阻断Src信号通路可阻止患者源性胃癌干细胞的干性基因表达和增殖。

IF 1.4 Q2 MEDICINE, GENERAL & INTERNAL
Tzu Chi Medical Journal Pub Date : 2024-09-30 eCollection Date: 2025-01-01 DOI:10.4103/tcmj.tcmj_133_24
Chi-Tan Hu, Chen-Fang Lin, Hsiu-Ming Shih, Ren-In You, Wen-Sheng Wu, Yen-Cheng Chen
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引用次数: 0

摘要

目的:胃癌(GC)是最恶性的肿瘤之一。越来越多的研究强调,胃癌干细胞(GCSCs)是晚期胃癌复发和耐药导致治疗失败的原因。然而,针对GCSC的靶向治疗改善胃癌预后在个体化治疗方面缺乏合适的模型和分子靶点。为了解决这一问题,分离了两种具有癌症干细胞(CSCs)的患者来源的GC细胞系SD209和SD292,以建立针对GC中关键转移信号的靶向治疗。材料和方法:从部分GC组织中建立原代患者来源的GCSCs,在细胞和分子水平上表征干细胞(SCs)表型。Western blot和免疫组化(IHC)检测GC组织中信号失调。应用免疫荧光法分析了附着在成纤维细胞上的GCSC的增殖和SC标记。吖啶橙和碘化丙啶分析GCSC在悬液中的存活情况。结果:在SD209和SD292的培养环境中,大量间充质成纤维细胞扩散并聚集在一起,并在其上牢固附着大量细胞团,怀疑为GCSC。在IHC分析中,GCSC干性基因CD44和Ep-CAM在SD209的肿瘤组织中表达增加,而Nanog-1和OCT-3在SD292的肿瘤组织中表达增加。通过对增殖标志物Ki67的免疫荧光分析,发现达沙替尼可以抑制SD209和SD292在间充质成纤维细胞上的生长。达沙替尼是Src激酶的抑制剂,在两种GCs的肿瘤组织中活性上调。达沙替尼还抑制了附着在间充质成纤维细胞上的SD292中Nanog-1和OCT-3的表达。结论:本研究可为今后临床前/临床中针对GCSCs/GCs进展的靶向治疗提供基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Blockade of Src signaling prevented stemness gene expression and proliferation of patient-derived gastric cancer stem cells.

Objectives: Gastric cancer (GC) is one of the most malignant tumors. Mounting studies highlighted gastric cancer stem cells (GCSCs) were responsible for the failure of treatment due to recurrence and drug resistance of advanced GC. However, targeted therapy against GCSC for improving GC prognosis suffered from lack of suitable models and molecular targets in terms of personalized medicine. To address this issue, two patient-derived GC cell lines SD209 and SD292 with cancer stem cells (CSCs) such as phenotype were isolated for establishing targeted therapy aiming at critical metastatic signaling in GC.

Materials and methods: The primary patient-derived GCSCs were established from parts of GC tissues for characterization of stem cells (SCs) phenotype at both cellular and molecular levels. Western blot and Immunohistochemistry (IHC) were performed for identifying the deregulated signaling in GC tissue. Immunofluorescence was used for analyzing proliferating and SC markers in GCSC attached on fibroblast. Acridine orange and propidium iodide analyses were performed for the survival of GCSC in suspensions.

Results: In the culture environments of both SD209 and SD292, a lot of mesenchymal fibroblasts spread and crowd together on which a lot of cell clumps, suspected as GCSC, were firmly attached. In the IHC analysis, the GCSC stemness genes CD44 and Ep-CAM increased in tumor tissues of SD209, whereas Nanog-1 and octamer-binding transcription factor 3 (OCT-3) increased in that of SD292. By immunofluorescent analysis of a proliferation marker Ki67, the growth of SD209 and SD292 on mesenchymal fibroblasts was found to be reduced by dasatinib, the inhibitor of the Src kinase whose activity was upregulated in tumor tissues of both GCs. Dasatinib also suppressed the expression of Nanog-1 and OCT-3 in SD292 attached on mesenchymal fibroblasts.

Conclusion: This study may provide a base for targeted therapy against GCSCs/GCs progression in future preclinical/clinical settings.

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来源期刊
Tzu Chi Medical Journal
Tzu Chi Medical Journal MEDICINE, GENERAL & INTERNAL-
CiteScore
3.40
自引率
0.00%
发文量
44
审稿时长
13 weeks
期刊介绍: The Tzu Chi Medical Journal is the peer-reviewed publication of the Buddhist Compassion Relief Tzu Chi Foundation, and includes original research papers on clinical medicine and basic science, case reports, clinical pathological pages, and review articles.
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