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孫光蕙

 

l 職稱:教授

l 辦公室:研究大樓 2F 226

l 學歷:國立陽明大學 微免所碩士

             國立陽明大學 微免所博士

 

l 研究領域

  本人的研究主要偏重全身性紅斑狼瘡(SLE)病理機轉之探討及癌症形成分子機制與療法之開發。已獲免疫學會頒發莊淑綺女士傑出醫學研究獎(94)及傑出研究學者獎(99)

1. 癌症形成分子機制及療法之開發: 癌細胞能夠持續地在體內生長,主要在於免疫系統無法辨認癌細胞。如何促使免疫系統辨識癌細胞,進而活化免疫系統,以清除不正常生長和轉移的癌細胞,是現今基因免疫抗癌研究的新驅勢。此外,了解癌症形成分子機制將提供可能之標靶治療

a. 肺癌分子機制及療法之開發:

(1)癌症形成分子機制: Galectin-1大量表現在惡性肺癌組織,進一步發現Galectin-1經由活化p38 MAPK、ERK及COX-2,促進肺癌細胞癌化現象和抗藥性(Clin Cancer Research (2012); Galectin-3經由與b-catenin結合,促進肺癌幹細胞形成和癌化現象 (Oncotarget 2015)

(2)發展apoptosis相關分子基因(FasL)及結合細胞激素(GM-CSF)之免疫療法:發現FasL表現在腫瘤形成初期可以誘發免疫反應,但表現在晚期則促進腫瘤生長(Mol carcinogenesis, 2012); 此外,共同表現FasL、GM-CSF和只表現FasL之腫瘤細胞株誘發保護性免疫反應比只表現GM-CSF之腫瘤細胞株效果較好。同時表現FasL及GM-CSF之腫瘤細胞株當成腫瘤疫苗的確能有效抑制小鼠已存在之肺癌腫瘤生長,且具有加成效果。 (Int J Cancer, 2008).

(3) 發展PGK-1 (phosphoglycerate kinase 1)治療肺癌: PGK-1細胞質內參與糖解作用的一種酵素,之前研究發現PGK-1能夠分泌到細胞外將血液中的plasmin切成許多較小片段的angiostatins進而抑制腫瘤的血管新生。進一步我們發現大量表現PGK-1會抑制COX-2,然後影響PGE2、VEGF以及細胞侵略能力、血管新生的能力以及刺激免疫細胞的功用,進而抑制LLC-1腫瘤的生長速率 (Int J Cancer, 2008) ; 此外,發現PGK-1抑制COX-2 乃經由其nucleotide-binding domain (NBD) ,與酵素活性無關(Cancer Science, 2010。PGK-1會經由抑制COX-2進而抑制肺癌腫瘤的生長,為本次研究重大的新發現!

(4)以IL-27治療肺癌: IL-27能誘導小鼠產生專一性抗腫瘤排斥反應,延緩體內腫瘤細胞生長,此外我們發現IL-     27可抑制 COX-2, PGE2 表現之反應進一步抑制 EMT 現象、移動能力及侵入能力,藉由以上機制影響小鼠體內肺癌細胞之生長(J Immunology, 2009).

b.細胞激素在腎臟癌癌化機制中角色之探討:

(1)促發炎細胞激素 (pro-inflammatory cytokines)與趨化激素(chemokines),是參與急性發炎反應的因子,會增加血管通透性、吸引活化淋巴球與巨噬細胞。在腎細胞癌病患,已發現血清中促發炎細胞激素 (IL-1b, IL-6及TNF-a) 與趨化激素 (CXCL4) 濃度上升與病程惡化有關聯性,為了進一步探討之間的關連性、找尋可能之促進因子及分子機制,我們選用不同惡性度腎清細胞癌細胞株(A498 (Grade IV)及786-O (Grade II))及免疫沈澱去除法,分析找尋影响惡性度差異之分子,結果發現惡性度較高癌細胞分泌較高TNF-a,而TNF-a會促進癌細胞EMT癌化現象 (Cancer Science, 2008); TNF-a促進腎臟癌細胞EMT癌化現象非經由活化NF-kB 訊息傳遞路徑(Exp Biol Med, 2011); 乃是經由活化GSK-3b訊息傳遞路徑促進腎臟癌細胞EMT現象 (Mol Cancer Research, 2012); 此外Galectin-1大量表現與腎臟癌病人預後與存活正相關,且發現Galectin-1是經由活化CXCR4促進腎臟癌癌化 (J Am Society Nephrology (IF=9.466), 2014)

