Study on Synaptonemal Complex Protein 3 (SCP3) mechanism to overcome immunnotherapy-refractory cancer
면역치료 내성암 극복을 위한 Synaptonemal Complex Protein 3 (SCP3) 분자기전 연구
- 주제(키워드) Cancer immunotherapy , Immunotherapeutic-refractory cancer , Immune resistance , multi-refractoriness , SCP3 , NANOG
- 발행기관 고려대학교 대학원
- 지도교수 김태우
- 발행년도 2019
- 학위수여년월 2019. 2
- 학위구분 박사
- 학과 대학원 의과학과
- 세부전공 의생명과학
- 원문페이지 91 p
- 실제URI http://www.dcollection.net/handler/korea/000000082888
- UCI I804:11009-000000082888
- DOI 10.23186/korea.000000082888.11009.0000825
- 본문언어 영어
- 제출원본 000045980456
초록/요약
Although a competent immune system is preserved in cancer patients, cancer cells could evade from host immunosurveillance through a process of cancer immune editing. Immune editing caused by anti-tumor immunity drives tumor cells to dramatically accelerate the evolution of cancer cells toward the acquisition of multi-refractoriness including the properties of stem-likeness, metastasis, as well as resistance to the cell-death caused by both immune cells such as CD8+ T cells and cancer modalities. These acquired-refractory properties can be associated with up-regulation of un-identified refractory-related proteins. One of candidates could be the pulripotency transcription factor NANOG, which is also well known for conferring refractory phenotypes, including a resistance to immunotherapy and chemotherapy, stem-like properties, and metastasis. However, pharmacologic inhibitors of NANOG are yet to be developed. In this study, synaptonemal complex protein3 (SCP3), a member of the Cor1 family, is gradually overexpressed in immune-edited cells. This gain of SCP3 was critical for acquisition of refractory phenotypes. SCP3 drove the multi-refractoriness through NANOG up-regulation by activating EGFR-AKT-Cyclin D1-CDK4/6 signaling pathway, coordinating expression of an anti-apoptotic and cell cycle molecules. In particular, SCP3 induced EGF gene expression through binding of JAB1/CSN5, which in turn drives SCP3-driven refractoriness via activation of EGFR-AKT-Cyclin D1-CDK4/6-NANOG axis. The SCP3 axis was conserved across a wide range of human cancer types, and correlated negatively with progression-free survival of cervical cancer patients. Blocking CDK4/6 with an inhibitor, palbociclib, reversed multi-refractoriness of SCP3high immune-edited tumor cells and induced long-term control of the disease. Collectively, our findings establish a firm molecular link of multi-refractoriness among SCP3, EGFR, AKT, NANOG, CyclinD1, and CDK4/6 and identify CDK4/6 inhibitors as actionable drugs for controlling SCP3high therapeutic-refractory cancer.
more목차
Chapter 1. SCP3 induces NANOG-mediated immune-refractory phenotypes via Cyclin D1-CDK4/6 1
Introduction 2
Materials and Methods 4
Results 12
Discussion 40
Chapter 2. SCP3 activates EGFR-AKT pathway through binding to JAB1 & The establishment of targeting strategies to overcome SCP3-driven immunotherapeutic refractoriness 43
Introduction 44
Materials and Methods 48
Results 51
Discussion 67
ACKNOWLEDGMENTS 70
REFERENCES 71
ABSTRACT IN KOREAN 76
