Lu-Hai Wang, Ph.D.
Institute of Molecular and Genomic Medicine
Ph.D., Molecular Biology, University of California, Berkeley (1976)
B.S. Zoology, National Taiwan University (1970)
1966-1970 Undergraduate, College of Sciences, National Taiwan University, Taiwan (Zoology, Chemistry).
Summer 1971 Research Assistant, Laboratory of Dr. Richard Calendar, Department of Molecular Biology, University of California at Berkeley: growth, quantitative assay and purification of bacteria and bacteriophages P2 and P4.
1971-1976 Graduate Research, Department of Molecular Biology, University of California at Berkeley.
1972-1976 Graduate Student, Laboratory of Dr. Peter Duesberg, Department of Molecular Biology, University of California at Berkeley. Genetic structure and enzymology of RNA tumor viruses.
1976-1977 Postgraduate Research Molecular Biologist, Laboratory of Dr. Peter Duesberg. Sequences and functions of avian tumor virus RNAs; mechanism of viral recombination.
1977-1979 Postdoctoral Fellow, Laboratory of Dr. Hidesaburo Hanafusa, The Rockefeller University, New York. Sequence analysis of avian sarcoma viruses generated by recombination between transformation-defective mutants and normal cellular sequences. Study of the relationship and origin of transforming genes of different strains of avian sarcoma viruses.
1979-1985 Assistant Professor, The Rockefeller University, New York. Sequences and functions of retroviral and cellular oncogenes; mechanism of recombination between viral and cellular sequences; viral RNA transcription and processing.
1985-1988 Associate Professor, The Rockefeller University, New York. Function of viral and cellular oncogenes; transforming potential of growth factor receptor genes; viral RNA transcription and processing.
1988-1992 Associate Professor (with tenure), Department of Microbiology, Mount Sinai School of Medicine, NYC, Expression and function of viral and cellular oncogenes; Transforming and tumorigenic potential of growth factor receptor genes; Mechanism of cell transformation, cancer development and progression. Signal transduction of protein tyrosine kinases and their messengers. Molecular basis of cancer cell survival, invasion and drug resistance. Development of targeted cancer therapy.
1992- 2009 Professor (with tenure), Department of Microbiology, Mount Sinai School of Medicine
1999-2004 Professor, Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine
2004- 2009 Professor, Department of Oncological Science, Mount Sinai School of Medicine
2008- 2017 Distinguished Investigator and Director, Division of Molecular and Genomic Medicine, National Health Research Institute, Taiwan
2009.04-07 Acing Director, Immunology Center, NHRI
2011-2013 Acting Vice President, National Health Research Institutes
2012.09-12 Acting President, National Health Research Institutes
2012.12-2014.07 vice President, National Health Research Institutes
2008- Present Adjunct professor, National Central University, Taiwan
2010- Present Joint professor, Chinese Medical University, Taiwan
2012- Present Chair Professor, Chinese Medical University, Taiwan
2012- Present Chair Professor, Chiao Tung University, Taiwan
Dr. Wang’s research interest is in exploring the cellular and molecular basis for tumor growth and metastasis using cell-based culture systems, syngeneic and xenograft mouse models as well as clinical specimens for the study of breast, ovarian, oral, lung and prostate cancers. Considerable emphasis has been placed on study of the interaction of tumor microenvironment or stroma with cancer cells in the regulation of progression and metastasis. Dr. Wang’s laboratory is also interested in investigating the role of cancer stem cells in metastasis, recurrence and drug resistance. The goal is not only to understand the mechanisms for carcinogenesis, but also to identify biomarkers useful for diagnosis, prognosis and development of intervening strategies and therapeutics.