2.全身性紅斑狼瘡(SLE)病理機轉之探討: 以狼瘡病人及老鼠為實驗對象,其中尤其針對抗雙股DNA抗體(Anti-dsDNA antibodies)和抗酸性核糖體P蛋白抗體在狼瘡病理機轉扮演的角色為主,目前已獲得下列具體成果:

a. 在抗雙股DNA抗體研究方面由MRL/lpr老鼠建立抗雙股DNA單株抗體,發現單株抗雙股DNA抗體可進入免疫細胞及星狀神經膠細胞,且抑制PHA引起之T細胞增生,此外單株抗體可直接促進IL-1b、IL-6、IL-8、IL-10及TNF-a之增加,以上結果顯示抗雙股DNA抗體在紅斑狼瘡病人體內助長發炎現象且抑制T細胞功能(Immunology, 2000)。利用蛋白質體學相關技術,鑑定此單株抗體與hnRNP A2交叉反應,且抗體會促進PRMT1 甲基化hnRNP A2 (Rheumatology 2003),此外,此單株抗體也與PGK-1交叉反應,並抑制Jurkat T Cells 之IL-2產生 (Clinical Immunology, 2006),此項結果說明抗雙股DNA單株抗體進入細胞後,與hnRNP A2, PGK反應,進而影響發炎細胞激素產生,並促使紅斑狼瘡病人免疫反應之趨極化及引起SLE相關病理特徵。最近發現抗雙股DNA抗體是經由電荷交互作用穿透細胞,且抗體CDR區域之Arginine影响抗體穿透細胞之能力(Eur J Immunol, 2008)此外,建立抗雙股DNA抗體基因轉殖鼠,證明DNA抗體及TLR4活化為引起SLE重要危險因子(J Autoimmun 2010),而細胞表面TLR4和endosomal TLR9同時作用,促進抗雙股DNA抗體基因轉殖鼠發病 (Exp Biol Med2014),並進一步以抑制抗雙股DNA抗體訊息傳遞路徑及Arginine治療狼瘡老鼠,改善了狼瘡症狀 (Arthritis Rheum 2010),此發現對SLE病態生理學有重大貢獻,即抗雙股DNA抗體穿透細胞、訊息傳遞路徑及細菌感染控制將是SLE新穎治療標的。

b.在抗酸性核糖體P蛋白抗體研究方面: 抗酸性核糖體P蛋白自體免疫抗體與狼瘡病人出現精神症狀、活動性腎炎和慢性活動性肝炎有關,也可能造成淋巴球減少症或淋巴球功能異常,但其致病機轉不明;目前已建立抗酸性核糖體P蛋白單株自體免疫抗體,發現抗體經由細胞表面上的P0蛋白進入細胞,並造成T細胞的細胞凋亡(Rheumatology, 2001),因此抗酸性核糖體P蛋白自體免疫抗體可能與狼瘡病人淋巴球減少症或淋巴球功能異常有關,但其機制未明。最近發現抗P蛋白單株自體免疫抗體抑制RAW macrophage細胞株及人類週邊血液monocytes產生IL-12, TNF及iNOS,但促進IL-10產生(J Autoimmunity, 2005),且是經由PI-3K活化訊息傳遞路徑而達成(Immunology, 2009),顯示抗P蛋白抗體及抗雙股DNA抗體在紅斑狼瘡病人體內皆會促進Th2且抑制Th1細胞功能,導致紅斑狼瘡病人免疫反應之趨極化及病情之惡化。

以上的發現對SLE的病理機轉及研究更進一步的了解,將有助於疾病的治療。

 

l 研究著作:

Ø Lee MY, Sun KH, Chiang CP, Huang CF, Sun GH, Tsou YC, Liu HY, Tang SJ.. Nitric oxide suppresses LPS-induced inflammation in a mouse asthma model by attenuating the interaction of IKK and Hsp90. EXPERIMENTAL BIOLOGY AND MEDICINE 2015;240(4):240(4):498-507 (SCI).(Impact factor: 2.226;Rank: 50.00%)第二作者

