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Metabolic Regulation in Glioblastoma and Its Association with Sex-Specific Survival- [electronic resource]
Metabolic Regulation in Glioblastoma and Its Association with Sex-Specific Survival- [electronic resource]
상세정보
- 자료유형
- 학위논문파일 국외
- 최종처리일시
- 20240214101939
- ISBN
- 9798380198462
- DDC
- 616.99
- 저자명
- Troike, Katie.
- 서명/저자
- Metabolic Regulation in Glioblastoma and Its Association with Sex-Specific Survival - [electronic resource]
- 발행사항
- [S.l.]: : Case Western Reserve University., 2022
- 발행사항
- Ann Arbor : : ProQuest Dissertations & Theses,, 2022
- 형태사항
- 1 online resource(199 p.)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
- 주기사항
- Advisor: Lathia, Justin;Yu, Jennifer.
- 학위논문주기
- Thesis (Ph.D.)--Case Western Reserve University, 2022.
- 사용제한주기
- This item must not be sold to any third party vendors.
- 사용제한주기
- This item must not be added to any third party search indexes.
- 초록/해제
- 요약Glioblastoma (GBM) is the most common primary brain tumor in adults and exhibits therapeutic resistance, recurrence, and poor prognosis. Hence, novel therapeutic strategies for outcomes in these patients are urgently needed. GBM tumor cells modulate expression of iron-associated genes to enhance iron uptake from the surrounding microenvironment, driving proliferation and tumor growth. The translocator protein 18kDa (TSPO) plays crucial roles in essential mitochondria-based physiological processes and is a validated biomarker of neuroinflammation, which is implicated in GBM progression. The TSPO gene has a germline single nucleotide polymorphism, rs6971, which is the most common SNP in the Caucasian population. We retrospectively analyzed the correlation of the TSPO polymorphic variant rs6971 with overall and progression-free survival in GBM patients using three independent cohorts. The rs6971 polymorphism was significantly associated with shorter overall survival and progression-free survival in male GBM patients but not in females in one large cohort and similar trends were observed in two other independent cohorts. GBM growth and progression can also be driven by enhanced iron uptake from the surrounding microenvironment by tumor cells. The HFE gene, encoding the iron sensing HFE protein, is upregulated in GBM and correlates with poor survival outcomes. However, the molecular mechanisms underlying these observations remain unclear. We interrogated the impact of cell-intrinsic Hfe expression on proliferation and tumor growth through genetic loss and gain of function approaches in syngeneic mouse glioma models. Loss of Hfe induced apoptotic cell death in vitro and inhibited tumor growth in vivo while overexpression of Hfe accelerated both proliferation and tumor growth. Analysis of iron gene signatures in Hfe knockdown cells revealed alterations in the expression of several iron-associated genes, suggesting global disruption of intracellular iron homeostasis. Analyzing differentially expressed pathways further identified oxidative stress as the top pathway upregulated with Hfe loss. Enhanced 55Fe uptake and generation of reactive oxygen species (ROS) were found with Hfe knockdown, implicating toxic iron overload resulting in apoptotic cell death. Collectively, these findings identify a novel role for TSPO in GBM prognosis and for HFE in regulating iron homeostasis in GBM tumors, providing potential avenues for future diagnostic and therapeutic development.
- 일반주제명
- Oncology.
- 일반주제명
- Biology.
- 일반주제명
- Molecular biology.
- 일반주제명
- Cellular biology.
- 키워드
- Glioblastoma
- 키워드
- Iron
- 키워드
- Sex differences
- 기타저자
- Case Western Reserve University Molecular Medicine
- 기본자료저록
- Dissertations Abstracts International. 85-03B.
- 기본자료저록
- Dissertation Abstract International
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520240214101939
■006m o d
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■020 ▼a9798380198462
■035 ▼a(MiAaPQ)AAI30725327
■035 ▼a(MiAaPQ)OhioLINKcase1657296205870864
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a616.99
■1001 ▼aTroike, Katie.
■24510▼aMetabolic Regulation in Glioblastoma and Its Association with Sex-Specific Survival▼h[electronic resource]
■260 ▼a[S.l.]:▼bCase Western Reserve University. ▼c2022
■260 1▼aAnn Arbor :▼bProQuest Dissertations & Theses, ▼c2022
■300 ▼a1 online resource(199 p.)
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-03, Section: B.
■500 ▼aAdvisor: Lathia, Justin;Yu, Jennifer.
■5021 ▼aThesis (Ph.D.)--Case Western Reserve University, 2022.
■506 ▼aThis item must not be sold to any third party vendors.
■506 ▼aThis item must not be added to any third party search indexes.
■520 ▼aGlioblastoma (GBM) is the most common primary brain tumor in adults and exhibits therapeutic resistance, recurrence, and poor prognosis. Hence, novel therapeutic strategies for outcomes in these patients are urgently needed. GBM tumor cells modulate expression of iron-associated genes to enhance iron uptake from the surrounding microenvironment, driving proliferation and tumor growth. The translocator protein 18kDa (TSPO) plays crucial roles in essential mitochondria-based physiological processes and is a validated biomarker of neuroinflammation, which is implicated in GBM progression. The TSPO gene has a germline single nucleotide polymorphism, rs6971, which is the most common SNP in the Caucasian population. We retrospectively analyzed the correlation of the TSPO polymorphic variant rs6971 with overall and progression-free survival in GBM patients using three independent cohorts. The rs6971 polymorphism was significantly associated with shorter overall survival and progression-free survival in male GBM patients but not in females in one large cohort and similar trends were observed in two other independent cohorts. GBM growth and progression can also be driven by enhanced iron uptake from the surrounding microenvironment by tumor cells. The HFE gene, encoding the iron sensing HFE protein, is upregulated in GBM and correlates with poor survival outcomes. However, the molecular mechanisms underlying these observations remain unclear. We interrogated the impact of cell-intrinsic Hfe expression on proliferation and tumor growth through genetic loss and gain of function approaches in syngeneic mouse glioma models. Loss of Hfe induced apoptotic cell death in vitro and inhibited tumor growth in vivo while overexpression of Hfe accelerated both proliferation and tumor growth. Analysis of iron gene signatures in Hfe knockdown cells revealed alterations in the expression of several iron-associated genes, suggesting global disruption of intracellular iron homeostasis. Analyzing differentially expressed pathways further identified oxidative stress as the top pathway upregulated with Hfe loss. Enhanced 55Fe uptake and generation of reactive oxygen species (ROS) were found with Hfe knockdown, implicating toxic iron overload resulting in apoptotic cell death. Collectively, these findings identify a novel role for TSPO in GBM prognosis and for HFE in regulating iron homeostasis in GBM tumors, providing potential avenues for future diagnostic and therapeutic development.
■590 ▼aSchool code: 0042.
■650 4▼aOncology.
■650 4▼aBiology.
■650 4▼aMolecular biology.
■650 4▼aCellular biology.
■653 ▼aGlioblastoma
■653 ▼aIron
■653 ▼aTranslocator protein
■653 ▼aSingle nucleotide polymorphism
■653 ▼aSex differences
■690 ▼a0992
■690 ▼a0306
■690 ▼a0307
■690 ▼a0379
■71020▼aCase Western Reserve University▼bMolecular Medicine.
■7730 ▼tDissertations Abstracts International▼g85-03B.
■773 ▼tDissertation Abstract International
■790 ▼a0042
■791 ▼aPh.D.
■792 ▼a2022
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16935491▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a202402▼f2024
