Deregulation of tumor suppressive pathways by KSHV microRNAs

Cancer is a consequence of the uncontrolled survival and multiplication of diseased cells. It may result from alterations (“mutations”) to the genetic material in affected cells or, in ~10-20% of cancers, from viral infection. Kaposi’s Sarcoma-associated herpesvirus (KSHV) causes Kaposi’s Sarcoma (KS), mainly in individuals with acquired immunodeficiency syndrome (AIDS). KS is the most common AIDS-associated cancer and, due to the AIDS epidemic, it has become the most common cancer in African men. KS also represents an emerging concern in the aging population of non-AIDS HIV patients in the United States and elsewhere. In addition to KS, KSHV causes rare, but very aggressive B cell primary effusion lymphoma, or PEL. Cancer researchers and virologists still do not understand completely how KSHV causes cancer. As a recipient of an American Cancer Society Scholars grant, I plan to investigate the role of newly identified viral regulators in the deregulation of cell multiplication by KSHV. KSHV produces several small molecules, called microRNAs (miRNAs), which we believe help KSHV overcome cellular barriers to cancer. When cells multiply, they undergo a series of events, collectively referred to as the cell cycle. Normal cells have built-in controls that ensure they stop multiplying, i.e. undergo “cell cycle arrest”, when cancerous changes, such as tumor virus infection, are present. We have discovered that several of the KSHV miRNAs could enable cells to evade these controls and thereby make them more susceptible to cancer. In Aim 1, we propose to investigate how the KSHV miRNAs escape the repressive effects of a molecule called transforming growth-factor beta (TGF-beta). It is unclear how KSHV infected cells become resistant to TGF-beta and our data suggest that KSHV miRNAs are important for this evasion. In Aim 2, we propose to investigate how the KSHV miRNAs antagonize a defense mechansims called oncogene-induced senescence (OIS), which leads to permanen