For study of cancer cell invasion and metastasis, syngeneic pairs of low and high invasive lines were established for breast, ovarian and oral cancers using in vitro and in vivo selection. Genes and microRNAs array analyses of those low and high invasive lines allowed us to identify genes and miRNAs, as well as their underlying mechanisms involved in tumor growth and metastasis. For breast cancer, miRNA-149 has been identified as a metastasis suppressor via targeting GIT1, which is important for integrin signaling and cell migration. Low miRNA-149 and high GIT1 expression is associated with poor prognosis of breast cancer patients. Currently, we are focusing on identifying and investigating the molecules and their functions in tumor microenvironment important for lymph node and lung metastasis. For ovarian cancer, miRNA-138 was shown to inhibit cancer cell invasion and metastasis by targeting SOX4 and Hif1-alpha. Low expression of miRNA-138 and high expression of SOX4 is associated with late stages ovarian cancer. Moreover, glucocorticoids were found to transcriptionally induce the expression of miRNA-708 to suppress ovarian cancer invasion and metastasis via targeting Rap-1B to inhibit migration and invasion. Low expression of miRNA-708 correlates with poor prognosis of patient survival. Stem cell-like “cancer initiator cell lines” were established from fresh ovarian tumors and an established human ovarian cancer line SKOV3 and those lines were shown to display stem-like properties including increased expression of stemness markers, as well as enhanced tumorigenicity and drug resistance. The underlying molecular mechanisms are under investigation. For oral cancer, we have identified miRNA-491-5p as a metastasis suppressor also via targeting GIT1, of which the elevated expression is associated with poor patient survival.
For lung cancer, using a Balb/C syngeneic mouse model, lung and liver organ tropic metastatic lines were established from the parental L1 line by in vivo selection, and they are being used for studying the molecular mechanism for early colonization of tumor cells in lung during early phase of distant metastasis.
For prostate cancer, we have previously shown that the GTP exchange factor Vav3 plays an important role in bone metastasis of the PC3 cells, and have established bone metastases-derived lines. Currently, those lines are being studied for molecular basis for mediating PC3 cells metastasis focusing on alteration of glycolysis enzymes.
HIGHLIGHTS OF RECENT RESEARCH
1. Glucocorticoids Mediate Induction of MicroRNA-708 to Suppress Ovarian Cancer Metastasis through Targeting Rap1B
Glucocorticoids are widely used in conjunction with chemotherapy for ovarian cancer to prevent hypersensitivity reactions. Our study we reveals a novel role for glucocorticoids in the inhibition of ovarian cancer metastasis. Glucocorticoids treatments induce the expression of miR-708, leading to the suppression of Rap1B, which result in the reduction of integrin-mediated focal adhesion formation, inhibition of ovarian cancer cell migration/invasion, and impaired abdominal metastasis in an orthotopic xenograft mouse model. Restoring Rap1B expression reverts glucocorticoids-miR-708 cascade-mediated suppression of ovarian cancer cell invasion and metastasis. Clinically, low miR-708 and high Rap1B are found in late state ovarian tumors, as compared to normal, and patients with high miR-708 show significantly better survival. Overall, our findings reveal an opportunity for glucocorticoids and their downstream mediators, miR-708 or Rap1B, as therapeutic modalities against metastatic ovarian epithelial cancer.
2. MicroRNA-149 targets GIT1 to suppress integrin signaling and breast cancer metastasis
Metastasis is the predominant cause of death in breast cancer patients. Several lines of evidences have shown that microRNAs can play an important role in cancer metastasis. Using isogenic pairs of low and high metastatic lines derived from a human breast cancer line, we have identified miR-149, to be a suppressor of breast cancer cell invasion and metastasis. We also identified GIT1 (G protein-coupled receptor kinase-interacting protein 1) as a direct target of miR-149. Knockdown of GIT1 reduced migration/invasion and metastasis of highly invasive cells. Re-expression of GIT1 significantly rescued miR-149-mediated inhibition of cell migration/invasion and metastasis. Expression of miR-149 impaired fibronectin-induced focal adhesion formation and reduced phosphorylation of FAK and paxillin, which could be restored by re-expression of GIT1. Inhibition of GIT1 led to enhanced protein degradation of paxillin and α5β1 integrin via proteasome and lysosome pathways respectively. Low level of miR-149 and high level of GIT1 was significantly associated with advanced stages of breast cancer as well as lymph node metastasis. It is concluded that miR-149 suppresses breast cancer cell migration/invasion and metastasis by targeting GIT1, suggesting potential applications of the miR-149/GIT1 pathway in clinical diagnosis and therapeutics.
