專業人才

黎欣白 ,Ph.D.
單位: 長庚大學
現職: 生物醫學研究所 微生物與免疫學科 助理教授
聯絡地址: 33302 桃園市龜山區文化一路259號
電話: 03-2118800 分機:3593
E-mail: paili@mail.cgu.edu.tw

研究領域:
  • 病毒/微生物
  • 癌症醫學
  • 生化及分子生物

工作經歷:
2008–迄今: 助理教授 (Assistant Professor) 長庚大學/ 醫學院/ 微免科 (Chang Gung University/ Department of Microbiology & Immunology)

2003 – 2008: 助理教授級研究員 (Research Faculty/ Assistant Professor) 長庚醫院/ 醫學研究部 (Chang Gung Memorial Hospital/ Department of Medical Research) SARS Research Group: (2003-2004, SARS Antigen Core)

1998 – 2003: 博士後研究 (Postdoctoral researcher) 長庚大學 張玉生教授 實驗室 Study the oncogenic effect of Epstein Barr virus oncoprotein LMP1 Screening drug(s) to inhibit EBV replication

1990 – 1992: 研究助理Research assistant 國立台大醫院 (National Taiwan University Hospital) 賴明陽醫師 實驗室 Examination of the p53 gene mutations in hepatocellular carcinoma (HCC) patients in Taiwan Study the correlation of HCC and hepatitis B virus (HBV) infection

學歷:
美國南加州大學 微免所 博士
國立中興大學 土壤系 學士

殊榮:
103學年 長庚大學 優良教師 (輔導類)
101學年 長庚大學 優良教師 (教學類)

代表論文:

1. Hsin-Pai Li+*, Hsin-Yi Huang+, Yi-Ru Lai, Jing-Xuan Huang, Kai-Ping Chang, Chuen Hsueh and Yu-Sun Chang (+Co-first author; *Corresponding)
Silencing of miRNA-148a by hypermethylation activates the integrin-mediated signaling pathway in nasopharyngeal carcinoma
Oncotarget 2014; (5)17:7610-24

2. Hsin-Pai Li*+, Chen-Ching Peng+, I-Che Chung, Mei-Yuan Huang, Shao-Tung Huang, Chia-Chun Chen, Kai-Ping Chang, Cheng-Lung Hsu, Yu-Sun Chang
(+Co-first author; *Corresponding)
Aberrantly Hypermethylated Transcription Repressor Homeobox A2 Derepresses Metalloproteinase-9 Activity Through TBP and Promotes Invasion in Nasopharyngeal Carcinoma
Oncotarget 2013; 4: 2154-2165

3. Chia-Lung Tsai+, Hsin-Pai Li+, Chuen Hsueh, Ying Liang, Chi-Long Chen, Sai Wah Tsao, Ka-Po Tse, Yen-Jung Lu, Jau-Song Yu and Yu-Sun Chang (+ Co-first author)
Activation of DNA methyltransferase 1 by Epstein-Barr Virus LMP1 involves JNK signaling.
Cancer Research 2006; 66:11668-11674.

4. Li HP, Leu YW, Chang YS.
Epigenetic changes in virus-associated human cancers
Cell Research 2005 Apr; 15(4):262-271

5. Li HP, Zhang X, Duncan R, Comai L, Lai MM.
Heterogeneous nuclear ribonucleoprotein A1 binds to the transcription-regulatory region of mouse hepatitis virus RNA.

Proc Natl Acad Sci U S A 1997 Sep 2;94(18):9544-9


所有論文著作一覽表

研究方向:
Epstein Barr Virus (EBV) oncoprotein latent membrane protein 1 (LMP1) activates cellular DNA methyltransferases, resulting in hypermethylation and silencing of cell adhesion molecule E-cadherin. We show that LMP1 directly induces the dnmt1 promoter activity through its COOH-terminal activation region-2 YYD domain. LMP1-mediated DNA methyltransferase-1 (DNMT1) activation involves JNK but not nuclear factor KB and p38/mitogenactivated protein kinase signaling. In addition, LMP1 induces formation of a transcriptional repression complex, composed of DNMT1 and histone deacetylase, which locates on E-cadherin gene promoter. Treatment with JNK inhibitor, SP600125, prevents the formation of this repression complex. Overall, our results support a mechanistic link between JNK-AP-1 signaling and DNA methylation induced by the EBV oncogene product LMP1. (Cancer Res 2006; 66(24): 11668-76)