Ø Yi-Ching Wu, Shye-Jye Tang, Guang-Huan Sun, and Kuang-Hui Sun. CXCR7 mediates TGFb1-promoted EMT and tumor initiating features in lung cancer. ONCOGENE 2015;: (SCI).(Impact factor: 8.559;Rank: 5.94%)第一或通訊作者

Ø Ling-Yen Chung, Shye-Jye Tang, Yi-Ching Wu, Guang-Huan Sun, Huan-Yun Liu, and Kuang-Hui Sun. Galectin-3 augments tumor initiating property and tumorigenicity of lung cancer through interaction with b-catenin. Oncotarget 2015;6(7):4936-52. (SCI).(Impact factor: 6.627;Rank: 8.42%)第一或通訊作者

Ø Lee TP, Huang JC, Liu CJ, Chen HJ, Chen YH, Tsai YT, Yang W, Sun KH.. Interactions of surface-expressed TLR-4 and endosomal TLR-9 accelerate lupus progression in anti-dsDNA antibody transgene mice. Experimental Biology and Medicine 2014;239:715-23 (SCI).(Impact factor: 2.226;Rank: 50.00%)第一或通訊作者

Ø Huang CS, Tang SJ, Chung LY, Yu CP, Ho JY, Cha TL, Hsieh CC, Wang HH, Sun GH, Sun KH. Galectin-1 Upregulates CXCR4 to Promote Tumor Progression and Poor Outcome in Kidney Cancer. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 2014;25:1486-95 (SCI).(Impact factor: 9.466;Rank: 2.67%)第一或通訊作者

Ø Hsu, Hui-Ling; Huang, Hsin-Hsien; Liang, Chung-Chih; Lin, Hung-Chi; Liu, Wen-Tssann; Lin, Feng-Ping; Kau, Jyh-Hwa; Sun, Kuang-Hui. Suspension bead array of the single-stranded multiplex PCR amplicons for enhanced identification and quantification of multiple pathogens. ANALYTICAL CHEMISTRY 2013;85(11):5562-8 (SCI).(Impact factor: 5.825;Rank: 5.26%)第一或通訊作者

Ø Cha TL, Chuang MJ, Tang SH, Wu ST, Sun KH, Chen TT, Sun GH, Chang SY, Yu CP, Ho JY, Liu SY, Huang SM, Yu DS. Emodin modulates epigenetic modifications and suppresses bladder carcinoma cell growth. MOLECULAR CARCINOGENESIS 2013;: (SCI).(Impact factor: 4.77;Rank: 21.29%)第四或以後作者

Ø Hsiao-Ying Chiu, Guang-Huan Sun, Shiow-Yi Chen, Hsiao-Hsien Wang, Ming-Yi Ho, Chia-Yi Chu, Wan-Lin Wu, Ren-Shiang Jhou, Yi-Lin Tsai, Rui-Ting Huang, Kuang-Hui Sun*, Shye-Jye Tang*. Pre-existing Fas ligand (FasL) in cancer cells elicits tumor-specific protective immunity, but delayed induction of FasL expression after inoculation facilitates tumor formation. MOLECULAR CARCINOGENESIS 2013;52:705-14 (SCI).(Impact factor: 4.77;Rank: 21.29%)第一或通訊作者

Ø Chuang MJ, Wu ST, Tang SH, Lai XM, Lai HC, Hsu KH, Sun KH, Sun GH, Chang SY, Yu DS, Hsiao PW, Huang SM, Cha TL. The HDAC inhibitor LBH589 induces ERK-dependent prometaphase arrest in prostate cancer via HDAC6 inactivation and down-regulation. PLoS One 2013;8(9):e73401 (SCI).(Impact factor: 3.534;Rank: 14.55%)第四或以後作者

Ø Hsiao-Ying Chiu, Kuang-Hui Sun, Shiow-Yi Chen, Hsiao-Hsien Wang, Ming-Yung Lee,Yu-Chi Tsou, Shyh-Chuan Jwo, Guang-Huan Sun, Shye-Jye Tang. Autocrine CCL2 promotes cell migration and invasion via PKC activation and tyrosine phosphorylation of paxillin in bladder cancer cells. CYTOKINE 2012;59 :423–432 (SCI).(Impact factor: 2.874;Rank: 47.22%)第二作者

