王湘翠 助理教授

Office Tel: 2826-7097

E-mail: htwang01@ym.edu.tw

Office location: 守仁樓5 514

一、主要研究方向

1.  對於環境暴露之汙染物丙烯醛 (acrolein)以及人類疾病的研究 。

2.  發展早期檢測人類疾病之biomarkers以及對於預防疾病方法之研究。

3.  對於環境暴露丙烯醛 (acrolein)與神經退化性疾病或中風之相關研究。

 

Ø  Acrolein and human lung diseases:

acroelin.tif

Figure 1. The sources and metabolic fate of acrolein (Toxicol Science. 143:242-55 (2015)).

丙烯醛(Acrolein)是一個極度不穩定且有活性的醛類 (a, b-unsaturated aldehdye),會與細胞中的DNA以及DNA修復蛋白質作用進而影響細胞正常功能。 Acrolein不僅在環境中可以發現,例如:車輛排放的廢氣、香菸以及炒菜油煙中;它也存在於人體體內,acroleinlipid peroxidation的副產物,研究顯示當細胞產生oxidative stress時會產生高含量的acrolein。目前本實驗室對於acrolein對於細胞毒性有進一步之探討,包含acrolein與粒線體DNA傷害之探討以及acrolein與核醣體生合成之機制探討。本實驗之研究主題將以了解acrolein如何造成細胞毒性之機轉加以探討,進一步希望可以發展出肺部疾病早期診斷之biomarker以及預防肺部疾病的方法。

 

Acrolein & Mitochondrial DNA damages

Acrolein (Acr), a highly reactive unsaturated aldehyde, can cause various lung diseases including asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. We have found that Acr can damage not only genomic DNA but also DNA repair proteins causing repair dysfunction and enhancing cells’ mutational susceptibility. While these effects may account for Acr lung carcinogenicity, the mechanisms by which Acr induces lung diseases other than cancer are unclear. In this study, we found that Acr induces damages in mitochondrial DNA (mtDNA), inhibits mitochondrial bioenergetics, and alters mtDNA copy number in human lung epithelial cells and fibroblasts. Furthermore, Acr induces mitochondrial fission which is followed by autophagy/ mitophagy and Acr-induced DNA damages can trigger apoptosis. However, the autophagy/ mitophagy process does not change the level of Acr-induced mtDNA damages and apoptosis. We propose that Acr-induced mtDNA damages triggers loss of mtDNA via mitochondrial fission and mitophagy. These processes and mitochondria dysfunction induced by Acr are causes that lead to lung diseases.

 

Acrolein & Ribosomal stress

Acrolein (Acr) is a potent cytotoxic and DNA damaging agent which is ubiquitous in the environment and abundant in tobacco smoke. Acr is also an active cytotoxic metabolite of the anti-cancer drugs cyclophosphamide and ifosfamide. The mechanisms via which Acr exerts its anti-cancer activity and cytotoxicity are not clear. In this study, we found that Acr induces cytotoxicity and cell death in human cancer cells with different activities of p53. Acr preferentially binds nucleolar ribosomal DNA (rDNA) to form Acr-deoxyguanosine adducts, and induces oxidative damage to both rDNA and ribosomal RNA (rRNA). Acr triggers ribosomal stress responses, inhibits rRNA synthesis, reduces RNA polymerase I binding to the promoter of rRNA gene, disrupts nucleolar integrity, and impairs ribosome biogenesis and polysome formation. Acr causes an increase in MDM2 levels and phosphorylation of MDM2 in A549 and HeLa cells which are p53 active and p53 inactive, respectively. It enhances the binding of ribosomal protein RPL11 to MDM2 and reduces the binding of p53 and E2F-1 to MDM2 resulting in stabilization/activation of p53 in A549 cells and degradation of E2F-1 in A549 and HeLa cells. We propose that Acr induces ribosomal stress which leads to activation of MDM2 and RPL11-MDM2 binding, consequently, activates p53 and enhances E2F-1 degradation, and that taken together these two processes induce apoptosis and cell death.

Fig. 10.tif

Fig. 2. Model of Acr-induced ribosomal stress responses in p53-active and -inactive cancer cells.

