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    Last Name

    Jason J Chen PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Virology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentCenter for AIDS Research


        Academic Background

        B.S., 1982, Shandong University
        Ph.D., 1991, Columbia University

        Cell cyclecheckpoints, genomic instability,and apoptosisin cells expressing papillomavirus oncogenes

        Photo: Jason J Chen, PhDInfection with human papillomaviruses (HPV) induces warts and is strongly associated with the development of cervical cancer. Two viral genes, E6 and E7, are necessary for HPV-induced malignancy. The mechanism by which HPV induces a tumor is not fully understood. Specific and effective therapies for HPV infection or HPV-induced malignancies are currently not available. Although the HPV vaccine is available, a prophylactic HPV vaccine will not be effective for those who are already infected with HPV or immunocompromised. Our long-term goal is to elucidate the molecular basis for HPV-associated cancers and to develop strategies for preventing and treating HPV-induced cancers.

        1. Induction of genomic instability by HPV oncogenes E6 and E7

        Polyploidy occurs as an early event during cervical carcinogenesis and predisposes cells to aneuploidy and chromosomal instability. Expression of the HPV E6 and E7 oncogenes in human keratinocytes leads to polyploidy in response to mitotic stress and DNA damage. Previously, it was thought that E6 and E7 induce polyploidy after microtubule disruption by abrogating the spindle checkpoint through degradation of the tumor suppressor p53 and pRb, respectively. However, our results demonstrate that E6 and E7 abrogate the postmitotic checkpoint to induce polyploidy. Interestingly, an E6 mutant defective in p53 degradation also induced polyploidy with lower efficiency and increased-apoptosis. Furthermore, some cyclins/cdks and c-Myc appear to play a role in E6 and E7-induced polyploidy. We also found that E7 induces DNA re-replication in response to DNA damage. Therefore we hypothesize that E6 induces polyploidy through both p53-dependent and p53-independent functions; activation of specific cyclins/cdks and c-Myc plays a role in this process; and this induction of polyploidy contributes to genomic instability. We are currently in the process of exploring the mechanism by which E6 and E7 abrogate the postmitotic checkpoint. These studies will shed light on mechanisms by which HPV induces polyploidy and genomic instability and should have preventive and therapeutic implications.

        2. Role of Cdc2 HPV E6-mediated apoptotic

        HPV E6 induces apoptosis in cervical cancer precursor lesions and cultured cells. Interestingly, this E6 function is attenuated in cervical cancer cells. The mechanism of E6-mediated apoptosis is poorly understood, nor do we know much about how apoptosis is reduced during the carcinogenesis. Our goal is to understand how apoptosis is induced in pre-malignant cells by E6 and how these mechanisms are overcome during tumor progression. We have shown that E6 sensitizes human keratinocytes to apoptosis. Using a proteomic approach, we found that the cell cycle-related Cdc2 protein is differentially expressed during E6-mediated apoptosis. Moreover, alteration of Cdc2 reduced apoptosis in E6 expressing cells. We are in the process of testing the hypothesis that modulation of Cdc2 plays an important role in E6-mediated cellular sensitization to apoptosis. We would also like to understand the role of anti-apoptotic proteins play in the development of cervical cancer.

        3. Identification and characterization of cervical cancer stem cells

        There is growing evidence to support the cancer stem cell concept, which hypothesizes that tumor cells are a mixture comprised of rare stem-like cells and abundant non-tumor initiating cells. Cells with stem cell properties have been identified in a range of tumors. However, we know very little about stem cells in the cervix or cervical cancer. Identification of cervical cancer stem cells is important since the eradication of many cancers by current therapies often leaves the originating transformed stem cells behind to cause potential relapse. Using the drug-resistance property of stem cells, we have recently identified putative stem cells from multiple cervical cancer cell lines. Our preliminary studies demonstrate that these cells have characteristics of stem cells, i.e., slow proliferation, resistance to the chemotherapeutic drug, and self-renewal. In addition and significantly, we have identified an embryonic stem cell marker that is expressed specifically in the cervical transformation zone where manifestations of cervical carcinogenesis occur. Future studies will further characterize these cells for stem cell properties and its relation with HPV infection and carcinogenesis. We also plan to identify drugs that are effective against the putative tumor stem cells.

