Causes Of Cancer Research And Genetic Development Of Ceervical Cancer

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RESEARCH STRATEGY A. SIGNIFICANCE Cervical cancer incidence in the United States has decreased dramatically since the development of the human papillomavirus (HPV) vaccine in 2006. The vaccine, in combination with regular cervical cytological screenings (Pap tests), has since rendered cervical cancer preventable (1,2). However, worldwide cervical cancer incidence and mortality rates remain high, with 528,000 new cases and 266,000 deaths reported in 2012 (3). Critical barriers to progress in cervical cancer research and therapeutic development are evident: most people with HPV infections do not develop cervical cancer (4), and not all cervical cancers are HPV-induced (5,6). Moreover, not all causes of cervical cancer are known (7), and…show more content…
We have also shown that MALAT1, SRSF1, and SRSF protein kinase 1 (SRPK1) form a complex. Interestingly, SRSF1 has been demonstrated to stabilize tumor suppressor p53 by preventing its ubiquitin-proteasome system-mediated degradation via complex formation with mouse double minute 2 homolog (Mdm2), a ubiquitin ligase, in the nucleus (20). The resulting phenomenon is oncogene-induced senescence (OIS) (21), a protective antiproliferative mechanism activated by oncogenic signaling upon stress-induced inactivation of a tumor suppressor. Based on our preliminary results, in conjunction with literature evidence, we hypothesize that MALAT1 overexpression disrupts RRM2 and RS domain interaction in SRSF1, subsequently impairing RS domain phosphorylation and SRSF1 nuclear translocation. This change in subcellular localization destabilizes p53, leading to loss of OIS in HPV-negative cervical cancer (HNCC). The goal of our lab is to examine the role of MALAT1 in SRSF1/p53-mediated OIS via HNCC in vitro (Aim 1) and in vivo (Aim 2) experimental models utilizing MALAT1-specific antisense oligonucleotide (ASO) therapy. Completion of this project will lead to a clearer understanding of whether MALAT1 is an underlying cause of HNCC development. The results generated from this proposal will improve scientific knowledge and clinical practices by providing a new MALAT1-mediated mechanism underlying HNCC tumorigenesis and

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