CSE1L通过抑制FAK磷酸化增强defactinib对胃癌细胞的作用。

IF 1.5 4区 医学 Q4 ONCOLOGY Translational cancer research Pub Date : 2024-12-31 Epub Date: 2024-12-18 DOI:10.21037/tcr-24-2049
Xin He, Yating Wang, Yanning Zhang, Arvind Sahu, Khaldoun Almhanna, Yan Liu
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引用次数: 0

摘要

背景:染色体分离样蛋白(CSE1L)过表达可促进肿瘤的增殖和迁移。在前期研究中,我们发现胃癌组织中CSE1L的表达高于正常组织。然而,CSE1L在GC中的生物学功能和分子机制尚不清楚。在本研究中,我们探讨了CSE1L在GC生物学中的功能及其相关的分子机制和治疗潜力。方法:利用公共数据库转录组数据评估GC中CSE1L信使RNA (mRNA)的表达水平。共评估83对GC手术样本以测定CSE1L蛋白表达水平。CSE1L在MGC-803中敲除,在BGC-823中过表达,以评价其在GC细胞中的生物学功能。采用RNA测序(RNA-seq)技术鉴定CSE1L调控的信号通路及其分子机制,并对转录组数据进行验证。Western blotting和免疫荧光法检测CSE1L对磷酸化局灶黏附激酶(p-FAK)的调控作用。结果:CSE1L mRNA在GC患者中表达升高,且CSE1L高表达与GC患者预后不良相关。CSE1L蛋白水平在GC手术标本中也有所升高。CSE1L促进GC细胞增殖、细胞迁移、细胞侵袭、克隆形成和粘附能力。RNA-seq结果表明,CSE1L上调了局灶黏附通路,这在mRNA水平和蛋白水平上得到了验证。此外,CSE1L上调p-FAK酪氨酸397 [p-FAK (Y397)],增强defactinib的疗效。敲除CSE1L后,defactinib对GC细胞的杀伤作用增强。结论:CSE1L是评价胃癌患者预后的潜在生物标志物。敲低CSE1L可通过抑制p-FAK (Y397)增强defactinib的疗效,p-FAK可能是defactinib的协同靶点。
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CSE1L in enhancing the effect of defactinib on gastric cancer cells via the inhibition of FAK phosphorylation.

Background: Chromosome segregation 1 like (CSE1L) overexpression can promote proliferation and migration in cancer. In previous study, we found that CSE1L expression was higher in gastric cancer (GC) tissues compared to normal tissues. However, the biological function and molecular mechanism of CSE1L in GC remains unclear. In this study, we investigate the function of CSE1L in GC biology and its related molecular mechanisms and therapeutic potentials.

Methods: Transcriptome data from public databases were used to assess CSE1L messenger RNA (mRNA) expression levels in GC. A total of 83 pairs of GC surgical samples were evaluated to determine CSE1L protein expression levels. CSE1L was knocked out in MGC-803 and overexpressed in BGC-823 to evaluate its biological function in GC cells. RNA sequencing (RNA-seq) was used to identify the signaling pathways regulated by CSE1L and the underlying molecular mechanisms, and the transcriptome data were validated. Western blotting and immunofluorescence were used to clarify the regulatory effect of CSE1L on phosphorylated focal adhesion kinase (p-FAK).

Results: CSE1L mRNA was increased in patients with GC, and the high expression of CSE1L was associated with poor prognosis in these patients. Protein levels of CSE1L were also increased in GC surgical samples. CSE1L promoted cell proliferation, cell migration, cell invasion, clone formation, and adhesion ability in GC cells. RNA-seq results suggested that CSE1L upregulated the focal adhesion pathway, which was verified at the mRNA level and protein level. Moreover, CSE1L upregulated p-FAK tyrosine 397 [p-FAK (Y397)] and enhanced the efficacy of defactinib. After the knockout of CSE1L, the killing effect of defactinib on GC cells was intensified.

Conclusions: CSE1L is a potential biomarker for evaluating the prognosis of patients with GC. Knockdown of CSE1L can enhance the efficacy of defactinib by inhibiting p-FAK (Y397), which may be a synergistic target of defactinib.

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来源期刊
CiteScore
2.10
自引率
0.00%
发文量
252
期刊介绍: Translational Cancer Research (Transl Cancer Res TCR; Print ISSN: 2218-676X; Online ISSN 2219-6803; http://tcr.amegroups.com/) is an Open Access, peer-reviewed journal, indexed in Science Citation Index Expanded (SCIE). TCR publishes laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer; results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of cancer patients. The focus of TCR is original, peer-reviewed, science-based research that successfully advances clinical medicine toward the goal of improving patients'' quality of life. The editors and an international advisory group of scientists and clinician-scientists as well as other experts will hold TCR articles to the high-quality standards. We accept Original Articles as well as Review Articles, Editorials and Brief Articles.
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