Hsin-Ling Hsu, Ph.D.
Institute of Molecular and Genomic Medicine
EDUCATION-Ph.D., Department of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan (1996)
-B.S., Department of Biology, Tung-Hai University, Taichung, Taiwan (1987)
PROFESSIONAL EXPERIENCES-Associate Investigator, Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan (2011, Oct-present)
-Assistant Investigator, Division of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan (2004, Oct-2011, Oct)
-Research Assistant Professor, Northwestern University Medical School, Chicago, IL (2002-2004)
-Scientist/Biochemist, Lawrence Berkeley National Laboratory, Berkeley, CA (2001-2002)
-Postdoctoral Fellow in Biochemistry, Lawrence Berkeley National Laboratory, Berkeley, CA (1999-2001)
-Postdoctoral Fellow in Biochemistry, Los Alamos National Laboratory, Los Alamos, NM (1996-1999)
-Instructor, Tung-Hai University, Taichung, Taiwan (1987-1989)
RESEARCH INTERESTS Dr. Hsin-Ling Hsu's researches focus on investigating the tumorigenic roles of oncogenic kinase activation and genome structure instability. Her laboratory is studying a novel oncogene, MCT-1 (multiple copies in T-cell malignancy). Multiple Copies in T-cell malignancy 1 (MCT-1) was originally identified as an amplified gene in a panel of lymphoma cell lines. MCT-1 protein is phosphorylated by CDC2 and ERK kinase in vitro and contains a putative RNA-binding motif. Recent studies have demonstrated that MCT-1 is involved in transcription/translational control. Her works have indicated that MCT-1 serves as an oncogenic modulator which implicates in DNA damage repair, checkpoint controls, tumor promotion, and oncogenic kinase activation. Several lines of clinical evidence have proved that MCT-1 oncoprotein is overexpressed in a subset of diffuse large B-cell lymphomas, lung carcinomas, and breast carcinomas in human. During cell-cycle progression, MCT-1 is shuttling between cytoplasm, nucleus and centrosome compartments, revealing its importance in cell growth and proliferation.
MCT-1 oncoprotein accelerates p53 protein degradation via a proteosome pathway. Synergistic promotion of the xenograft tumorigenicity has been demonstrated in circumstance of p53 loss alongside MCT-1 overexpression. However, the molecular regulation between MCT-1 and p53 in tumor development remains unclear. She now identifies that MCT-1 is a novel target gene of p53 transcriptional regulation and MCT-1 promoter region contains the response elements reactive with wild-type p53 but not mutant p53. Functional p53 represses MCT-1 promoter activity and MCT-1 mRNA stability. In a negative feedback regulation, constitutively expressed MCT-1 decreases p53 promoter function and p53 mRNA stability. The apoptotic events are also significantly prevented by oncogenic MCT-1 in both p53-dependent and -independent fashions, according to the genotoxic mechanisms. Moreover, oncogenic MCT-1 promotes the tumorigenicity in mice xenografts of p53-null and p53-positive lung cancer cells. In support of the tumor growth is irrepressible by p53 reactivation in vivo, the inhibitors of p53 (MDM2, Pirh2, and Cop1) are constantly stimulated by the oncogenic MCT-1. The molecular oppositions between MCT-1 and p53 are firstly confirmed at multistage processes of transcription control, mRNA metabolism, and protein expression. For that reason, MCT-1 oncogenicity can overcome p53 function that persistently advances the tumor development.
Though many researchers have focused on MCT-1 oncogenic outcomes, it is unknown whether MCT-1 deregulates mitotic or centrosomal function. Her recent data have elucidated that MCT-1 is a novel centrosomal proto-oncoprotein. The shRNA interference of MCT-1 expression effectively suppresses the post-mitotic cell survival and significantly delays the completion of mitosis. Under a p53-compromised background, oncogenic MCT-1 further promotes pleiotropic mitotic catastrophe that synergistically induces centrosome amplification and cytokinesis failure. The structural abnormalities of nucleus and chromosome are potentially promoting tumorigenic strength under the MCT-1 oncogenic background. Study of MCT-1's oncogenicity could help to elucidate the underlying biological mechanisms responsible for the tumor development and offer the possibility of designing improved the target therapy of human cancer.
RESEARCH ACTIVITIES & ACCOMPLISHMENTS Dr. Hsin-Ling Hsu has more than 15 years experience in basic medical research of cell biology, genomic structure, radiation oncology and tumor biology. Her current researches focus on the molecular mechanism of MCT-1 oncogene in promoting genomic instability, mitotic aberrations and tumor metastasis. She has identified the MCT-1 oncogenic kinase pathways which are involved in the microRNA expression, tumorigenicity, cancer cell invasion/migration and inhibition of tumor suppressors. Her studies have found MCT-1 expression profiling in different types of human breast and lung cancers which gain a direct insight of clinical evidence for understanding the MCT-1 oncogenic activity. Her laboratory establishes a unique in vitro three dimensional dissection of tumorigenic microenvironment to analyze the therapeutic agents and an in vivo animal work to demonstrate the MCT-1 tumorigenic outcomes and the impact of MCT-1 knockdown on the tumor suppression. These findings have high prospects to develop more sensitive diagnosis, effective therapeutic methods that potentially administrate poorly prognostic or aggressive chemo/radio-resistant carcinomas.
