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趙清貴

趙清貴 (Chuck C.-K. Chao)

職稱:組主任/講座教授

研究室名稱:腫瘤細胞研究室

最高學歷:Ph.D.

學校/國家:德州大學西南醫學院/美國

分機號碼:5157

電子郵件帳號cckchao@mail.cgu.edu.tw

個人網頁網址:http://cckchao1.wix.com/chao-lab

研究室現有: 博士後研究員 1

 博士班研究生  2

 碩士班研究生 0

專任研究助理  2

大學部專題生  1

 

研究方向及研究室特色

癌症及遺傳疾病的成因與治療机制是我們的研究興趣。運用基因生物學 (genomics) 及生物資訊 (bioinformatics) 的組合 ,我們可以藉由細胞及動物操作,有效地窺探人類的癌症及遺傳疾病的生物學基礎,最終期望能提供研發新藥參考及臨床醫學對策。目前較投入的研究如下:

I. 抗藥基因與標靶治療 (Chemoresistance gene & target therapy)

  癌症化療常伴隨抗藥現象,造成療效不佳,如果能夠瞭解其分子機制,可以預期改善癌症化療效果。 我們的首要目標是要瞭解抗藥癌細胞的那些基因表現改變使之逃避死亡,那些分子訊號控制這樣的改變。運用基因科技修改藥物活性,標靶特定細胞抑長及細胞凋亡 (cell growth arrest & apoptosis) 可以瞭解抗藥機制及克服癌細胞的抗藥現象。運用基因晶片 (DNA chip/microarray) /轉錄體 (transcriptome) 及蛋白質體 (proteome) 大量快速篩選抗藥細胞異量表現的基因產物,再配合基因轉殖 (transgenics) 增加基因功能或用干擾核酸 (RNA interference) 降低基因功能,以確認新的抗藥基因及動物試驗之後,可提供發展新藥的參考。
        對於傳统化療葯物 (e.g., cisplatin & taxol) 的抗藥研究,我們已經發現數種主要抗藥基因。對於較新的標靶葯物 (e.g, sorafenib) 的作用机制,我們也初步發現涉及的重要基因。另外,這些葯物作用基因表現的調控也是重要議題,包括華人特有病毒蛋白 (e.g., 肝炎HBV-HBx, 鼻咽癌 EBV-LMP1) 的調控角色,我們也有高度興趣。

II. 幹細胞、分化與發育 (Stem cells, differentiation & development):

   幹細胞分化及系統發育是我們的另一個研究重點。藉由致癌,抑癌與凋亡基因 (oncogene, tumor suppressor and apoptotic genes) 的遺傳操作,來分析細胞生長分化,可以 找出關鍵的細胞分子以瞭解腦神經等疾病及癌症的部分成因,並有助於發展新的治療藥物。細胞分化必需先抑止生長 (growth arrest),在這個抑長 階段特別表現的抑長基因 (growth-arrest-specific gene,簡稱 Gas),可能決定細胞是否能夠順利分化,否則就會凋亡 (apoptosis) 我們已發現多個的抑長基因,譬如 Gas7 (growth-arrest-specific 7) 是一種類似 Pombe Cdc15 蛋白質,對腦神經細胞及骨骼細胞分化是必要的。 Gas7 也與細胞骨幹 (cytoskeleton) F-actin/tubulin/peripherin 結合,可以調節其 assembly,可能參與細胞骨幹的相關功能如細胞結構形態变化。 此外 Gas7 基因可表現 Gas7-a/Gas7-b 等類型蛋白,並可以在細胞及動物體接受不同刺激的調節。最近我們也發現 Gas7 在斑馬魚表現在神經肌肉系統,擬以這個動物模式來探討 Gas7 基因在系統發育的角色。 此外 DNA 損壞可導致細胞老化及代謝失調。Cited2 靜默導致 CBP/p300 epigenetic 調控基因 (DNA repair, cell cycle, apoptosis etc.) 不當及引起嚴重的DNA 損壞,可能在細胞分化發育及代謝扮演重要角色。我們的大目標在探討細胞分化及系統發育的關鍵分子,以及其在相關疾病的角色。目前以探討 Gas7 Cited2 的分子細胞功能 (molecular and cellular function) 及表現型功能 (phenotypic function) 為主,以期瞭解腦神經、脂肪與骨骼肌肉的發育 (development)、恆定 (maintenance) 與相關疾病的分子機制。

III. 腫瘤微環境基因與病理 (Genetics and pathogenesis of tumor microenvironment):

這是最近我們新起的主題....(建構中)

 

 

 

最近五年所發表論文 (among 114peer-reviewed papers)

1. Wu, Z.-Z., Lu, H.-P. and Chao, C.C.-K. Identification and functional analysis of genes which potentially confer resistance to cisplatin in tumor cells. Biochem. Pharmacol. 80: 262-276, 2010 SCI IF=5.009

2. Sun, N.-K.*, Sun, C.-L.*, Lin, C.-H., Pai, L.-M. and Chao, C.C.-K. Damaged DNA-binding protein 2 (DDB2) protects against UV irradiation in human cells and Drosophila. J. Biomed. Sci., 2010 (*equal contribution) IF=2.763

