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Liu Lab
(Dr. Kebin Liu)
From left Kebin Liu, Feiyan Liu, Mary Zimmerman, Dafeng Yang, and Lynn Hu
Research Interests:
Cytotoxic T Lymphocytes and cancer immunosurveillance
Apoptosis resistance, immune evasion and tumor escape/progression
Epigenetic regulation of tumor suppressor gene
Research Program:
The immune system constantly detects and eliminates proneoplastic cells long before the development of clinical cancer. Tumor-specific immune responses can also be induced in cancer-bearing hosts via active or adaptive immunotherapy. Yet tumors still develop in an immune-competent host, and complete tumor eradication occurs infrequently in vivo. The biologic failure of the immune system to effectively suppress neoplastic disease in immune-competent hosts is not fully understood and has remained a fundamental paradox of tumor immunobiology. Our research program is in the areas of cancer immunology and biology and reflects two fundamental aspects of tumor immunobiology: 1) the dynamic nature of the host T lymphocyte-tumor cell interaction in the tumor microenvironment; and 2) the molecular mechanisms underlying apoptosis resistance, inflammation and tumor progression.
Model of immune cell and tumor cell interactions: when tumor cells arise in normal tissue, an inflammatory response is induced which attracts immune cells migrating to the tumor site. Interactions between immune cells and tumor cells involve direct cell-cell physical contact and release of modulator molecules (i.e. IFN-γ, TNFα and many other molecules). In this life and death battle, on the one hand, the immune cells may prevail and eradicate the tumor. On the other hand, tumor cells can counterattack the immune cells by producing inhibitory molecules, manipulating the immune suppressive cells, or acquiring resistant mechanisms to avoid induction of apoptosis by the immune cells. Thus, the anti-tumor immune response can be a two-edged sword and can result in both positive and negative consequences.
Cytotoxic T lymphocytes (CTLs) are the primary effector cells against tumor cells. CTLs function primarily through two effector mechanisms. The first cytolytic pathway of the CTLs depends on the polarized secretion of perforin and granzymes. The second effector mechanism involves the interaction of FasL on activated CTLs with its receptor Fas on the target tumor cells. Although perforin- and Fas-mediated cytotoxic effector mechanisms are critically important for suppression of tumor development, recent studies have demonstrated the importance of perforin- and Fas-independent effector mechanisms of tumor-specific CTLs in tumor rejection. Our cancer immunobiology research program focuses on the function of Fas-mediated effector mechanism and the perforin- and Fas-independent cytotoxic mechanisms of the tumor specific CTL in tumor rejection.
The anti-tumor immune response is a two-edged sword. The immune system consistently monitors the host and suppresses tumor development. However, at the same time, the anti-tumor immune response can also “edit” the tumor cells, and promotes or selects tumor escape variants with enhanced resistance to the extrinsic cytotoxicity of the immune system. This phenomenon is conceptually akin to the generation of antibiotic-resistant bacteria, or chemoresistant neoplastic clones. Among the multiple mechanisms, acquisition of resistance to apoptosis is a hallmark of tumor escape and progression. As the neoplastic process becomes more progressive, the resulting subpopulations of tumor cells tend to exhibit a more apoptotic-resistant phenotype. Accordingly, our cancer biology research program focuses on apoptosis resistance and tumor progression. Our major interest is to elucidate the molecular mechanisms underlying epigenetic mechanism-mediated silencing of tumor suppressors and other genes that are important in inflammation, apoptosis and metastasis.
Selected Publications:
Haoming Chen, Genfeng Zhu, Yong Li, Ravi N. Padia, Zheng Dong, Zhixing K. Pan, Kebin Liu and Shuang Huang. 2009. Extracellular Signal-Regulated Kinase Signaling Pathway Regulates Breast Cancer Cell Migration by Maintaining slug Expression. Cancer Res. [In Press].
Cresci, G. A., Thangaraju, M., Mellinger, J. D., Liu, K., and Ganapathy, V. 2009. Colonic gene expression in conventional and germ-free mice with a focus on the butyrate receptor GPR109A and the butyrate transporter SLC5A8. J Gastrointestinal Sur. [in press].
Trina Stewart, Kristy Greeneltch, Julia Reid, David Liewehr, Seth Steinberg, Kebin Liu and Scott Abrams. 2009. Interferon Regulatory Factor-8 Modulates the Development of Tumor-Induced CD11b+Gr1+ Myeloid Cells. J Cell Mol Med. In Press.
Ganapathy V, Moister B, Roon P, Mysona B, Duplantier JN, Dun Y, Moister TV, Farley MJ, Prasad PD, Kebin Liu, Smith SB. Endogenous Elevation of Homocysteine Induces Retinal Neuron Death in the Cystathionine-b-synthase Mutant Mouse. Invest Ophthalmol Vis Sci [In Press]. 2009.