HONORS & AWARDS- Poster Award Given by The 1st International Cancer Symposium, Taichung, Taiwan, 2007
- Telomere Award Given by the Telomere and Telomerase Meeting, Cold Spring Harbor, 2001
- 1ST Prize of Dr. Chien-Tien Hsu's Science Award Given by the Chinese Society of Cell and Molecular Biology, Taiwan, 1996
- Pre-doctoral Fellowship, National Yang-Ming University, Taipei, Taiwan, 1989-1996
SELECTED PUBLICATIONS1. Wu MH, Chen YA, Chen HH, Chang KW, Chang IS, Wang LH, Hsu HL* (*corresponding author). MCT-1 expression and PTEN deficiency synergistically promote neoplastic multinucleation through the Src/p190B signaling activation. Oncogene. 2014 May 26.
2. Shih HJ, Chu KL, Wu MH, Wu PH, Chang WW, Chu JS, Wang LH, Takeuchi H, Ouchi T, Hsu HL*(*corresponding author). (2012) The involvement of MCT-1 oncoprotein in inducing mitotic catastrophe and nuclear abnormalities. Cell Cycle. 11: 934-952.
3. Shih HJ, Chen HH, Chen YA, Wu MH, Liou GG, Chang WW, Chen L, Wang LH, Hsu HL* (*corresponding author). (2012) Targeting MCT-1 oncogene inhibits Shc pathway and xenograft tumorigenicity. Oncotarget. 2012. 3:1401-15.
4.Wu CL, Chou Y.H, Chang YJ, Teng NY, Hsu HL, Chen L. Interplay between cell migration and neurite outgrowth determines SH2B1?-enhanced neurite regeneration of differentiated PC12 cells. PLoS One. 2012, 7:e34999.
5. Shih HJ, Chu KL, Wu MH, Wu PH, Chang WW, Chu JS, Wang LH, Takeuchi H, Ouchi T, Hsu HL*. The involvement of MCT-1 oncoprotein in inducing mitotic catastrophe and nuclear abnormalities. Cell Cycle. 2012, 11(5). 934-952.
6. Kasiappan R, Shih HJ, Wu MH, Choy CO, Lin TD, Chen L. Hsu HL.*. The antagonism between MCT-1 and p53 affects the tumorigenic outcomes. Molecular Cancer 2010, 9:311.
7. Lu WC, Chen CJ, Hsu HC, Hsu HL, Chen L. The adaptor protein SH2B1? reduces hydrogen peroxide-induced cell death in PC12 cells and hippocampal neurons. Journal of Molecular Signaling 2010, 5:17.
8. Kasiappan R., Shih HJ, Chu KL, Chen WT, Liu HP, Huang SF, Choy CO, Shu CL, Din R, Chu JS, Hsu HL.* Loss of p53 and MCT-1 overexpression synergistically promote chromosome instability and tumorigenicity. Molecular Cancer Research. 2009, 7:536-548.
9. Hsu HL*, Choy CO, Kasiappan R, Shih HJ, Sawyer JR, Shu CL, Chu KL, Chen YR, Hsu HF, Gartenhaus RB. MCT-1 oncogene downregulates p53 and destabilizes genome structure in the response to DNA double-strand damage. DNA Repair. 2007, 6:1319-32.
10. Nandi S, Reinert LS, Hachem A, Mazan-Mamczarz K, Hsu HL, Hagner P, He H, Gartenhaus RB. Phosphorylation of MCT-1 by p44/42 MAPK is required for its stabilization in response to DNA damage. Oncogene. 2007, 26:2674.
11. Lin HH, Hsu HL, Yeh NH. Apoptotic cleavage of NuMA at the C-terminal end is related to nuclear disruption and death amplification. J Biomed Sci. 2007, 14:681-694.
12. Hsu HL, Shi B, Gartenhaus RB. The MCT-1 oncogene product impairs cell cycle checkpoint control and transforms human mammary epithelial cells. Oncogene. 2005, 24:4956-4964.
13. Shi B, Hsu HL, Evens AM, Gordon LI, Gartenhaus RB. Expression of the candidate MCT-1 oncogene in B- and T-cell lymphoid malignancies. Blood. 2003, 102: 297-302.
14. Hsu HL, Yannone S, and Chen DJ. Defining interactions between DNA-PK and XRCC4/ligase IV. DNA Repair 2002, 17: 1-11.
15. Hsu HL, Gilley D, Galande SA, Hande MP, Allen B, Kim SH, Li GC, Campisi J, Kohwi-Shigematsu T, and Chen DJ. Ku acts in a unique way at the mammalian telomere to prevent end joining. Genes Dev 2000, 14:2807-2812.
16. Hsu HL, Gilley D, Blackburn EH, and Chen DJ. Ku is associated with the telomere in mammals. Proc. Natl. Acad. Sci. U S A 1999, 96:12454-12458.
17. Yang CR, Yeh S, Leskovk K, Odegaard E, Hsu HL, Chang C, Kinsella TJ, Chen, DJ, Boothman DA. Isolation of Ku70-binding proteins (KUBs). Nucleic Acids Res. 1999, 27:2165-2174.
18. Hsu HL, and Yeh NH. Dynamic changes of NuMA during the cell cycle and possible appearance of a truncated form of NuMA during apoptosis. J. Cell Sci. 1996, 109:277-288.
(*= corresponding author)