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 permanent cell cycle arrest. It is known that KSHV triggers the signals that would normally lead to OIS, but KSHV-infected cells escape these signals and progress through the cell cycle. We have shown that the presence of the KSHV miRNAs is required to escape oncogene-induced senescence. Our preliminary work suggests that KSHV miRNAs strongly and specifically inhibit a key inducer of OIS. We believe that the proposed research will lead to critical insights into how KSHV causes cancer. We also expect that our research will result in important insights into how miRNAs in general contribute to the development of cancers. Because miRNAs have been studied only in the last decade, a detailed mechanistic understanding of their roles in cancer has so far mostly remained elusive. Because the clinical inhibition of miRNAs is feasible, viral or human miRNAs and the mechanisms by which they cause cancer may also become attractive targets for therapeutic strategies.
|Effective start/end date||7/1/16 → 12/31/20|
- American Cancer Society (RSG-16-061-01-RMC)