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MO-2097通过靶向RAF/MEK/ERK信号通路抑制结直肠癌中的上皮-间质转化和血管生成。

MO-2097 inhibits EMT and angiogenesis in colorectal cancer by targeting RAF/MEK/ERK signaling.

作者信息

Kim Sumin, Han Ho Jin, Han Junyeol, Choi Yerim, Ryoo In-Ja, Sivaraman Aneesh, Lee Kyeong, Kim Bo Yeon, Moon Eun-Yi, Soung Nak-Kyun

机构信息

Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, 28116, Republic of Korea.

Department of Biomolecular Science, Korea National University of Science and Technology, Daejeon, 34113, Republic of Korea.

出版信息

Sci Rep. 2025 Jul 1;15(1):21781. doi: 10.1038/s41598-025-05203-w.


DOI:10.1038/s41598-025-05203-w
PMID:40595789
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12216171/
Abstract

Colorectal cancer is a leading cause of cancer-related deaths, with metastasis being the primary contributor to its poor prognosis. Despite the development of various therapeutic strategies, metastatic colorectal cancer prognosis still needs improvement. MO-2097, a novel therapeutic compound, was evaluated for its potential to inhibit metastasis by targeting critical processes such as cancer cell migration and invasion. The ability of MO-2097 to inhibit cancer cell migration was confirmed through wound healing and trans-well migration assays. Further investigation using western blot analysis revealed that MO-2097 inhibited the RAF/MEK/ERK signaling pathway by destabilizing RAF-1, a key regulator of cancer progression and metastasis. Moreover, MO-2097 treatment led to the downregulation of mesenchymal markers N-cadherin and Vimentin while reducing the expression of EMT-related transcription factors such as Snail, Slug, and ZEB1. In a 3D spheroid invasion model, MO-2097 significantly inhibited cancer cell invasion by reducing their ability to penetrate the extracellular matrix. Furthermore, MO-2097 disrupted the vascular network formation in HUVECs, indicating its impact on angiogenesis, a process essential for tumor growth and metastasis. These findings demonstrate MO-2097's promise as both an anti-metastatic and anti-angiogenic agent, offering a novel therapeutic approach for treating metastatic colorectal cancer and emphasizing its potential for future clinical applications.

摘要

结直肠癌是癌症相关死亡的主要原因之一,转移是其预后不良的主要因素。尽管已经开发了各种治疗策略,但转移性结直肠癌的预后仍需改善。新型治疗化合物MO-2097通过靶向癌细胞迁移和侵袭等关键过程来评估其抑制转移的潜力。通过伤口愈合和Transwell迁移试验证实了MO-2097抑制癌细胞迁移的能力。使用蛋白质印迹分析的进一步研究表明,MO-2097通过使RAF-1(癌症进展和转移的关键调节因子)不稳定来抑制RAF/MEK/ERK信号通路。此外,MO-2097处理导致间充质标志物N-钙黏蛋白和波形蛋白的下调,同时降低了Snail、Slug和ZEB1等EMT相关转录因子的表达。在三维球体侵袭模型中,MO-2097通过降低癌细胞穿透细胞外基质的能力,显著抑制了癌细胞的侵袭。此外,MO-2097破坏了人脐静脉内皮细胞中的血管网络形成,表明其对血管生成的影响,血管生成是肿瘤生长和转移所必需的过程。这些发现证明了MO-2097作为抗转移和抗血管生成药物的前景,为治疗转移性结直肠癌提供了一种新的治疗方法,并强调了其在未来临床应用中的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b0/12216171/096a0ba7f416/41598_2025_5203_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b0/12216171/8404c17d9ff7/41598_2025_5203_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b0/12216171/3ad52d623211/41598_2025_5203_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b0/12216171/46aa2d85f37c/41598_2025_5203_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b0/12216171/096a0ba7f416/41598_2025_5203_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b0/12216171/8404c17d9ff7/41598_2025_5203_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b0/12216171/3ad52d623211/41598_2025_5203_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b0/12216171/46aa2d85f37c/41598_2025_5203_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9b0/12216171/096a0ba7f416/41598_2025_5203_Fig4_HTML.jpg

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本文引用的文献

[1]
A novel tubulin inhibitor, No.07, shows anti-cancer and anti-metastatic effects in colon cancer and tumoroids.

Life Sci. 2025-7-1

[2]
Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.

CA Cancer J Clin. 2024

[3]
Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies.

Signal Transduct Target Ther. 2023-12-18

[4]
HIF-1α inhibition by MO-2097, a novel chiral-free benzofuran targeting hnRNPA2B1.

J Adv Res. 2024-10

[5]
Epithelial-to-mesenchymal transition in cancer progression: unraveling the immunosuppressive module driving therapy resistance.

Cancer Metastasis Rev. 2024-3

[6]
Collagen code in tumor microenvironment: Functions, molecular mechanisms, and therapeutic implications.

Biomed Pharmacother. 2023-10

[7]
The role of the ERK signaling pathway in promoting angiogenesis for treating ischemic diseases.

Front Cell Dev Biol. 2023-6-22

[8]
Live-cell imaging-based dynamic vascular formation assay for antivascular drug evaluation and screening.

iScience. 2023-4-23

[9]
Angiogenic signaling pathways and anti-angiogenic therapy for cancer.

Signal Transduct Target Ther. 2023-5-11

[10]
RAF1 contributes to cell proliferation and STAT3 activation in colorectal cancer independently of microsatellite and KRAS status.

Oncogene. 2023-5

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