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Hyperactivation of BLT2 cascade implicated in cancer progression

Hyperactivation of BLT2 cascade implicated in cancer progression

자료유형
학위논문
개인저자
장재현, 張宰炫
서명 / 저자사항
Hyperactivation of BLT2 cascade implicated in cancer progression / Jae-hyun Jang
발행사항
Seoul :   Greduate School, Korea University,   2021  
형태사항
vii, 92장 : 삽화(일부천연색), 도표 ; 26 cm
기타형태 저록
Hyperactivation of BLT2 Cascade Implicated in Cancer Progression   (DCOLL211009)000000235568  
학위논문주기
학위논문(박사)-- 고려대학교 대학원: 생명공학과, 2021. 2
학과코드
0510   6YD48   527  
일반주기
지도교수: 김재홍  
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참고문헌 수록
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비통제주제어
SNP , Lung cancer , BLT2,,
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008 201230s2021 ulkad bmAC 000c eng
040 ▼a 211009 ▼c 211009 ▼d 211009
041 0 ▼a eng ▼b kor
085 0 ▼a 0510 ▼2 KDCP
090 ▼a 0510 ▼b 6YD48 ▼c 527
100 1 ▼a 장재현, ▼g 張宰炫
245 1 0 ▼a Hyperactivation of BLT2 cascade implicated in cancer progression / ▼d Jae-hyun Jang
260 ▼a Seoul : ▼b Greduate School, Korea University, ▼c 2021
300 ▼a vii, 92장 : ▼b 삽화(일부천연색), 도표 ; ▼c 26 cm
500 ▼a 지도교수: 김재홍
502 1 ▼a 학위논문(박사)-- ▼b 고려대학교 대학원: ▼c 생명공학과, ▼d 2021. 2
504 ▼a 참고문헌 수록
530 ▼a PDF 파일로도 이용가능; ▼c Requires PDF file reader(application/pdf)
653 ▼a SNP ▼a Lung cancer ▼a BLT2
776 0 ▼t Hyperactivation of BLT2 Cascade Implicated in Cancer Progression ▼w (DCOLL211009)000000235568
900 1 0 ▼a Jang, Jae-Hyun, ▼e
900 1 0 ▼a 김재홍, ▼g 金宰弘, ▼e 지도교수
945 ▼a KLPA

전자정보

No. 원문명 서비스
1
Hyperactivation of BLT2 cascade implicated in cancer progression
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소장정보

No. 소장처 청구기호 등록번호 도서상태 반납예정일 예약 서비스
No. 1 소장처 과학도서관/학위논문서고/ 청구기호 0510 6YD48 527 등록번호 123065658 도서상태 대출가능 반납예정일 예약 서비스 B M
No. 2 소장처 과학도서관/학위논문서고/ 청구기호 0510 6YD48 527 등록번호 123065659 도서상태 대출가능 반납예정일 예약 서비스 B M

컨텐츠정보

초록

Leukotriene B4 receptor 2 (BLT2), a member of G-protein-coupled receptor (GPCR) family, plays a critical role in the pathogenesis of several diseases, including airway inflammation and cancer. Despite the importance of single-nucleotide polymorphism (SNP) of GPCR in physiopathology, no studies on BLT2 SNP effects have been reported to date. In my study, I demonstrate that the BLT2 SNP (rs1950504, Asp196Gly), a Gly-196 variant of BLT2 (BLT2 D196G), causes enhanced cell motility under low-dose stimulation of its ligands. I demonstrated that Akt activation and subsequent production of reactive oxygen species (ROS), and the ligand binding affinity are increased by BLT2 D196G in response to low-dose ligand stimulation. Through homology modeling analysis, it was predicted that BLT2 D196G loses ionic interaction with R197, potentially resulting in increased ligand-receptor interaction. To the best of my knowledge, this report is the first to describe a SNP study on BLT2 and shows that BLT2 D196G enhances ligand sensitivity, thereby increasing cell motility in response to low-dose ligand stimulation.
Next, I explored the role of BLT2 in human airway inflammatory diseases, especially lung cancer. Lung cancer is the leading cause of cancer deaths worldwide and KRAS is the most frequently mutated oncogene among lung cancer cases, the signaling mechanism responsible for KRAS-driven lung cancer is still incompletely elucidated. Here, I observed that the expression levels of BLT2 and its ligand-producing enzymes (5-LOX, 12-LOX) were highly increased by mutant KRAS and that BLT2 blockade attenuated cell proliferation and interleukin-6 production. I demonstrate that blockade of BLT2 effectively attenuate the lung cancer progression both in transgenic mice with lung-specific expression of mutant KRAS (KrasG12D), and KrasG12D/BLT2 knock-out double-mutant mouse model. Additionally, I observed high BLT2 expression in patient-derived tissue samples of KrasG12D-expressing lung adenocarcinoma, supporting the role of BLT2 in KRAS-driven human lung cancer. Collectively, my study is the first to describe the role of BLT2 as a potential contributor to KRAS-driven lung cancer.
Lastly, I examined weather the BLT2 related to metastasis in human lung cancer cells. I found that expression of BLT2 was significantly elevated in primary tumor of lung cancer patients, by analysis of TCGA Lung Cancer database. I observed that the motility and the invasive potential of human lung cancer cell lines (A549, SK-LU-1) were significantly dependent on BLT2. Moreover, the BLT2-mediated migration and invasion in human lung cancer cells were mediated through the stimulation of epithelial-mesenchymal transition (EMT). To my knowledge, this is the first report describing the role of BLT2 in lung cancer migration and invasion, and these results may contribute to the identification of an attractive therapeutic target for lung cancer.

목차

1) List of Figures  6
2) List of Abbreviations  8
3) Abstract  9
4) Chapter I. Leukotriene B4 receptor 2 gene polymorphism (rs1950504, Asp196Gly) leads to enhanced cell motility under low-dose ligand stimulation  11
 1. Abstract  12
 2. Introduction  13
 3. Materials and methods  15
 4. Results  21
 5. Discussion  34
 6. References  37
5) Chapter II. Leukotriene B4 receptor-2 contributes to KRAS-driven lung tumor formation by promoting interleukin-6-mediated inflammation  43
 1. Abstract  44
 2. Introduction  45
 3. Materials and methods  47
 4. Results  52
 5. Discussion  66
 6. References  69
6) Chapter III. BLT2 is implicated in the migration and invasion of human lung cancer cells through epithelial-mesenchymal transition  76
 1. Abstract  77
 2. Introduction  78
 3. Materials and methods  80
 4. Results  84
 5. Discussion  91
 6. References  93
7) Conclusion  95
8) Abstract in Korean  97
9) Acknowledgement  99