3. Wu, Z.-Z. and Chao, C.C.-K. Knockdown of NAPA using short-hairpin RNA sensitizes cancer cells to cisplatin: implications to overcome chemoresistance. Biochem. Pharmacol. 80: 827-837, 2010 IF=5.009

4. Kuo, T.-C. and Chao, C.C.-K. Hepatitis B virus X protein prevents apoptosis of hepatocellular carcinoma cells by upregulating SATB1 and HURP expression. Biochem. Pharmacol. 80: 1093-1102, 2010 IF=5.009

5. Hung, F.-C. and Chao, C.C.-K. Knockdown of growth-arrest-specific 7b gene (gas7b) using short-hairpin RNA desensitizes neuroblastoma cells to cisplatin: implications to prevent apoptosis of neurons. J. Neurosci. Res. 88: 3578-3587, 2010  IF=2.594

6. Wu, Z.-Z., Sun, N.-K. and Chao, C.C.-K. Knockdown of CITED2 using short-hairpin RNA sensitizes cancer cells to cisplatin through stabilization of p53 and enhancement of p53-dependent apoptosis. J. Cell. Physiol.226: 2415-2428, 2011 IF=3.839

7. Chao, C.C.-K. A Search for the genes involved in resistance to cisplatin chemotherapy: Review of the experimental evidence. Curr. Top. Pharmacol. 14: 47-54, 2011 January [invited review article]

8. Chao, C.C.-K. The role of DDB2 in regulating cell survival and apoptosis following DNA damage - a mini-review. In DNA Repair (ed., Kruman, I.), InTech: 2011 July (ISBN 978-953-307-697-3) [invited review]

9. Hung, F.-C., Chang, Y.-H., Lin-Chao, S. and Chao, C.C.-K. Gas7 mediates the differentiation of human bone marrow-derived mesenchymal stem cells into functional osteoblasts by enhancing Runx2-dependent gene expression. J. Orthopaedic Res. 29: 1528-1535, 2011 IF=2.986

10. Kuo, T.-C.*, Lu, H.-P.* and Chao, C.C.-K. The tyrosine kinase inhibitor sorafenib sensitizes hepatocellular carcinoma cells to taxol by suppressing the HURP protein. Biochem. Pharmacol. 82: 184-194, 2011 (*equal contribution) IF=5.009

11. Wu, Z.-Z., Sun, N.-K., Chien, K.-Y. and Chao, C.C.-K. Silencing of the SNARE protein NAPA sensitizes cancer cells to cisplatin by inducing ERK1/2 signaling, synoviolin ubiquitination and p53 accumulation. Biochem Pharmacol. 82: 1630-1640, 2011 IF=5.009

12. Wu, Z.-Z.*, Chow, K.-P.N.*, Kuo, T.-C., Chang, Y.-S., Chao, C.C.-K. Latent membrane protein 1 of Epstein–Barr virus sensitizes cancer cells to cisplatin by enhancing NF-B p50 homodimer formation and downregulating NAPA expression. Biochem. Pharmacol. 82: 1860-1872, 2011 (*equal contribution) IF=5.009

13. Kuo, T.-C., Chang, P.-Y., Huang, S.-F., Chou, C.-K. and Chao, C.C.-K. Knockdown of HURP inhibits the proliferation of hepatocellular carcinoma cells via downregulation of gankyrin and accumulation of p53. Biochem Pharmacol. 83: 758- 768, 2012 IF=5.009

14. Chao, C.C.-K. Adapting new ways to escape attacks by anti-cancer drugs: Epigenetic changes and alternative splicing. Adaptive Medicine 4: 64-68, 2012 [invited review]

15. Sun, N.-K., Huang, S.-L., Chien, K.-Y. and Chao, C.C.-K. Golgi-SNARE GS28 potentiates cisplatin-induced apoptosis by forming GS28/MDM2/p53 complexes and by preventing the ubiquitination and degradation of p53. Biochem. J. 444: 303-314, 2012 IF=4.396

16. Huang, B.-T., Chang, P.-Y., Su, C.-H., Chao, C.C.-K. and Lin-Chao, S. Deficiency of Gas7 in mice reveals motor coordination defects due to abnormal motor neuron function and muscle fiber composition during aging. PLoS ONE 7(5): e37702. DOI:10.1371/journal.pone.0037702, 2012 IF=3.234

17. Lu, H.-P. and Chao, C.C.-K. Cancer cells acquire resistance to anticancer drugs: An update. Biomed. J. 35: 479-491, 2012 [invited review]

18. Hung, F.-C., Cheng, Y.-C., Sun, N.-K. and Chao, C.C.-K. Identification and characterization of zebrafish gas7 gene in early development. J, Neurosci. Res. 91:51-61, 2013  IF=2.594

19. Chao, C.C.-K., Hung, F.C. and Chao, J.J. Gas7 is required for mesenchymal stem cell-derived bone development. Stem Cells Int. vol. 2013, Article ID 137010, 6 pages, 2013. DOI:10.1155/2013/137010 [invited review] IF=2.813