Muthusamy Thangaraju, Gail Cresci, Kebin Liu, Sudha Ananth, Jaya Gnanaprakasam, Darren Browning, John Mellinger, Sylvia Smith, Gregory Digby, Nevin Lambert, Puttur Prasad, and Vadivel Ganapathy. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 69:2826-32. 2009.
Dafeng Yang, Suizhao Wang, Craig Brooks, Zheng Dong, Patricia Schoenlein, Vijay Kumar, Xinshou Ouyang, Huabao Xiong, Guy Lahat, Andrea Hayes-Jordan, Alexander Lazar, Raphael Pollock, Dina Lev and Kebin Liu. IRF8 Sensitizes Soft Tissue Sarcoma Cells to Death Receptor-initiated Apoptosis via Repression of FLIP Expression. Cancer Res. 69:1080-1088. 2009.
Navjotsingh Pabla, Robert F. Murphy, Kebin Liu, and Zheng Dong. 2009. The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity. Am J. Physiol. Renal Physiol. 296(3):F505-11. 2009.
Jon M. McGough, Dafeng Yang, Shuang Huang, David Georgi, Stephen M. Hewitt, Christoph Röcken, Marc Tänzer, Matthias P. A. Ebert, and Kebin Liu. 2008. DNA Methylation Represses IFN-&gamma-induced and STAT1-mediated IRF8 Activation in Colon Carcinoma Cells. Mol Cancer Res. 6:1841-1851.
Dafeng Yang, Trina I. Stewart, Kimberly, K. Smith, David Georgi, Scott I. Abrams, and Kebin Liu. 2008. Downregulation of IFN-&gammaR in Association with Loss of Fas Function is Linked to Tumor Progression. Int. J. Cancer. 122:350-362.
Kirti Bhatt, Leping Feng, Navjotsingh Pabla, Kebin Liu, Sylvia Smith, Zheng Dong. 2008 Effects of targeted Bcl-2 expression in mitochondria or endoplasmic reticulum on renal tubular cell apoptosis. Am J. Physiol. Renal Physiol. 294:F499-F507.
In-Kiu Kwon, Patricia V. Schoenlein, Jennifer Delk, Kebin Liu, Muthusmy Thangaraju, Nickolai Dulin, Vadivel Ganapathy, Franklin Berger, and Darren D. Browning. 2008. Expression of PKG in Metastatic Colon Carcinoma Cells Blocks Tumor Angiogenesis. Cancer. 112:1462-1470.
Kristy M. Greeneltch, Monika Schneider, Seth M. Steinberg, David J. Liewehr, Trina J. Stewart, Kebin Liu, and Scott Abrams. 2007. Host Immunosurveillance Controls Tumor Growth via IRF-8-Dependent Mechanisms. Cancer Res. 67:10406-10416.
Dafeng Yang, Muthusamy Thangaraju, Darren D. Browning, Zheng Dong, Borys Korchin, Dina C. Lev, Vadivel Ganapathy, and Kebin Liu. 2007. Interferon Regulatory Factor 8 Mediates Apoptosis in Non-hemopoietic Tumor Cells via Regulation of Fas Expression. J. Immunol. 179:4775-4782.
Dafeng Yang, Najam ud Din, Darren D. Browning, Scott I. Abrams, and Kebin Liu. 2007. Targeting Lymphotoxin b Receptor with Tumor-Specific T Lymphocytes for Tumor Regression. Clin Cancer Res. 13:5202-5210.
Dafeng Yang, Muthusmy Thangaraju, Kristy Greeneltch, Darren Browning, Patricia Schoenlein, Tomohiko Tamura, Keiko Ozato, Vadivel Ganapathy, Scott I. Abrams, and Kebin Liu. 2007. Repression of IRF8 by DNA Methylation is a Molecular Determinant of Apoptotic Resistant and Metastatic Phenotype in Metastatic Tumor Cells. Cancer Res. 67:3301-3309.
Akio Ohta, Elieser Gorelik, Simon Prasad, Franca Ronchese, Dmitriy Lukashev, Michael Wong, Xiaojun Huang, Sheila Caldwell, Kebin Liu, Patrick Smith, Jiang-Fan Chen, Edwin Jackson, Sergey Apasov, Scott Abrams, Michail Sitkovsky. 2006. A2A Adenosine Receptor Protects Tumors From Anti-tumor T cells. Proc. Natl. Acad. Sci. USA. 103:13132-13137.
