POM121 매개 mTOR/p70S6K 신호전달 축에 의한 위암 진행의 분자기전 = POM121 Drives Gastric Cancer Progression via the mTOR/p70S6K Signaling Axis

다국어 초록 (Multilingual Abstract)

POM121 Drives Gastric Cancer Progression via the mTOR/p70S6K Signaling Axis Kim Seong Hun Advisor : Prof. Park Sang Gon,M.D.Ph.D. Department of Medicine, Graduate School of Chosun University Gastric cancer is a representative gastrointestinal malignancy with high incidence and mortality worldwide. While early diagnosis has improved gastric cancer outcomes, advanced stages remain notoriously difficult to treat, often leading to a poor prognosis. Gastric carcinogenesis and tumor progression are driven by complex signaling networks that regulate cellular growth, protein synthesis, metabolic control, and invasive capacity, alongside diverse genetic and epigenetic alterations. Identifying novel molecular targets that drive this malignant progression is crucial for exploring new avenues in prognostic prediction and therapeutic development. POM121 is a transmembrane nucleoporin that constitutes the nuclear pore complex, playing an essential role in nucleocytoplasmic transport. Recent studies have increasingly linked the aberrant expression of nucleoporins in various cancers to altered cell proliferation, invasion, and transcription factor trafficking. However, the specific expression pattern, functional role, and underlying signaling mechanisms of POM121 in gastric cancer have not been fully elucidated. In this study, POM121 expression was analyzed using gastric cancer cell lines and public clinical datasets, followed by an evaluation of the biological effects of siRNA-mediated POM121 knockdown in gastric cancer cells. After suppressing POM121 expression in AGS and KATO-III cells, changes in cell proliferation, migration, anchorage-independent growth, and tumor-forming ability in an animal xenograft model were assessed. Furthermore, the downstream signaling pathways modulated by POM121 were investigated using phospho-kinase array and western blot analyses. underlying signaling mechanisms of POM121 in gastric cancer have not been fully elucidated. The results demonstrated that POM121 was upregulated in several gastric cancer cell lines compared to normal gastric epithelial cells. Knockdown of POM121 significantly reduced the proliferation, migration, and colony-forming capacity of these cells. In the xenograft model using POM121-silenced AGS cells, tumor growth was markedly delayed. Mechanistically, POM121 knockdown decreased the phosphorylation of p70S6K at Thr389 and Thr421/Ser424, as well as mTOR at Ser2448, without altering their total protein levels. These findings imply that POM121 regulates the malignant phenotype of gastric cancer cells primarily through the mTOR/p70S6K signaling axis. In summary, this study provides experimental evidence that POM121 acts as a tumor-promoting factor in gastric cancer, enhancing both proliferative and invasive properties via the modulation of mTOR/p70S6K signaling. These findings highlight the potential of POM121 as a novel prognostic biomarker and a promising therapeutic target for advanced gastric cancer. Key words: POM121, gastric cancer, nuclear pore complex. nucleoporin, mTOR, p70S6K, tumor progression, porgnostic biomaker

목차 (Table of Contents)

• 1. 서론 1
• 2.연구재료 및 방법 3
• A.공개 데이터베이스를 이용한 POM121발현 및 생존율 분석 3
• B.세포주 및 세포배양 3
• C.siRNA를 이용한 POM121 발현억제 4
• D.세포증식 분석 4
• E.Transwell migration assay 4
• F.Soft agar colony formation assay 5
• G.Western blot 분석 6
• H.Human phospho – kinase array 분석 6
• I.Nude mouse xenograft 모델 7
• J.통계분석 8
• 3.연구결과 8
• A. 위암 조직 및 위암세포주에서 POM121 발현 증가 8
• B. POM121 발현 억제에 따른 위암세포 증식 감소 9
• C. POM121 발현 억제에 따른 위암세포 이동 능력 감소 9
• D. POM121 발현 억제에 따른colony 형성 능력 감소 10
• E. POM121에의한 mTOR/p70S6K 신호전달 조절 10
• F. POM121 발현 억제에 따른 생체내 종양 성장 감소 11
• 4.고찰 12
• A.위암의 전신치료의 발전과 문제점 12
• B.위암에서의 표적치료의 발전과 한계 12
• C.핵세포질수송단백질의 표적으로서의 가능성 14
• D.위암에서POM121의 기능적 의미 15
• E.위암에서POM121의mTOR/p70S6K Signaling Axis와의 관계 16
• F.POM121 발현 위암에서의 mTOR/p70S6K 억제제의 가능성 16
• 5.결론 및 연구의 한계점 17
• 6.참고문헌 25