Ø Ming-Yi Ho, Shye-Jye Tang, Mei-Jen Chuang, Tai-Lung Cha, Jing-Yao Li, Guang-Huan Sun, Kuang-Hui Sun. TNF-a induces epithelial-mesenchymal transition of renal cell carcinoma cells via a GSK3b-dependent mechanism. MOLECULAR CANCER RESEARCH 2012;10:1109-19 (SCI).(Impact factor: 4.502;Rank: 22.28%)第一或通訊作者

Ø Ling-Yen Chung, Shye-Jye Tang, Guang-Huan Sun, Teh-Ying Chou, Tien-Shun Yeh, Sung-Liang Yu and Kuang-Hui Sun. Galectin-1 promotes lung cancer progression and chemoresistance by upregulating p38 MAPK, ERK and cyclooxygenase-2. CLINICAL CANCER RESEARCH 2012;18:4037-47 (SCI).(Impact factor: 8.193;Rank: 6.44%)第一或通訊作者

Ø Lee CW, Leu SJ, Tzeng RY, Wang SF, Tsai SC, Sun KH, Chen RH, Huang JC.. Latent membrane protein 1 of Epstein-Barr virus regulates death-associated protein kinase 1 in lymphoblastoid cell line. VIROLOGY 2011;413(1):19-25 (SCI).(Impact factor: 3.278;Rank: 50.00%)第四或以後作者

Ø Sheng-Tang Wu, Guang-Huan Sun, Chih-Ying Hsu, Chang-Shuo Huang, Yu-Hsin Wu, Hsiao-Hsien Wang and Kuang-Hui Sun. TNF-alfa induces epithelial-mesenchymal transition of renal cell carcinoma cells via a NF-kB-independent mechanism. EXPERIMENTAL BIOLOGY AND MEDICINE 2011;236 :1022–1029 (SCI).(Impact factor: 2.226;Rank: 50.00%)第一或通訊作者

Ø Ho MY, Tang SJ, Sun KH, Yang W. Immunotherapy for lung cancers. JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY 2011;2011(250860): (SCI).(Impact factor: 2.706;Rank: 32.12%)第一或通訊作者

Ø Hung KS, Liu SM, Fang TY, Tzou WS, Lin FP, Sun KH, Tang SJ. Characterization of a salt-tolerant xylanase from Thermoanaerobacterium saccharolyticum NTOU1. BIOTECHNOLOGY LETTERS 2011;33(7):1441-7. (SCI).(Impact factor: 1.736;Rank: 61.21%)第四或以後作者

Ø Hung KS, Chen SY, Liu HF, Tsai BR, Chen HW, Huang CY, Liao JL, Sun KH, Tang SJ. C-terminal region of Candida rugosa lipases affects enzyme activity and interfacial activation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2011;59(10):5396-401. (SCI).(Impact factor: 3.107;Rank: 3.57%)第四或以後作者

Ø Ying-Chyi Song, Shye-Jye Tang, Tai-Ping Lee, Wen-Chien Hung, Shu-Chi Lin, Chang-Youh Tsai, Wailap Victor Ng, Ming-Fang Wu, Kuang-Hui Sun.. Reversing interleukin-2 inhibition mediated by anti-dsDNA autoantibody ameliorates glomerulonephritis in MRL-lpr/lpr mice. ARTHRITIS AND RHEUMATISM 2010;62:2401-2411 (SCI).(Impact factor: 7.871;Rank: 10.00%)第一或通訊作者

Ø Ming-Yi Ho, Shye-Jye Tang, Wailap Victor Ng,Winnie Yang, Shr-Jeng Jim Leu, Ying-Chun Lin, Chi-Kuang Feng, Jung-Sung Sung, Kuang-Hui Sun. The nucleotide-binding domain of phosphoglycerate kinase 1 reduces tumor growth by suppressing cyclooxygenase 2 expression. Cancer science 2010;101(11):2411-6 (SCI).(Impact factor: 3.534;Rank: 33.66%)第一或通訊作者

Ø Tai-Ping Lee, Shye-Jye Tang, Ming-Fang Wu, Ying-Chyi Song, Chia-Li Yu, Kuang-Hui Sun. Transgenic overexpression of anti-double-stranded DNA autoantibody and activation of Toll-like receptor 4 in mice induce severe systemic lupus erythematosus syndromes. JOURNAL OF AUTOIMMUNITY 2010;35:358-367 (SCI).(Impact factor: 7.018;Rank: 10.42%)第一或通訊作者

