초록 ▼

연구결과
1) SEI-1 암 유발 유전자의 세포내 다른 위치에서의 서로 다른 기능들의 전반적이고 체계적 기작 연구 및 환경적 스트레스 상태 하에서 SEI-1의 세포사멸 억제 기전을 규명함. 종양미세 환경의 하나인 지방세포에서 분비되는 아디포넥틴에 의한 암증식, 전이 억제기전을 밝히고 관련된 유전자인 CIP2A가 에스트로겐에 의하여 증가하여 암증식을 촉진하는 기전을 규명함. Omics 기술을 융합한 유방암 관련 유전자 프로파일 분석 및 암세포주 모델링 기반 돌연변이 유전형에 따른 항암제 민감도, 유전자/단백질 발현 변화의 통합

연구결과
1) SEI-1 암 유발 유전자의 세포내 다른 위치에서의 서로 다른 기능들의 전반적이고 체계적 기작 연구 및 환경적 스트레스 상태 하에서 SEI-1의 세포사멸 억제 기전을 규명함. 종양미세 환경의 하나인 지방세포에서 분비되는 아디포넥틴에 의한 암증식, 전이 억제기전을 밝히고 관련된 유전자인 CIP2A가 에스트로겐에 의하여 증가하여 암증식을 촉진하는 기전을 규명함. Omics 기술을 융합한 유방암 관련 유전자 프로파일 분석 및 암세포주 모델링 기반 돌연변이 유전형에 따른 항암제 민감도, 유전자/단백질 발현 변화의 통합 분석을 통한 암 조절 기전 및 약물 개발에 기초를 제공하였음.
2) 면역세포의 활성화를 유도하는 신규 면역 조절 물질 및 종양표지자의 발굴과 in vitro에서 면역조절 및 항암효과를 규명하였고. 특히 수지상세포와 T 세포를 중심으로 표현형 및 기능적 측면에서 면역 조절 물질 (IL-32, adiponectin, AIMP1, etc)의 역할을 파악하였으며 여성암 공통 항원인 CM1이 면역세포에 미치는 영향을 미침을 규명함. 또한 IL-18 및 Thymosin β4, Erdr-1, IL-32 등을 이용한 항암 효과 가능성을 In vitro 및 In vivo 수준에서 검증하였으며 더 나아가 지방줄기세포에서 분비된 물질들이 유방암 세포의 이동 및 증식을 증가시킴을 규명함.
3) 종양억제유전자 NDRG2의 기능을 규명하였으며, 특히 전이관련 조절인자의 발현 및 기능에 간섭하는 특성을 규명함. Kai1 유전자결손 생쥐와 MMTV-neu 유방암 모델생쥐를 교배하여 새로운 모델을 확립하였고 Ubp43 유전자 결손 생쥐의 골수세포 분석을 통해서 골다공증과의 관련성을 규명함. 또한 신규 ER 수용체 조절 화합물을 개발하고 평가하였으며 TRPV1 저해제의 작용기전을 규명하여 골전이 치료제로의 개발 가능성을 확인함.

Abstract ▼

Purpose
First, to untangle the mechanism of tumor proliferation and metastasis using tumor cells and their microenvironment cells and to find out metastasis-related genes using systemic approach. Second, a variety of immune cells and regulating factors are interactively involved in cancer growth

Purpose
First, to untangle the mechanism of tumor proliferation and metastasis using tumor cells and their microenvironment cells and to find out metastasis-related genes using systemic approach. Second, a variety of immune cells and regulating factors are interactively involved in cancer growth and metastasis. The project is to identify novel regulating molecules to control T cell subsets and also to investigate their efficacies and action mechanisms in vivo. Furthermore, this project is to determine roles of ASC-derived factors and their underlying mechanisms in breast cancer cells. Third, to perform basic research for the development of anti-cancer agents regulating molecular targets, the regulatory effects of tumor suppressor gene on tumor development and metastasis are investigated. Mouse model is used to systematically investigate development, progression and metastasis of breast cancer. Finally, one sub-project is also to develop candidates of molecular targeted cancer therapeutics from synthetic organic compounds.
Contents
We have studied on the different roles of SEI-1 in different cellullar locations and inhibitory roles of SEI-1 in programed cell deaths under the stressful conditions. We also studied tumor proliferation and metastasis suppression mechanism by adiponectin which is secreted from adipose tissues as one of tumor microenvironment, and estrogen-induced tumor proliferation mechanism through CIP2A. Gene expression profiling related to breast cancer using omics technology, integrated analysis of mutational genotype-driven anticancer drug sensitivity, and gene/protein expressional change using cancer cell lines were performed to get modeling for cancer regulatory mechanisms and drug development.
We have identified new immune regulating molecules and tumor surface molecules, confirming their in vitro efficacies using cancer and immune cells. Particularly, we elucidated roles of new immune-regulating molecules (Il-32, adiponectin, AIMP1, etc) in the cross-talk of dendritic cells and T cells, and investigate effects of CM1, common antigens on women's cancers, on immune cells. we have dissected roles and action mechanisms of thymosin beta4, Erdr-1, IL-32 in growth and metastasis of breast cancer cells. Furthermore, we identified soluble factors to affect growth and motility of breast cancer cells by comparing effects of CMs derived from activated and non-activated ASCs, respectively. We have identified action mechanisms of EMT-related proteins in NDRG2-overexpressing breast cancer cells and relationship between NDRG2 expression and inhibition of tumor metastasis. We also generated novel mouse model by crossing Kai1 k/o mice to MMTV-neu mammary tumor model and analyzed bone marrow cells in Ubp43-deficient mice. To develop candidates of molecular targeted cancer therapeutics, new synthetic compounds were tested for receptor binding affinity to ER, and inhibitors of transient receptor potential vanilloid (TRPV) were tested for their potential as a therapeutics to hamper cancer bone metastasis.
Expected Contribution
Acceleration of development of cancer treatment by providing vital information through elucidation of different roles of SEI-1 with various cellular functions ⦁Identification of adiponectin and CIP2A as novel breast cancer therpeutic targets ⦁Contribution to the advance of personalized medicine through establishment of platform for the development of mutational genotype-sensitive anticancer agents using cancer cell lines modeling and systematic analysis ⦁Knowledge and roles of immune escape, immune regulation and immune tolerance in women's cancer can be broadened. ⦁Diagnostic and therapeutic agents or methods can be develop to alleviate women's cancers ⦁Development of novel antitumor therapeutic drugs that can contribute to greatly increase international competitiveness and generate enormous economic values ⦁Many students and researchers in the fields of women's cancer and immune regulation can be educated throughout this study