 

Ø  Acrolein and stroke:

丙烯醛(Acrolein) 是一個未受到重視的食物安全議題。丙烯醛是一個具有高度活性的不飽和醛類,會在食品加工烹調過程中產生,主要藉由美拉德反應將動植物性脂肪、醣類以及胺基酸的加熱過程中被製造而得。此外,丙烯醛也在長期過度加熱的食用油所釋放的油煙中偵測到,在油炸食物例如薯條中被發現具有很高的含量。因此,人類可能藉由接觸到此類食物而對健康產生風險。丙烯醛是一個活性很高的醛類,餵食試驗只發現動物會提早死亡,但無確定病因;使用疾病動物模式或人體組織卻發現丙烯醛與神經系統相關性疾病有關,例如:缺血性中風、帕金森氏症以及阿茲海默症;以上差異之原因仍不明。在這些疾病中,缺血性中風是造成台灣死亡率第三位以及行動不便最常見原因。過去研究顯示中風病人血液中,可測得大量的丙烯醛與蛋白質鍵結物,其濃度與中風病人的疾病癌嚴重度有高度相關性。目前流行病學研究顯示飲食的選擇與中風的發生率有相關性,由於丙烯醛可在食物加工烹調中產生且與中風所產生的腦組織壞死有關,因此丙烯醛可能是中風與飲食選擇的主要連結因子。為此,我們提出一個假說: 由食品加工烹調中所產生的丙烯醛是造成缺血性中風及相關腦組織壞死的主要因子。此研究將幫助建立丙烯醛的危害鑑定,並探討藉由食物加工烹調所暴露丙烯醛與腦部疾病及損傷之相關性,進一步可以找出俱有潛能之預防方法。

 

二、國際期刊發表

1.     Alterations in acrolein metabolism contribute to Alzheimer’s disease. Tsou HH, Hsu WC, Fuh JL, Chen SP, Liu TY, Wang HT# Journal of Alzheimer's Disease. (In press) (#Corresponding author)

2.     Neuroprotective effects of baicalein on acrolein-induced neurotoxicity in the nigrostriatal dopaminergic system of rat brain. Zhao WZ, Wang HT, Huang HJ, Lo YL, Lin AM. Mol Neurobiol. 2017 Sep 2. doi: 10.1007/s12035-017-0725-x.

3.     Acrolein induces mtDNA damages, mitochondrial fission and mitophagy in human lung cells. Wang HT#, Lin JH, Yang CH, Haung CH, Weng CW, Lin AM, Lo YL, Chen WS and Tang MS. Oncotarget. 2017; 8:70406-70421. https://doi.org/10.18632/oncotarget.19710 (#Corresponding author)

4.     Acrolein acts as a neurotoxin in the nigrostriatal dopaminergic system of rat: involvement of α-synuclein aggregation and programmed cell death. Wang YT, Lin HC, Zhao WZ, Huang HJ, Lo YL, Wang HT#, Maan-Yuh Lin A# Sci Rep. 2017 Apr 12;7:45741. doi: 10.1038/srep45741. (#Co-Corresponding author)

5.     AFB1 hepatocarcinogenesis is via lipid peroxidation that inhibits DNA repair, sensitizes mutation susceptibility and induces aldehyde-DNA adducts at p53 mutational hotspot codon 249. Weng MW*, Lee HW*, Choi B*, Wang HT*, Hu Y, Mehta M, Desai D, Amin S, Zheng Y, Tang MS. Oncotarget. 2017 Mar 14;8(11):18213-18226. doi: 10.18632/oncotarget.15313. (* Equal contribution)

6.     Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells. Wang HT#, Chen TY, Weng CW, Yang CH, Tang MS. Oncotarget. 2016 Dec 6;7(49):80450-80464. doi: 10.18632/oncotarget.12608. (#Corresponding author)

7.     Enhancing Anticancer Effect of Gefitinib across the Blood-Brain Barrier Model Using Liposomes Modified with One α-Helical Cell-Penetrating Peptide or Glutathione and Tween 80. Lin KH, Hong ST, Wang HT, Lo YL, Lin AM, Yang JC. Int J Mol Sci. 2016 Nov 29;17(12). pii: E1998.

8.     Lee HW*, Wang HT*, Weng MW, Chin C, Huang W, Lepor H, Wu XR, Rom WN, Chen LC, Tang MS. Cigarette side-stream smoke lung and bladder carcinogenesis: inducing mutagenic acrolein-DNA adducts, inhibiting DNA repair and enhancing anchorage-independent-growth cell transformation. Oncotarget. 2015 Oct 20;6(32):33226-36. (* Equal contribution)

9.     Lee HW*, Wang HT*, Weng MW, Hu Y, Chen WS, Chou D, Liu Y, Donin N, Huang WC, Lepor H, Wu XR, Wang H, Beland FA, Tang MS. Acrolein- and 4-Aminobiphenyl-DNA adducts in human bladder mucosa and tumor tissue and their mutagenicity in human urothelial cells. Oncotarget. 2014 Jun 15;5(11):3526-40. (* Equal contribution)

10.  Wang HT, Weng MW, Chen WC, Yobin M, Tang MS. Effect of CpG Methylation at Different Sequence Context on Acrolein-DNA Binding and Mutagenesis. Carcinogenesis; 34:220-7(2013).

