Hsin-Ling Hsu, Ph.D.
Institute of Molecular and Genomic Medicine
-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)
2011/10-present, Associate Investigator – Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan
Research on tumor biology and translational medical research
Adjunct Associate Professor
Tung-Hai University (2012-present)
National Taiwan University (2011-2015)
2004/10-2011/9, Assistant Investigator – Division of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan
Research on molecular oncology in basic research
2002-2004, Research Assistant Professor – Northwestern University Medical School, Chicago, IL
Research on hematology and oncology medical research
Co-principle investigator responsible for clinical and translational studies
2001-2002, Scientist/Biochemist – Lawrence Berkeley National Laboratory, Berkeley, CA
Research on molecular mechanism of DNA repair machinery
1999-2001, Postdoctoral Fellow in Biochemistry – Lawrence Berkeley National Laboratory, Berkeley, CA Research on molecular mechanism in maintenance of telomere structure
1996-1999, Postdoctoral Fellow in Biochemistry – Los Alamos National Laboratory, Los Alamos, NM
Research on molecular regulation in DNA damage repair
1987-1989, Instructor – Tung-Hai University, Taichung, Taiwan
Instruction on biology, genetics, and immunology courses
Dr. Hsu’s research interest is to investigating the oncogenic mechanisms that induce DNA damage, chromosomal instability, mitotic catastrophe, neoplastic multinucleation, tumor progression, metastasis and microenvironment. Dr. Hsu’s current works focus on the fundamental mechanism of MCT-1 oncogene in promoting of tumor metastasis and malignant microenvironment. Her laboratory has identified the oncogenic kinase pathways involving the microRNA biogenesis, EMT signaling activation and tumor progression/metastasis. Dr. Hsu has confirmed the clinical relevance of the MCT-1 activation in different types of aggressive breast cancers and lung carcinoma. Her laboratory also establishes a unique ex vivo three dimensional dissection of tumorigenic microenvironment to analyze the therapeutic effect and utilizes an in vivo animal work to demonstrate the tumorigenic outcomes upon gain or loss of the oncogenic activity. These findings have good prospects to develop new diagnosis and effective therapeutic methods that administrate aggressive chemo/radio-resistant carcinomas.
MCT-1 is an RNA-binding protein involving in the translational initiation. Dr. Hsu lab have proved that MCT-1 oncogene is highly expressed in lung adenocarcinoma and in triple negative breast cancer. Aberrant activation of MCT-1 in cancer cells induces generation of intracellular ROS, tumor-promoted cytokines and the miRNAs which potentially activate the differentiation of immune cells, endothelial cells and fibroblasts. Moreover, MCT-1 overexpression induces EMT signaling cascade via activation of EGFR and Src pathway by which promote tumor progression and metastasis. Therefore, suppressing the MCT-1 oncogenic mechanism may strengthen the cancer therapeutic outcomes. Furthermore, combining the effect of tumor suppressor miRNAs induced by loss-function of MCT-1 and the therapeutic agent(s) may be innovative way for change of tumor microenvironments and for achievement of maximal therapeutic outcome.
Centrosome amplification and chromosome abnormality are frequently identified in neoplasia and tumorigenesis. Dr. Hsu has demonstrated that MCT-1 is a novel centrosomal protein that may be independent of its translation function. Targeting MCT-1 results in intercellular bridging, chromosome mis-segregation, cytokinesis delay and post-mitotic death. Furthermore, loss-function p53 alongside MCT-1 overexpression promote pleiotropic mitotic catastrophes, including centrosome amplification, chromosome missegregation, and cytokinesis failure. Consequently, the incidences of nuclear aberration and chromosomal instability are dramatically increased. Thereby, the studies identify the information for understanding the stepwise progression of tumors under the oncogenic stress.
Src homolog and collagen homolog (Shc) compromised three isoforms with distinct molecular weights (46, 52 and 66 kDa) is the adaptor proteins that transmit the signaling of cell surface receptors, such as EGF receptor (EGFR), erbB-2 receptor and insulin receptor. Overexpressing Shc proteins play important roles in mitogenesis, carcinogenesis and metastasis. Dr. Hsu has proved that MCT-1 is a novel regulator of Shc-Ras-MEK-ERK signaling and demonstrated for the first time that both MCT-1 and Shc genes are highly activated in human lung and breast cancers. Knockdown of MCT-1 enhances apoptotic cell death accompanied with reduction of Shc, activation of caspases and cleavage of the substrates under environmental stress. Moreover, the cancer cell proliferation, chemo-resistance and tumorigenic capacity are effectively suppressed by silencing MCT-1. Collectively, enhanced MCT-1 activation can be recognized as a biomarker for tumor development and served as a therapeutic target.
Multinucleation is associated with malignant neoplasms. Dr. Hsu demonstrates that increased MCT-1 expression antagonizes the functional activity of PTEN that promotes PI-3K/AKT signaling, survival rate and the malignant effects particular in PTEN-deficient condition. MCT-1 physically interacts with p190B and Src in vivo, supporting they are in proximity of the signaling complexes. The Src/p190B signaling function that leads to inhibition of RhoA activity is synergistically augmented by MCT-1 overexpression and PTEN loss. Through Src/p190B/RhoA pathway, MCT-1 enhances the incidences of mitotic catastrophe in spindle multipolarity and cytokinesis failure that drive neoplastic multinucleation. Most important, targeting MCT-1 dramatically represses the Src/p190B signaling cascade that improves nuclear structure and suppresses tumorigenicity of PTEN-null breast cancer cells. Clinical evidence also further confirms that MCT-1 gene stimulation is correlated with p190B gene promotion and PTEN gene suppression in human breast cancer. Accordingly, MCT-1 gene induction can be recognized as a potential biomarker of breast tumor development. Abrogating MCT-1 function may be a promising stratagem for management of breast cancer involving Src hyperactivation and/or PTEN dysfunction.
