彭瑞銘 副研究員

細胞力學與訊息傳遞
腫瘤生物學與微環境
癌症生物標記與治療

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(07) 731-7123 ext 8597

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r.jmpeng@gmail.com

VIM 促進腫瘤的 EMT-MET 轉化和細胞轉移

上皮間質轉化 (EMT) 過程是惡性腫瘤發生的重要原因，腫瘤微環境在誘導 EMT 過程中具有重要的作用。在形態發育的過程中，EMT 最初是指上皮细胞轉化為具轉移能力的细胞。後來用來描述癌細胞在癌症進展和轉移過程中的轉化現象。其主要的訊息傳遞路徑包括 TGF-β、Wnt、Notch、生長因子接受體、發炎因子和缺氧等，其中 TGF-β 調控路徑被認為是 EMT 發生的主要原因。癌細胞通常在發生 EMT 過程後轉移，在新的環境中形成第二個聚落。因此，EMT 過程在腫瘤轉移中有著促進的作用。目前已知，腫瘤在其侵襲性細胞的前端將通過 EMT 轉化為間質型細胞，使其轉移到周圍組織或血管內。然而，這些在前端具侵襲性的細胞透過 EMT 訊息傳遞路徑來影響細胞骨架重組的機制尚未清楚。因此，了解 EMT 過程在這些侵襲性細胞中的作用機制將有利於藥物開發。

Vimentin (VIM) 異常增加是癌症惡化的重要指標之一。VIM 是一種中間絲蛋白，是細胞骨架蛋白的成員之一，在 EMT 過程中，VIM 在細胞從貼附轉變成移動的過程中扮演著關鍵作用。目前，VIM 的表達量可能是胃癌患者預後不良的指標之一，但在其他腫瘤的臨床病理特徵及預後仍然存在爭議。因此，探討 VIM 在 EMT 進展中的功能及其機制，可以為臨床癌症診斷提供更清楚的定義。

VIM 調控肌動蛋白應力纖維的形成和侵襲性前導細胞的細胞貼附

肌動蛋白的結構和黏附蛋白 (focal adhesion proteins) 的排列與細胞轉移有關，利用創傷癒合實驗，我們發現對照組細胞存在大量的肌動蛋白應力纖維及黏附蛋白 (Vinculin) 在細胞內部，使前導細胞運動逐漸變慢。而 VIM 的缺失會大幅減少肌動蛋白的應力纖維形成，並導致 Vinculin 移位到細胞膜週邊，這有助於細胞快速前進。在前導細胞缺乏 VIM 的情況下，細胞內含較少的肌動蛋白應力纖維和較多的 vinculin 在細胞膜附近，進而大幅促進細胞的移動。

在創傷癒合實驗過程中，前導細胞會產生逐漸產生大量的細胞內肌動蛋白應力纖維，而 VIM 的缺失使肌動蛋白應力纖維明顯減少。在細胞移動過程中隨著肌動蛋白形成細絲，VIM 的表現也會逐漸增加，並促進肌動蛋白絲結合形成纖維束而產生強有力的結構。TGF-β 的刺激會促進 VIM 的表現，而抑制 TGF-B 可以減少 VIM 的產生。在免疫細胞辨識和攻擊癌細胞的過程中，阻斷 TGF-β 的作用會協同增强抗 PD-L1 抗體促進免疫細胞浸潤的治療效果，因而 EMT-MET 轉化過程在免疫細胞運作時亦扮演重要的影響，探討其作用機制將有助於腫瘤免疫治療的應用。

Selected recent publications (Pubmed Search)
 († Contributed equally to the article; * Correspondence author of the article)

Peng JM, Bera R, Chiou CY, Yu MC, Chen TC, Chen CW, Wang TR, Chiang WL, Chai SP, Wei Y, Wang H, Hung MC, Hsieh SY*. Actin cytoskeleton remodeling drives epithelial-mesenchymal transition for hepatoma invasion and metastasis in mice. Hepatology, 67(6): 2226-2243 (2018)

Bera R, Chiou CY, Yu MC, Peng JM, He CR, Hsu CY, Huang HL, Ho UY, Lin SM, Lin YJ, Hsieh SY*. Functional genomics identified a novel protein tyrosine phosphatase receptor type F-mediated growth inhibition in hepatocarcinogenesis. Hepatology, 59(6): 2238-2250 (2014)

Chiu CF, Ho MY, Peng JM, Hung SW, Lee WH, Liang CM, Liang SM*. Raf activation by Ras and promotion of cellular metastasis require phosphorylation of prohibitin in the raft domain of the plasma membrane. Oncogene, 32(6): 777-787 (2013)