HONORS & AWARDS
1969 Coupon Award from National Taiwan University for Outstanding Undergraduate Achievement.
1977 Damon Runyon-Walter Winchell Cancer Fund Postdoc. Fellowship.
1979 Scholar of American Leukemia Society (declined).
1979 American Cancer Society Junior Faculty Award (declined).
1979-1984 Research Career Development Award (NIH).
1996-1997 President, Tri-state Chapter, Society of Chinese Bioscientists in America
1998 Honorary Professor, Peking Union Medical College, China
2010 Academician, Academia Sinica, Taiwan
2010-2014 President, Chinese Asso of Cell and Molecular Society
2012 Fellow, TWAS (The World Academy of Science)
2013 Outstanding Breast Cancer Research Award, Breast Cancer Foundation, Taiwan
American Society of Virology
American Society of Microbiology
New York Academy of Sciences
Society of Chinese Biochemists in America (Life Member)
SCBA Bio/Pharm Division Member
Chinese Society of Cell and Molecular Biology, member and board, (2009-2015)
- Cheng GZ, Zhang W, Wang LH. (2008) Regulation of cancer cell survival, migration and invasion by Twist: AKT2 comes to interplay. Cancer Research 68:957-960.
- Uttamsingh S, Bao X, Nguyen KT, Bhanot M, Gong J, Chan JL, Liu F, Chu TT, Wang LH. (2008) Synergistic effect between EGF and TGF-1 in inducing oncogenic properties of intestinal epithelial cells. Oncogene 27:2626-2634.
- Cheng GZ, Zhang WZ, Sun M, Wang, Q, Coppola D, Mansour M, Xu LM, Costanzo C, Cheng JQ, Wang LH. (2008) Twist is Induced by Activation of STAT3 and Mediates STAT3 Oncogenic Function. J. Biol. Chem. 283:14665-73.
- Zhang W, Cheng GZ, Gong J, Hermanto U, Zong CS, Chan J, Cheng JQ, Wang LH. (2008) RACK1 and CIS mediate the degradation of BinEL in Cancer cells. J. Biol. Chem. 283:16416-26.
- Schlosshauer PW, Li W, Lin KT, Chan JL, Wang LH. (2009) Rapamycin by itself and additively in combination with carboplatin inhibits the growth of ovarian cancer cells. Gynecologic Oncology 114:516-522.
- Lin KT, Gong J, Li CF, Jang TH, Chen WL, Chen HJ, Wang LH. (2012) Vav3-rac1 signaling regulates prostate cancer metastasis with elevated Vav3 expression correlating with prostate cancer progression and posttreatment recurrence. Cancer Research 72 (12):3000-3009.
- Yeh YM, Chuang CM, Chao KC, Wang LH. (2013) MicroRNA-138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF-1a. Intl J. Cancer 133(4):867-78
- Huang WC, Chan SH, Jang TH, Chang JW, Ko YC, Yen TC, Chiang SL, Chiang WF, Shieh TY, Liao CT, Juang JL, Wang HC, Cheng AJ, Lu YC, Wang LH. (2014) Identification of miRNA-491-5p and GIT1 as the modulators and biomarkers for oral squamous cell carcinoma (OSCC) invasion and metastasis. Cancer Research 74:751-764.
- Chan SH, Huang WC, Chang JW, Chang KJ, Kuo WH, Wang MY, Lin KY, Uen YH, Hou MF, Lin CM, Jang TH, Tu CW, Lee YR, Lee YH, Tien MT, Wang LH. (2014) MicroRNA-149 targets GIT1 to suppress breast cancer metastasis. Oncogene 33(36):4496-507
- Lin KT, Yeh YM, Chuang CM, Yang SY, Chang JW, Sun SP, Wang YS, Chao KC, Wang LH. (2015) Glucocorticoids Mediate Induction of MicroRNA-708 to Suppress Ovarian Cancer Cell Invasion and Metastasis through Targeting Rap1B. Nature Comm Jan 8;6:5917. doi: 10.1038/ncomms6917