20. Sun, N.-K., Huang, S.-L., Chang, T.-C. and Chao, C.C.-K. Sorafenib induces apoptosis in endometrial carcinoma cells by inhibiting Elk-1-dependent Mcl-1 gene expression and by inducing Akt/GSK3β-dependent Mcl-1 protein degradation. J. Cell. Biochem. 114: 1819-1831, 2013 IF=3.263

21. Chang, P.-Y.*, Wu, Z.-Z.*, Sun, N.-K. and Chao, C.C.-K. EBV-encoded LMP-1 sensitizes nasopharyngeal carcinoma cells to genotoxic drugs by down-regulating Cabin1 expression. J. Cell. Physiol. 229: 309-322, 2014 (*equal contribution) IF=3.839

22. Sun, N.-K.*, Huang, S.-L.*, Chang, P.-Y., Lu, H.-P. and Chao, C.C.-K. Transcriptomic profiling of taxol-resistant ovarian cancer cells identifies FKBP5 and the androgen receptor as critical markers of chemotherapeutic response. Oncotarget 5: 11939-11956, 2014 (*equal contribution) IF=6.359

23. Chao, C.C.-K. Mechanisms of p53 degradation. Clinica Chimica Acta 438: 139-147, 2015 (online: Aug. 13, 2014, doi: 10.1016/j.cca.2014.08.015) [invited review] IF=2.824

24. Huang, S.-L. and Chao, C.C.-K. Linking immunophilin FKBP5 to taxol resistance in ovarian cancer. Cancer Cell & Microenviron. 2015; 2: e692. doi: 10.14800/ccm.692 [invited research highlight]

25. Lin, Y.-T., Lu, H.-P. and Chao, C.C.-K. Oncogenic c-Myc and prothymosin-alpha protect hepatocellular carcinoma cells against sorafenib-induced apoptosis. Biochem. Pharmacol. 93: 110-124, 2015 (first online: 3 Nov. 2014, DOI:10.1016/j.bcp.2014.10.012) IF=5.009

26. Lin, Y.-T. and Chao, C.C.-K. Sorafenib induces apoptosis in hepatocellular carcinoma Cells by inhibiting c-Myc and prothymosin-alpha. Cancer Cell & Microenviron. 2015; 2: e788. doi: 10.14800/ccm.788 [invited research highlight]

27. Huang, S.-L. and Chao, C.C.-K. Silencing of taxol-sensitizer genes in cancer cells: Lack of sensitization effects. Cancers 7: 1052-1071, 2015; doi:10.3390/cancers7020824 (special issue - Cancer Cell Proliferation) [invited article].

28. Ho, C.H., Hsu, J.L., Liu, S.P., Hsu, L.C., Chang, W.L., Chao, C.C.-K., Guh, J.H. Repurposing of phentolamine as a potential anticancer agent against human castration-resistant prostate cancer: A central role on microtubule stabilization and mitochondrial apoptosis pathway. Prostate 75 (13):1454-1466, 2015 IF=3.565

29. Sun, N.-K.*, Huang, S.-L.*, Lu, H.-P., Chang, T.-C. and Chao, C.C.-K. Integrative transcriptomics-based identification of cryptic drivers of taxol-resistance genes in ovarian carcinoma cells: analysis of the androgen receptor. Oncotarget 6: 27065-27082, 2015 (*equal contribution) IF=6.359

30. Liu, Y.-C., Chang, P.-Y. and Chao, C.C.-K. CITED2 silencing sensitizes cancer cells to cisplatin by inhibiting p53 trans-activation and chromatin relaxation on the ERCC1 DNA repair gene. Nucleic Acids Res. 43: 10760-10781, 2015 IF=9.112

31. Lin, Y.-T. and Chao, C.C.-K. Identification of the  β-catenin/JNK/prothymosin-alpha axis as a novel target of sorafenib in hepatocellular carcinoma cells. Oncotarget 6: 38999-39017, 2015 IF=6.359

32. Hung, F.-C.*, Shih, H.-Y.*, Cheng, Y.-C. and Chao, C.C.-K. Growth-arrest-specific 7 gene regulates neural crest formation and craniofacial development in zebrafish. Stem Cells Dev. 24: 2943-2951, 2015 (*equal contribution) IF=3.727

33.Chang, PY#, Huang, Y #, Hung, TY, Chong, KY, Chang, YS, Chao, CC-K* and Chow, KPN* Spontaneous metastases in immunocompetent mice harboring a primary tumor driven by oncogene latent membrane protein 1 from Epstein-Barr virus. Biomed J 39: 261-271, 2016 (#equal contribution, *co-correspondence)

34. Chao, C.C.-K. Inhibition of apoptosis by oncogenic hepatitis B virus X protein: Implications for the treatment of hepatocellular carcinoma. World J. Hepatol. 8(25): 1061-1066, 2016 [invited review/highlight]

35. Lin, Y.-T., Liu, Y.-C. and Chao, C.C.-K. Inhibition of JNK and prothymosin-alpha sensitizes hepatocellular carcinoma cells to cisplatin. Biochem. Pharmacol. 122: 80-89, 2016. IF=5.091

 

 

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