Ø Ming-Yi Ho, Shr-Jeng Jim Leu, Guang-Huan Sun, Mi-Hua Tao, Shye-Jye Tang, Kuang-Hui Sun. IL-27 Directly Restrains Lung Tumorigenicity by Suppressing Cyclooxygenase-2-Mediated Activities. JOURNAL OF IMMUNOLOGY 2009;183 :6217–6226. (SCI).(Impact factor: 5.362;Rank: 16.67%)第一或通訊作者

Ø Tai-Ping Lee, Shr-Jeng Jim Leu, Jason C. Huang, Ying-Chyi Song, Ren-Shiang Jhou, Shye-Jye Tang and Kuang-Hui Sun. Anti-ribosomal P autoantibody triggers IL-10 over-production via PI3K-dependent signaling pathways in LPS-activated macrophages. Immunology 2009;127:91-102 (SCI).(Impact factor: 3.735;Rank: 31.94%)第一或通訊作者

Ø Ren-Shiang Jhou, Kuang-Hui Sun, Guang-Huan Sun, Hsiao-Hsien Wang, Chung-I Chang, Hsiao-Chun Huang, Shou-Yun Lu, and Shye-Jye Tang. Inhibition of cyclin-dependent kinases by Olomoucine and Roscovitine reduces lipopolysaccharide-induced inflammatory Responses via down-Regulation of nuclear factor kB. Cell Proliferation 2009;42:141-149 (SCI).(Impact factor: 3.28;Rank: 51.35%)第二作者

Ø Shye-Jye Tang, Ming-Yi Ho, Huan-Chieh Cho, Ying-Chun Lin, Guang-Huan Sun, Kwan-Hwa Chi, Yu-Shan Wang, Ren-Shiang Jhou, Winnie Yang, and Kuang-Hui Sun. Phosphoglycerate kinase 1-overexpressing lung cancer cells reduce cyclooxygenase 2 expression and promote anti-tumor immunity in vivo . INTERNATIONAL JOURNAL OF CANCER 2008;123 :2840–2848 (SCI).(Impact factor: 5.007;Rank: 16.83%)第一或通訊作者

Ø Ming-Yi Ho, Guang-Huan Sun, Shr-Jeng Jim Leu, Shuk-Man Ka, Shye-Jye Tang, and Kuang-Hui Sun. Combination of FasL and GM-CSF Confers Synergistic Antitumor Immunity in an In Vivo Model of the Murine Lewis Lung Carcinoma. International Journal of Cancer 2008;123:123-133 (SCI).(Impact factor: 5.007;Rank: 16.83%)第一或通訊作者

Ø Hsing-Hui Li, He-Hsiung Cheng, Kuang-Hui Sun, Chi-Chen Wei,Chien-Feng Li, Wen-Chung Chen, Wen-Mein Wu, Ming-Shi Chang.. Interleukin-20 targets renal mesangial cells and is associated with lupus nephritis. CLINICAL IMMUNOLOGY 2008;129:277-85 (SCI).(Impact factor: 3.992;Rank: 27.78%)第三作者

Ø Mei-Jen, Chuang, Kuang-Hui Sun, Shye-Jye Tang, Ming-Wei Deng, Yu-Hsin Wu, Jung-Sung Sung, Tai-Lung Cha and Guang-Huan Sun. Tumor-derived TNF-a promotes progression and epithelial-mesenchymal transition in renal cell carcinoma cells. Cancer Science 2008;99:905-913 (SCI).(Impact factor: 3.534;Rank: 33.66%)第二作者

Ø Ying-Chyi Song, Guang-Huan Sun, Tai-Ping Lee, Jason C. Huang, Chia-Li Yu, Chia-Hung Chen, Shye-Jye Tang, Kuang-Hui Sun.. Arginines in the CDR of Anti-dsDNA Autoantibodies facilitate cell internalization via electrostatic interactions. EUROPEAN JOURNAL OF IMMUNOLOGY 2008;38(11):3178-90. (SCI).(Impact factor: 4.518;Rank: 20.14%)第一或通訊作者