Peng JM, Chen YH, Hung SW, Chiu CF, Ho MY, Lee YJ, Lai TC, Hsiao M, Liang CM, Liang SM*. Recombinant viral protein promotes apoptosis and suppresses invasion of ovarian adenocarcinoma cells by targeting alpha5beta1 integrin to down-regulate Akt and MMP-2. British Journal of Pharmacology, 165(2): 479-493 (2012)

Chiu CF, Peng JM, Hung SW, Liang CM, Liang SM*. Recombinant viral capsid protein VP1 suppresses migration and invasion of human cervical cancer by modulating phosphorylated prohibitin in lipid rafts. Cancer letters, 320(2): 205-214 (2012)

羅佳紋

EDUCATION:

2004 – 2011 Ph.D.
Institute of Biochemical Sciences,
National Taiwan University, Taiwan

1998 – 2000 M.S.
Institute of Microbiology,
National Taiwan University, Taiwan

PROFESSIONAL EXPERIENCE:

2018/8 ~ present  Assistant Professor
Institute for Translational Research in Biomedicine,
Kaohsiung Chang Gung Memorial Hospital,
Kaohsiung, Taiwan

2012/5 ~ 2018/7  Postdoctoral Research Fellow
Liver Research Unit,
Chang Gung Memorial Hospital, Linko, Taiwan

AWARDS:

2009  The award of excellent poster, the 24th Joint Annual Conference of Biomedical Sciences, The Taiwan Society of Biochemistry and Molecular Biology.
2006  Best student in the Ph.D. poster competition, Institute of Biochemical Sciences, National Taiwan University, Taiwan.
2005  The award of outstanding research, Institute of Biochemical Sciences, National Taiwan University, Taiwan.
2004  The award of outstanding research, Jung-Yaw Lin Foundation, Taiwan.

RESEARCH INTERESTS:

• Molecular mechanisms of cell cytoskeleton
• Discovery of cancer biomarkers
• Tumor microenvironment
• Prevention and therapy of cancer: preclinical study

PUBLICATION LIST:

1. Peng JM, Bera R, Chiou CY, Yu MC, Chen TC, Chen CW, Wang TR, Chiang WL, Chai SP, Wei Y, Wang H, Hung MC, Hsieh SY. Actin cytoskeleton remodeling drives epithelial-mesenchymal transition for hepatoma invasion and metastasis in mice. Hepatology, 67(6): 2226-2243 (2018)

2. Bera R, Chiou CY, Yu MC, Peng JM, He CR, Hsu CY, Huang HL, Ho UY, Lin SM, Lin YJ, Hsieh SY. Functional genomics identified a novel protein tyrosine phosphatase receptor type F-mediated growth inhibition in hepatocarcinogenesis. Hepatology, 59(6): 2238-2250 (2014)

3. Chiu CF, Ho MY, Peng JM, Hung SW, Lee WH, Liang CM, Liang SM. Raf activation by Ras and promotion of cellular metastasis require phosphorylation of prohibitin in the raft domain of the plasma membrane. Oncogene, 32(6): 777-787 (2013)

4. Peng JM, Chen YH, Hung SW, Chiu CF, Ho MY, Lee YJ, Lai TC, Hsiao M, Liang CM, Liang SM. Recombinant viral protein promotes apoptosis and suppresses invasion of ovarian adenocarcinoma cells by targeting alpha5beta1 integrin to down-regulate Akt and MMP-2. British Journal of Pharmacology, 165(2): 479-493 (2012)

5. Chiu CF, Peng JM, Hung SW, Liang CM, Liang SM. Recombinant viral capsid protein VP1 suppresses migration and invasion of human cervical cancer by modulating phosphorylated prohibitin in lipid rafts. Cancer letters, 320(2): 205-214 (2012)

6. Huang CY, Liang CM, Chu CL, Peng JM, Liang SM. A fibrillar form of fibronectin induces apoptosis by activating SHP-2 and stress fiber formation. Apoptosis, 15(8): 915-926 (2010)

7. Peng JM, Liang SM, Liang CM. VP1 of foot-and-mouth disease virus induces apoptosis via the Akt signaling pathway. Journal of Biological Chemistry, 279(50): 52168-52174 (2004)

8. Wang JH, Liang CM, Peng JM, Shieh JJ, Jong MH, Lin YL, Sieber M, Liang SM. Induction of immunity in swine by purified recombinant VP1 of foot-and-mouth disease virus. Vaccine, 21(25-26): 3721-3729 (2003)

9. Lin YC, Peng JM, Wang WB. The N-terminal common domain of simian virus 40 large T and small t antigens acts as a transformation suppressor of the HER-2/neu oncogene. Oncogene, 19(22): 2704-2713 (2000)