        4. Prevention and therapy of HPV-associated malignancies

        Approximately half of the drugs currently used in the clinic are of natural product origin. The crude extract of the herb B. javanica has shown impressive efficacy for treating various diseases including cancer in China. Our preliminary studies have demonstrated a tumor specific growth inhibition and apoptosis induction in cervical cancer cells by B. javanica. Significant increase of the steady-state level of the tumor suppressor p53 was observed. However, the major bioactive ingredient(s) of B. javanica responsible for induction of apoptosis in cervical cancer cells remains to be identified. Our recent attempt to identify bioactive ingredients from the aqueous extract of B. javanica using Liquid chromatography (LC)/mass spectrometry (MS)has demonstrated a number of fractions with cell toxicity and corresponding peaks. These preliminary results suggest that our approach may allow the further separation, isolation and identification of several active constituents in the extract. We are currently in the process of identifying and characterizing bioactive ingredients from an aqueous extract of B. javanica using a combination of techniques including LC/MS and nuclear magnetic resonance. These studies may lead to a novel therapeutic treatment against HPV-associated malignancies.

        Rotation Projects

        Potential Rotation Project

        Role of cell cycle-related proteins in E6-induced polyploidy. Through genetic and molecular approaches, we will determine the role and mechanism by which the cell cycle-related proteins abrogates the postmitotic checkpoint in E6 expressing cells.

        Role of anti-apoptotic proteins in cervical carcinogenesis. The goal of this project is to understand the role of anti-apoptotic proteins in the development of cervical cancer.

        Mechanism underlying HPV E7-induces re-replication. Through biochemistry and molecular approaches, we will determine the extent to which DNA replication initiating factors are required for HPV-E7 to induce re-replication.

        Identification and characterization of cervical stem cells. Using known markers combined with functional assays, we will identify and characterize stem cells from cervix and examine their role in tumorigenesis.

        selected publications
        List All   |   Timeline
        1. Zhang X, Chen H, Wang X, Zhao W, Chen JJ. Expression and transcriptional profiling of the LKB1 tumor suppressor in cervical cancer cells. Gynecol Oncol. 2014 Aug; 134(2):372-8.
          View in: PubMed
        2. Fan X, Liu Y, Heilman SA, Chen JJ. Human papillomavirus E7 induces rereplication in response to DNA damage. J Virol. 2013 Jan; 87(2):1200-10.
          View in: PubMed
        3. Fan X, Liu Y, Heilman S, and Chen JJ. The Human Papillomavirus E7 Induces Re-replication in Response to DNA Damage. J Virol. 2012.
        4. Zhang W, Li J, Kanginakudru S, Zhao W, Yu X, Chen JJ. The human papillomavirus type 58 E7 oncoprotein modulates cell cycle regulatory proteins and abrogates cell cycle checkpoints. Virology. 2010; 397:139-44.
        5. Heilman SA, Nordberg JJ, Liu Y, Sluder G, Chen JJ. Abrogation of the postmitotic checkpoint contributes to polyploidization in human papillomavirus E7-expressing cells. J Virol. 2009; 83:2756-64.
        6. Liu ZG, Zhao LN, Liu YW, Li TT, Fan DM, Chen JJ. Activation of Cdc2 contributes to apoptosis in HPV E6 expressing human keratinocytes in response to therapeutic agents. J Mol Biol. 2007; 374:334-45.
        7. Liu Y, Heilman SA, Illanes D, Sluder G, Chen JJ. p53-independent abrogation of a postmitotic checkpoint contributes to human papillomavirus E6-induced polyploidy. Cancer Res. 2007; 67:2603-10.
        8. Liu Y, Liu Z, Gao H, Zhou Y, Androphy EJ, Chen JJ. Opposing effects of bovine papillomavirus type 1 E6 and E7 genes on Fas-mediated apoptosis. Oncogene. 2005; 24:3942-53.
        9. Fan X, Liu Y, Chen JJ. Activation of c-Myc contributes to bovine papillomavirus type 1 E7-induced cell proliferation. J Biol Chem. 2003; 278:43163-8.
        10. Liu Y, Hong Y, Androphy EJ, Chen JJ. Rb-independent induction of apoptosis by bovine papillomavirus type 1 E7 in response to tumor necrosis factor alpha. J Biol Chem. 2000; 275:30894-900.
        11. Rapp L, Liu Y, Hong Y, Androphy EJ, Chen JJ. The bovine papillomavirus type 1 E6 oncoprotein sensitizes cells to tumor necrosis factor alpha-induced apoptosis. Oncogene. 1999; 18:607-15.
        12. Chen JJ, Hong Y, Rustamzadeh E, Baleja JD, Androphy EJ. Identification of an alpha helical motif sufficient for association with papillomavirus E6. J Biol Chem. 1998; 273:13537-44.
        13. Chen JJ, Reid CE, Band V, Androphy EJ. Interaction of papillomavirus E6 oncoproteins with a putative calcium-binding protein. Science. 1995; 269:529-31.
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