Kebin Liu*, Sheila A. Caldwell*, Kristy Greeneltch, Dafeng Yang and Scott Abrams. 2006. CTL Adoptive Immunotherapy Concurrently Mediates Tumor Regression and Tumor Escape. J. Immunol. 176:3374-3382. (* equal contribution).
Kebin Liu, Sheila A. Caldwell and Scott I. Abrams. 2005. Immune Selection and Emergence of Aggressive Tumor Variants as Negative Consequence of Fas-mediated Cytotoxicity and Altered IFNg-regulated Gene Expression. Cancer Res. 65:4376-4388.
Kebin Liu, Sheila Caldwell and Scott I. Abrams. 2005. Cooperative Disengagement of Fas and ICAM-1 in Neoplastic Cells Confers Enhanced Colonization Efficiency. Cancer Res. 65:1045-1054.
Kebin Liu, Elwood McDuffie and Scott I. Abrams. 2003. Exposure of Human Primary Colon Carcinoma Cells to Anti-Fas Interactions Influences the Emergence of Pre-existing Fas-Resistant Metastatic Subpopulations. J. Immunol. 171:4164-4174.
Kebin Liu and Scott I. Abrams. 2003. Coordinate Regulation of ICSBP and Caspase-1 in the Sensitization of Human Colon Carcinoma Cells to Fas-Mediated Apoptosis by IFN-g. J. Immunol 170:6329-6337.
Kebin Liu and Scott I. Abrams. 2003. Alterations in Fas Expression are Characteristic of, but not Solely Responsible for, Enhanced Metastatic Competence. J. Immunol. 170:5973-5980.
Mala Chakraborty, Scott I. Abrams, Kevin Camphausen, Kebin Liu, Tamalee Scott, C. Norman Coleman, and James W. Hodge. 2003. Irradiation of Tumor Cells Upregulates Fas, Enhances CTL Lytic Activity and CTL Adoptive Immunotherapy. J. Immunol. 170:6338-6347.
Kebin Liu, Marta Catalfamo, Yu Li, Pierre A. Henkart, and Nan-ping Weng. 2002. IL15 mimics T cell receptor crosslinking in the induction of cellular proliferation, gene expression, and cytotoxicity in CD8+ memory T cells. Proc. Natl. Acad. Sci. USA. 99:6192-6197.
Kebin Liu, Yu Li, Vinayakumar Prabhu, Lynn Young, Kevin Becker, Peter Munson, and Nan-ping Weng. 2001. Augmentation in Expression of Activation-induced Genes Differentiates Memory from Naïve CD4+T Cells and Is a Molecular Mechanism of Enhanced Cellular Response of Memory CD4+ T Cells. J. Immunol. 166:7335-7344.
Kebin Liu, Richard J. Hodes and Nan-Ping Weng. 2001. Cutting Edge:Telomerase Activation in Human T Lymphocytes Does Not Require Increase in Telomerase Reverse Transcriptase (hTERT) Protein But Is Associated with hTERT Phosphorylation and Nuclear Translocation. J. Immunol. 166:4826-4830.
Kebin Liu, Michelle M. Schoonmaker, Bruce L. Levine, Carl H. June, Richard J. Hodes and Nan-Ping Weng. 1999. Constitutive and regulated expression of telomerase reverse transcriptase (hTERT) in human lymphocytes. Proc. Natl. Acad. Sci. USA. 96:5147-5152.
Kebin Liu and Guangpu Li. 1998. Catalytic domain of the p120 Ras GAP binds to Rab5 and stimulates its GTPase activity. J. Biol. Chem. 273:10087-10090.
Michelle M. Hanna and Kebin Liu. 1998. Nascent RNA in transcription complexes interacts with CspE, a small protein in E. coli implicated in chromatin condensation. J. Mol. Biol. 282:227-239.
Kebin Liu, Yuying Zhang, Konstantin Severinov, Asis Das and Michelle M. Hanna. 1996. Role of Escherichia coli RNA polymerase alpha subunit in mudulation of pausing, termination and anti-termination by transcription elongation factor NusA. The EMBO J. 15:150-161.
Kebin Liu and Shauna Somerville. 1996. Cloning and characterization of a highly repeated DNA sequence in Hordeum vulgare L. Genome. 39:1159-1168.
Kebin Liu and Michelle M. Hanna. 1995. NusA contacts nascent RNA in Escherichia coli transcription complexes. J. Mol. Biol. 247:547-558.
Kebin Liu and Michelle M. Hanna. 1995. NusA interferes with interactions between the nascent RNA and the C-terminal domain of the alpha subunit of RNA polymerase in Escherichia coli transcription complexes. Proc. Natl. Acad. Sci. USA. 92:5012-5016.