KLHL5通过促进细胞周期进程和抑制凋亡细胞死亡参与结直肠癌细胞存活。

IF 5.7 2区 医学 Q1 Medicine
Cancer Science Pub Date : 2025-07-01 DOI:10.1111/cas.70108
Kyosuke Habu, Yosuke Matsuoka, Hiromi Hiyoshi, Jun Nakayama, Katsuya Watanabe, Sota Tate, Tomohisa Sakaue, Junko Murai, Konomu Uno, Hirotada Nishie, Eiji Kubota, Hiromi Kataoka, Takashi Joh, Yuji Watanabe, Taro Oshikiri, Shigeki Higashiyama
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引用次数: 0

摘要

kelch样蛋白5 (KLHL5)在结直肠癌(CRC)中较邻近正常粘膜高表达,且随CRC分期表达水平升高,与预后不良因素相关。然而,其在恶性进展中的功能作用仍然未知。为了阐明KLHL5在CRC中的作用,我们在KLHL5缺失的条件下对人类CRC细胞系(包括HCT116和SW480)进行了表征。klhl5缺失的HCT116和SW480细胞在培养中抑制了它们的生长和迁移。以抗凋亡因子Bcl-2下调和促凋亡因子Bac、Boc、Puma、Bid、Noxa和Bik上调为特征的持续时间诱导的细胞死亡。蛋白质组学分析表明,KLHL5缺失通过影响多种途径抑制细胞周期进程,包括激活G2/M DNA损伤途径和抑制G1/S转变。进一步的生化和细胞生物学分析表明,CDT1和CDC6蛋白(DNA复制起始的重要因素)和细胞周期蛋白A和B (S期和G2/M期进展的重要因素)下调。被阻滞的细胞发生细胞凋亡。综上所述,这些数据强烈表明,在恶劣的肿瘤微环境下,结直肠癌中KLHL5的表达可以作为一种生存因子,加强细胞周期,防止细胞凋亡死亡。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
KLHL5 Contributes to Colorectal Cancer Cell Survival by Promoting Cell Cycle Progression and Suppressing Apoptotic Cell Death.

Kelch-like protein 5 (KLHL5) is highly expressed in colorectal cancer (CRC) compared to that in adjacent normal mucosa, and its expression level increases with CRC stage, showing a correlation with poor prognostic factors. However, its functional role in the malignant progression still remains unknown. To elucidate the role of KLHL5 in CRC, we characterized human CRC cell lines, including HCT116 and SW480, under KLHL5-depleted conditions. KLHL5-depleted HCT116 and SW480 cells suppressed their growth and migration in culture. Further duration induced cell death characterized by apoptotic cell death with down-regulation of antiapoptotic factor Bcl-2 and up-regulation of proapoptotic factors Bac, Boc, Puma, Bid, Noxa, and Bik. Proteomic analyses indicated KLHL5 depletion suppressed cell cycle progression by affecting multiple pathways, including the activation of the G2/M DNA damage pathway and inhibition of the G1/S transition. Further biochemical and cell biological analyses revealed the downregulation of CDT1 and CDC6 proteins, which are essential factors for the initiation of DNA replication, and the downregulation of cyclins A and B, which are essential factors for the progression of S and G2/M phases. Arrested cells undergo apoptotic cell death. Taken together, these data strongly indicate that KLHL5 expression in CRC serves as a survival factor to strengthen the cell cycle and protect against apoptotic cell death under harsh tumor microenvironments.

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来源期刊
Cancer Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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