistance p53 PDAM knockdown + cisplatin (DNA damage) ? Why would p53-wild-type glioma cells become cisplatin-resistant when PDAM was knocked down? Cisplatin is a DNA damaging agent  p53- mediated DNA damage response  cell death

  16. Effects of PDAM knockdown and cisplatin on p53 Western blotting RT-PCR A172 U87MG p53 p21 p53 p21

  17. cisplatin resistance PDAM knockdown + cisplatin (DNA damage) p53 stablization + upregulation ? • DNA damage • response

  18. A172 U87MG Anti-apoptosis Pro-apoptosis Cisplatin resistance PDAM knockdown antagonizes apoptosis

  19. BCL-xL knockdown reverses PDAM-dependent cisplatin resistance

  20. BCL-xL upregulation + BCL2 partial derepression cisplatin resistance Anti- apoptosis p53 stablization + upregulation PDAM knockdown + cisplatin (DNA damage) PDAM may modulate apoptosis via regulation of p53-dependent anti-apoptotic genes PDAM : P53-Dependent Apoptosis Modulator

  21. Summary • A novel gene PDAM is found to be frequently downregulated, mediated through epigenetic modifications and genomic loss, in OTs. These findings suggest that PDAM plays a role in the OT development • A novel mechanism for cisplatin resistance is discoverd, in which PDAM may possess the ability to modulate p53-dependent DNA damage response

  22. Acknowledgements The Chinese University of Hong Kong Anatomical and Cellular Pathology Ng Ho-Keung Li Ka Wai Kay Chung Yuk Fei Li Hiu Ming Yang Ling Surgery Poon Wai Sang Clinical Oncology Lui Wai Yan Vivian Sun Yat-sen University Neurosurgery Chen Zhong-ping Fudan University, Huashan Hospital Neurosugery Zhou Liangfu Grant support Research Grants Council of Hong Kong

  23. Thank you !

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