In recent years, there has been a growing recognition of the importance of tumor associated microenvironment in the initiation and progression of tumors. However, a mechanistic understanding of the complicated biological interplay between the stromal framework and malignant regions of the tumor remains incompletely understood. In this study, we address mechanisms by which hypoxia in the tumor microenvironment leads to attenuation of miRNA biogenesis by downregulation of two key enzymes, Drosha and Dicer in cancer cells. Previous data from our laboratory had shown the clinical relevance of downregulated Dicer and Drosha in ovarian and other cancer types, but a clear mechanistic understanding is needed for future clinical intervention strategies to curb deleterious effect of miRNA biogenesis downregulation. Using several in vitro techniques, orthotopic in vivo models and clinical patient samples, we demonstrate novel deregulatory mechanisms involved in Dicer and Drosha downregulation under hypoxia. Data from deep sequencing of normoxia and hypoxia treated cells demonstrate clear effect of this downregulation on miRNA maturation. Collectively, we show substantial functional effects of this downregulation on cancer progression under in vivo conditions by use of siRNAs incorporated in liposomes mediated gene silencing. Our work will provide the missing links for this mechanistic understanding, with a goal of novel interventions to rescue the Dicer and Drosha-miRNA biogenesis pathway. The findings described in this thesis have significant clinical implications with respect to understanding mechanisms of tumor growth and metastasis and the design of new therapeutic approaches in cancers.
","abstract_html":"<p>In recent years, there has been a growing recognition of the importance of tumor associated microenvironment in the initiation and progression of tumors. However, a mechanistic understanding of the complicated biological interplay between the stromal framework and malignant regions of the tumor remains incompletely understood. In this study, we address mechanisms by which hypoxia in the tumor microenvironment leads to attenuation of miRNA biogenesis by downregulation of two key enzymes, Drosha and Dicer in cancer cells. Previous data from our laboratory had shown the clinical relevance of downregulated Dicer and Drosha in ovarian and other cancer types, but a clear mechanistic understanding is needed for future clinical intervention strategies to curb deleterious effect of miRNA biogenesis downregulation. Using several <em>in vitro</em> techniques, orthotopic <em>in vivo</em> models and clinical patient samples, we demonstrate novel deregulatory mechanisms involved in Dicer and Drosha downregulation under hypoxia. Data from deep sequencing of normoxia and hypoxia treated cells demonstrate clear effect of this downregulation on miRNA maturation. Collectively, we show substantial functional effects of this downregulation on cancer progression under <em>in vivo</em> conditions by use of siRNAs incorporated in liposomes mediated gene silencing. Our work will provide the missing links for this mechanistic understanding, with a goal of novel interventions to rescue the Dicer and Drosha-miRNA biogenesis pathway. The findings described in this thesis have significant clinical implications with respect to understanding mechanisms of tumor growth and metastasis and the design of new therapeutic approaches in cancers.</p>","abstract_has_math":false,"creators":["rupaimoole, rajesha"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Anil Sood","Eric J Wagner","Gary E Gallick"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-12-01T08:00:00Z","date_published":"2014-12-01T08:00:00Z","updated_at":"2026-07-24T05:49:16Z","subjects":["miRNAs","Ovarian Cancer","Hypoxia","Medicine and Health Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/527","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Anil Sood","Eric J Wagner","Gary E Gallick"]},{"key":"dc:creator","label":"Author","values":["rupaimoole, rajesha"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2015-12-04T08:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation (PhD)"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["miRNAs","Ovarian Cancer","Hypoxia","Medicine and Health Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/527"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["In recent years, there has been a growing recognition of the importance of tumor associated microenvironment in the initiation and progression of tumors. However, a mechanistic understanding of the complicated biological interplay between the stromal framework and malignant regions of the tumor remains incompletely understood. In this study, we address mechanisms by which hypoxia in the tumor microenvironment leads to attenuation of miRNA biogenesis by downregulation of two key enzymes, Drosha and Dicer in cancer cells. Previous data from our laboratory had shown the clinical relevance of downregulated Dicer and Drosha in ovarian and other cancer types, but a clear mechanistic understanding is needed for future clinical intervention strategies to curb deleterious effect of miRNA biogenesis downregulation. Using several in vitro techniques, orthotopic in vivo models and clinical patient samples, we demonstrate novel deregulatory mechanisms involved in Dicer and Drosha downregulation under hypoxia. Data from deep sequencing of normoxia and hypoxia treated cells demonstrate clear effect of this downregulation on miRNA maturation. Collectively, we show substantial functional effects of this downregulation on cancer progression under in vivo conditions by use of siRNAs incorporated in liposomes mediated gene silencing. Our work will provide the missing links for this mechanistic understanding, with a goal of novel interventions to rescue the Dicer and Drosha-miRNA biogenesis pathway. The findings described in this thesis have significant clinical implications with respect to understanding mechanisms of tumor growth and metastasis and the design of new therapeutic approaches in cancers.
"]},{"key":"dc:title","label":"Title","values":["Hypoxia Mediated Downregulation of Mirna Biogenesis Leads to Increased Tumor Progression"]}]}],"canonical_facts":{"dc:contributor":["Anil Sood","Eric J Wagner","Gary E Gallick"],"dc:creator":["rupaimoole, rajesha"],"dc:date.available":["2015-12-04T08:00:00Z"],"dc:description.abstract":["In recent years, there has been a growing recognition of the importance of tumor associated microenvironment in the initiation and progression of tumors. However, a mechanistic understanding of the complicated biological interplay between the stromal framework and malignant regions of the tumor remains incompletely understood. In this study, we address mechanisms by which hypoxia in the tumor microenvironment leads to attenuation of miRNA biogenesis by downregulation of two key enzymes, Drosha and Dicer in cancer cells. Previous data from our laboratory had shown the clinical relevance of downregulated Dicer and Drosha in ovarian and other cancer types, but a clear mechanistic understanding is needed for future clinical intervention strategies to curb deleterious effect of miRNA biogenesis downregulation. Using several in vitro techniques, orthotopic in vivo models and clinical patient samples, we demonstrate novel deregulatory mechanisms involved in Dicer and Drosha downregulation under hypoxia. Data from deep sequencing of normoxia and hypoxia treated cells demonstrate clear effect of this downregulation on miRNA maturation. Collectively, we show substantial functional effects of this downregulation on cancer progression under in vivo conditions by use of siRNAs incorporated in liposomes mediated gene silencing. Our work will provide the missing links for this mechanistic understanding, with a goal of novel interventions to rescue the Dicer and Drosha-miRNA biogenesis pathway. The findings described in this thesis have significant clinical implications with respect to understanding mechanisms of tumor growth and metastasis and the design of new therapeutic approaches in cancers.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/527"],"dc:subject":["miRNAs","Ovarian Cancer","Hypoxia","Medicine and Health Sciences"],"dc:title":["Hypoxia Mediated Downregulation of Mirna Biogenesis Leads to Increased Tumor Progression"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:49:16Z"}