HIGHLIGHTS OF RECENT RESEARCH
Neoplastic mutilnucleation in oncogene MCT-1 activation and loss of the tumor suppressor(s)
|Aberrant nuclear organizationUnsynchronized cell cycle progression occurs in the multi-nuclear cell (denoted by arrow, asterisk, and star).|
Multinucleation is often identified in cancer cells. Dr. Hsu’s lab found that multinucleate cells were greatly increased when oncogene MCT-1 is overexpressed and p53 is suppressed. Her lab found three interphase nuclei (arrow), a mitotic nucleus with chromosome alignment at the metaphase plate (star) and some micro-nuclei (asterisk) that were all enclosed within a single cell. This proves that unsynchronized cell cycle progression at different nuclear compartments of a multi-nuclear cell enable perpetuate the rate of aneuploidy and promote chromosomal instability during tumor progression. (Molecular Cancer Research. 2009, 7:536-548, Cover story)
Dr. Hsu’s lab further found that MCT-1 physically interacts with p190B and Src in vivo and induces the Src/p190B signaling function that inhibits RhoA activity in PTEN loss condition. Through MCT-1/Src/p190B/RhoA pathway, the incidences of mitotic catastrophe in spindle multipolarity and cytokinesis failure that drive neoplastic multinucleation are dramatically enhanced. Most important, targeting MCT-1 dramatically represses the Src/p190B signaling that improves nuclear structure and suppresses tumorigenicity of PTEN-null breast cancer cells. MCT-1 gene induction has now been recognized as a potential biomarker of breast cancer development. Abrogating MCT-1 activity may be promising stratagem for management of breast cancer. This study not only uncovers a novel mechanism of nuclear aberration but also offers new strategy for cancer treatment. (Oncogene. 2014. 33:5109-5120).
HONORS & AWARDS
2008-2011 NRPGM Grant Award, NSC
2007-2010 Young Investigator Career Development Award, NSC
2001 Telomere Award Given by the Telomere and Telomerase Meeting, Cold Spring Harbor
1996 1ST Prize of Dr. Chien-Tien Hsu’s Science Award Given by the Chinese Society of Cell and Molecular Biology, Taiwan
1989-1996 Pre-doctoral Fellowship, National Yang-Ming University, Taipei, Taiwan
- Hsu HL, Gilley D, Blackburn EH, Chen DJ. (1999) Ku is associated with the telomere in mammals. Proc. Natl. Acad. Sci. U S A 96:12454-12458. (IF. 10.26)
- Hsu HL, Gilley D, Galande SA, Hande MP, Allen B, Kim SH, Li GC, Campisi J, Kohwi-Shigematsu T, Chen DJ. (2000) Ku acts in a unique way at the mammalian telomere to prevent end joining. Gene. Dev. 14:2807-2812. (IF. 19.676)
- Hsu HL, Shi B, Gartenhaus RB. (2005) The MCT-1 oncogene product impairs cell cycle checkpoint control and transforms human mammary epithelial cells. Oncogene. 24:4956-4964. (IF. 6.872)
- Shih HJ, Chu KL, Wu MH, Wu PH, Chang WW, Chu JS, Wang LH, Takeuchi H, Ouchi T, Hsu HL*. (2012) The involvement of MCT-1 oncoprotein in inducing mitotic catastrophe and nuclear abnormalities. Cell Cycle. 11: 934-952. (*corresponding author) (IF. 5.243), 44/185/Cell Biology (23.7%)
- Shih HJ, Chen HH, Chen YA, Wu MH, Liou GG, Chang WW, Chen L, Wang LH, Hsu HL*. (2012) Targeting MCT-1 oncogene inhibits Shc pathway and xenograft tumorigenicity. Oncotarget. 2012. 3:1401-15. (*corresponding author) (IF 6.636), 21/197/Oncology (10.65%)
- Wu MH, Chen YA, Chen HH, Chang KW, Chang IS, Wang LH, Hsu HL*. MCT-1 expression and PTEN deficiency synergistically promote neoplastic multinucleation through the Src/p190B signaling activation. Oncogene, 33:5109 (2014) (*corresponding author). (IF 8.459), 13/211/Oncology (6.16%)
- Tseng HY, Chen YA, Jen J, Shen PC, Chen LM, Lin TD, Wang YC and Hsu HL*. Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression. Oncogenesis 6, e313 (2017). (*corresponding author). (IF 4.722), 54/223/Oncology (24.2%)
- Chen LM, Liu PY, Chen YA, Tseng HY, Shen PC,Hwang PA and Hsu HL*. Oligo-Fucoidan prevents IL-6 and CCL2 production and cooperates with p53 to suppress ATM signaling and tumor progression. Scientific Reports. (2017, 7:11864). (*corresponding author) (IF. 4.122), 12/64/MULTIDISCIPLINARY SCIENCES (18.75%)
- Weng YS, Tseng HY, Chen YA, Shen PC,Al Haq AT, Chen LM, Tung YC and Hsu HL*. MCT-1/IL-6/IL-6R signaling modulates EMT progression, cancer stemness and microenvironment in aggressive breast cancer. (Molecular Cancer, in press, 2019) (*corresponding author) (IF. 10.679) 11/229/Oncology (4.8%)
- Chen LM, Tseng HY, Chen YA, Al Haq AT, Hwang PA, Hsu HL*. Oligo-Fucoidan Prevents M2 Macrophage Differentiation and HCT116 Tumor Progression. Cancers (2020, 12(2). pii: E421 ) (*corresponding author) (IF. 6.12) 31/230 Oncology(13.4%)