한빛사논문
- 조회1,484
Bo‑Kyung Kim1,2,3*, Da‑Mi Kim1, Hyunkyung Park1, Seon‑Kyu Kim1,2, Mi‑Aie Hwang1,4, Jungwoon Lee2,5, Mi‑Jung Kang1, Jae‑Eun Byun6, Joo‑Young Im1, Minho Kang1, Kyung Chan Park1,2, Young Il Yeom1,2, Seon‑Young Kim2,7, Haiyoung Jung2,6, Dae‑Hyuk Kweon4, Jae‑Ho Cheong8,9* and Misun Won1,2,3*
1Personalized Genomic Medicine Research Center, KRIBB, 125 Kwahag‑ro, Yuseong‑gu, Daejeon 34141, South Korea. 2Present Address: KRIBB School of Bioscience, University of Science and Technology, Daejeon, South Korea. 3R&D Center, oneCureGEN, Daejeon, South Korea. 4Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, South Korea. 5Environmental Diseases Research Center, KRIBB, Daejeon, South Korea. 6Immunotherapy Research Center, KRIBB, Dae‑jeon, South Korea. 7Korea Bioinformation Center, KRIBB, Daejeon, South Korea. 8Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea. 9Serverance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.
*Corresponding author.
Abstract
Background
Identifying biomarkers related to the diagnosis and treatment of gastric cancer (GC) has not made significant progress due to the heterogeneity of tumors. Genes involved in histological classification and genetic correlation studies are essential to develop an appropriate treatment for GC.
Methods
In vitro and in vivo lentiviral shRNA library screening was performed. The expression of Synaptotagmin (SYT11) in the tumor tissues of patients with GC was confirmed by performing Immunohistochemistry, and the correlation between the expression level and the patient’s survival rate was analyzed. Phospho-kinase array was performed to detect Jun N-terminal kinase (JNK) phosphorylation. SYT11, JNK, and MKK7 complex formation was confirmed by western blot and immunoprecipitation assays. We studied the effects of SYT11 on GC proliferation and metastasis, real-time cell image analysis, adhesion assay, invasion assay, spheroid formation, mouse xenograft assay, and liver metastasis.
Results
SYT11 is highly expressed in the stem-like molecular subtype of GC in transcriptome analysis of 527 patients with GC. Moreover, SYT11 is a potential prognostic biomarker for histologically classified diffuse-type GC. SYT11 functions as a scaffold protein, binding both MKK7 and JNK1 signaling molecules that play a role in JNK1 phosphorylation. In turn, JNK activation leads to a signaling cascade resulting in cJun activation and expression of downstream genes angiopoietin-like 2 (ANGPTL2), thrombospondin 4 (THBS4), Vimentin, and junctional adhesion molecule 3 (JAM3), which play a role in epithelial-mesenchymal transition (EMT). SNU484 cells infected with SYT11 shRNA (shSYT11) exhibited reduced spheroid formation, mouse tumor formation, and liver metastasis, suggesting a pro-oncogenic role of SYT11. Furthermore, SYT11-antisense oligonucleotide (ASO) displayed antitumor activity in our mouse xenograft model and was conferred an anti-proliferative effect in SNU484 and MKN1 cells.
Conclusion
SYT11 could be a potential therapeutic target as well as a prognostic biomarker in patients with diffuse-type GC, and SYT11-ASO could be used in therapeutic agent development for stem-like molecular subtype diffuse GC.
논문정보
- Research article
- 2022년 06월 (BRIC 등록일 2022-07-15)
- 국내 연구진
- 생명과학 > 노화/암생물학
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