A model for LMP1-mediated DNMT1 activation via JNK/AP-1 signaling. Activated DNMT1 hypermethylates E-cadherin promoter and recruits a transcriptional repression complex leading to gene silencing. The YYD domain of LMP1 activates the JNK signaling pathway and activated JNK, in turn,phosphorylat es transcription factor c-Jun. Phosphorylated c-Jun of AP-1 complex binds and transactivates the dnmt1 promoter. Elevated DNMT1 expression leads to hypermethylation of E-cadherin gene and formation of a transcriptional repression complex including DNMTs,meth yl-binding proteins (MBD),and HDAC. This LMP1-mediated DNMT1 activation can be blocked by JNK inhibitor SP600125,dominant negative mutant (DN-JNK),and dsRNAs (JNK-si,c-Jun-si,TRADD -si,and LMP1-si).


I focus on aberrant DNA methylation and the mechanism of the transcriptional silencing of (1) coding gene and (2) non-coding gene (miRNA) in nasopharyngeal carcinoma.
(1) Aberrantly hypermethylated transcription repressor homeobox A2 derepresses metalloproteinase-9 activity through TBP and promotes invasion in nasopharyngeal carcinoma. (Oncotarget 2013; 4:2154-2165)
A differential hypermethylated transcription repressor, Homeobox A2 (HOXA2), is identified in NPC tumor, which may render NPC cells invasive and metastaic. Aberrant hypermethylation of HOXA2 led to low RNA expression in NPC tumors and cells. Addition of methylation inhibitor 5’aza restored HOXA2 RNA expression in NPC cells. Methylated HOXA2 promoter reduces the binding affinity of the transcriptional co-activator p300, causing transcriptional repression of HOXA2. In NPC cells, re-expression of ectopic HOXA2 was correlated with decreased invasive ability and reduced metalloproteinase MMP-9 RNA and protein expression. Promoter, ChIP and DNA-pull down assays indicated that HOXA2 competes with the transcription activator, TATA-box binding protein (TBP) for a recognition sequence near the MMP-9 transcription start site, and suppresses MMP-9 transcription. Thus, HOXA2 acts as a suppressor or TBP-antagonist to inhibit MMP-9 expression; while methylation-mediated inactivation of HOXA2 in NPC derepresses MMP-9 production and increases invasion of NPC cells. In NPC plasma samples, increased plasma EBV copy number was correlated with increased in cell-free HOXA2 hypermethylation and elevated MMP-9 levels.

In normal cells, transcription of HOXA2 is activated by p300 binding. Subsequently, HOXA2 binds to the MMP-9 TATA-box and interferes the binding of TBP resulting in suppression of MMP-9 expression. In NPC cells, methylation of the HOXA2 impairs the p300 binding thereby inactivates the HOXA2 gene. In the absence of transcription repressor HOXA2, TBP and RNA polII can bind to the TATA-box of MMP-9 and activate MMP-9 expression. Elevated MMP-9 level, in turn, promotes the invasiveness of NPC cells.


(2) Silencing of miRNA-148a by hypermethylation activates the integrin-mediated signaling pathway in nasopharyngeal carcinoma.
(Oncotarget 2014; (5)17:7610-24)
MiRNA-148a is downregulated through hypermethylation in NPC biopsies and NPC cell lines compared with adjacent normal and NP cells respectively. Promoter assays demonstrated that upstream stimulatory factor 1 (USF1) is a crucial transcription factor that activates miR-148a promoter activity. EMSA assays confirmed that purified USF1 binds better toward the unmethylated than the methylated CG-containing USF1 consensus probe. The ectopic expression of miR-148a inhibits cell migration in NPC cells through the suppression of integrin-mediated signaling by targeting VAV2, WASL and ROCK1. Furthermore, immunohistochemical staining and Western blotting analysis revealed that the 3 oncogenic targets of miR-148a were overexpressed in NPC biopsies, suggesting that the inactivation of miR-148a caused by DNA methylation promotes NPC progression. Overall, our findings revealed that miR-148a can act as tumor suppressor miRNA for NPC.

In normal cells, hypomethylated miR-148a promoter allows the binding of transcription activator USF1, resulting in the activation of miR-148a expression. Mature miR-148a represses the protein expression of the integrin pathway downstream targets such as ITGB8, VAV2, ROCK1 and WASL, and thereby inhibits cell migration. Conversely, in NPC cells, hypermethylated miR-148a promoter prevents the binding of USF1 and causes silencing of miR-148a. In the absence of miR-148a, NPC cells overexpress oncogenic integrin pathway targets and, in turn, trigger cell migration.