11.  Pan J, Awoyemi B, Xuan Z, Vohra P, Wang HT, Dyba M, Greenspan E, Fu Y, Creswell K, Zhang L, Berry D, Tang MS, Chung FL. Detection of Acrolein-Derived Cyclic DNA Adducts in Human Cells by Monoclonal Antibodies. Chem Res Toxicol; 25:2788-95(2012).

12.  Wang HT, Hu Y, Tong D, Huang J, Gu L, Wu XR, Chung FL, Li GM, Tang MS. Effect of carcinogenic acrolein on DNA repair and mutagenic susceptibility. J Biol Chem; 287(15):12379-12386. (2012)

13.  Tang MS, Wang HT, Hu Y, Chen WS, Akao M, Feng Z, Hu W. Acrolein induced DNA damage, mutagenicity and effect on DNA repair. Mole Nut and Food Res ; 55(9):1291-300 (2011).

14.  Wang HT*, Choi B*, Tang MS. Melanocytes are deficient in repair of oxidative DNA damage and UV-induced photoproducts. Proc Natl Acad Sci U S A; 107(27):12180-5. (2010). (* Equal contribution)

15.  Wang HT, Zhang S, Hu Y, Tang MS. Mutagenicity and sequence specificity of acrolein-DNA adducts. Chem Res Toxicol; 22(3):511-7. (2009)

16.  Wang HT, Tang MS. Acrolein-DNA Adducts Are Mutagenic. Chem. Res. Toxicol; 22 (5):753–754. (2009)

 

 

 

三、邀請演講

1.       Effect of acrolein on mitochondrial DNA damage response. Joint Conference of Cell signaling in China, Hang Zhou, China, 10/2015

2.       Aflatoxin B1 hepatocarcinogenesis via lipid peroxidation inducing cyclic propano-DNA adduct at p53 codon 249, inhibiting DNA repair and enhancing mutation susceptibility. Society of Chinese Bioscientists in America, Taiwan, 06/2015

3.       The effect of Acrolein in DNA Damage, DNA Repair and Lung Carcinogenesis. Toxicology society of Taiwan, Joint Annual Conference of Biomedical Science, National Defense Medical Center, Taiwan, 03/2014

 

四、研討會議Poster發表

1.      Wang HT*, Chen TY, Weng CW, Yang CH, Tang MS. Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells. Cold Spring Harbor Laboratory (CSHL) meeting-DNA Replication and Genomic Maintenance. USA, 2017

2.      Lin JH, Wang HT* Acrolein induces mitochondrial DNA damages, fission and mitophagy in human lung cells. Annual Conference of Biomedical Science, National Defense Medical Center, Taiwan, 2017

3.      Yang CH, Lin JH, Yang James CH, Lin Anya MY, Wang HT*. The role of HER2 755PL in-frame (HER2PL) mutation in human lung cancer cells. Annual Conference of Biomedical Science, National Defense Medical Center, Taiwan, 2017

4.      Chen TY, Wang HT*, Acrolein induces ribosomal stress in human cells. Joint Annual Conference of Biomedical Science, National Defense Medical Center, Taiwan, 2016

5.      CW Weng, JH Lin, HT Wang*, Effect of acrolein on mitochondrial DNA damage response, Society for Mitochondrial Research and Medicine, National Yang Ming University, Taiwan, 2015

6.      Wang HT, MW Weng, HW Lee , Huang WC, Liu Y, Lepor H, Wu XR and Tang MS. The Role of p63 and p53 Mutant in the Regulation of DNA Repair, Mutator and Invasive Phenotype of Bladder Cancer Cells. Society of Chinese Bioscientists in America, Academia Sinica, Taiwan, 2015

7.      Wang HT, Lee HW, Weng MW, Kuo J, Huang W, Lepor H, Donin N, Wu XR, Tang MS. Invasive bladder cancer cells are deficient in DNA repair and have mutator phenotypes that are due to suppression of p63 gene expression. American Urology Association, 2013

8.      Lee HW, Wang HT, Weng MW, Liu Y, Donin N, Huang W, Wu XR, Lepor H, Tang MS. Quantitation of DNA adduct induced by bladder carcinogens - aminobiphenyl and acrolein -in normal human urothelial mucosa and bladder tumor tissue. American Urology Association, 2013

9.      Wang HT, Hu Y, Tong D, Huang J, Gu L, Wu XR, Chung FL, Li GM, Tang MS. Effect of carcinogenic acrolein on DNA repair and mutagenic susceptibility. American Association for Cancer Research Annual Meeting, 2012

10.   Wang HT, Choi B, Tang MS. Melanocytes are deficient in repair of oxidative DNA damage and UV-induced photoproducts. American Association for Cancer Research Annual Meeting, 2010

11.   Wang HT, Kuo LH, Huang W, Wu XR, Tang MS. Invasive and non-invasive bladder cancer cells have different DNA excision repair capacity and mutator phenotypes."Recent Advances in Urological Research Symposium" sponsored by NYU medical center, 2010