肿瘤抑制基因P53和PTEN在cd44介导的胃腺癌多药耐药中的作用

IF 6.9 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Laura Perez-Silva , Elisa Herraez , Rebeca P. Marijuan , Maria Reviejo , Elisa Lozano , Luis Bujanda , Mar Abad , Rocio I.R. Macias , Oscar Briz , Jose J.G. Marin
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引用次数: 0

摘要

胃腺癌(GAC)通常在晚期诊断出来,此时治疗选择有限,并且已经出现明显的化疗耐药。尽管肿瘤抑制基因(TSGs)在GAC中经常发生改变,但它们对化疗耐药的影响尚不清楚。来自癌症基因组图谱队列TCGA-STAD的基因表达数据在西班牙GAC队列中通过RT-qPCR验证。在人GAC细胞系AGS中,使用CRISPR/Cas9进行基因敲除。测定细胞活力(MTT-formazan试验)和增殖率(数字全息显微镜)。在最常失活的tsg中,TP53、PTEN和ARID1A被选中进行进一步的研究。在GAC样本中,TP53上调,而PTEN和ARID1A下调。这些tsg的突变导致其靶基因表达的一致改变。AGS细胞表现出与GAC相似的TSG表达谱,支持其作为体外模型的适用性。敲除ARID1A (ARID1AKO)增强了细胞的化学敏感性。相比之下,沉默TP53 (p53KO)或PTEN (PTENKO)导致对铂类药物、阿霉素、表柔比星和多西他赛的耐药性增加。利用TaqMan低密度阵列对抗性组进行表征。在p53KO和PTENKO细胞中,UGT1A和CD44的表达发生了改变。在这些细胞中额外的CD44沉默部分逆转了它们的化学耐药。此外,毛蕊花苷对CD44的药理抑制使p53KO和PTENKO细胞对抗癌药物敏感。总之,功能失调的TP53和PTEN有助于改变GAC的药物反应。此外,我们还发现了可能对这些肿瘤的化学敏感化有用的药理学脆弱性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Role of tumor suppressor genes P53 and PTEN in CD44-mediated gastric adenocarcinoma multidrug resistance
Gastric adenocarcinoma (GAC) is often diagnosed at advanced stages, when curative options are limited and marked chemoresistance is already present. Although tumor suppressor genes (TSGs) are frequently altered in GAC, their impact on chemoresistance is not well understood. Gene expression data from The Cancer Genome Atlas cohort TCGA-STAD were validated by RT-qPCR in a Spanish cohort of GAC. In the human GAC cell line AGS, gene knocking-out was performed using CRISPR/Cas9. Cell viability (MTT-formazan test) and proliferation rate (digital holographic microscopy) were determined. Among the most frequently inactivated TSGs, TP53, PTEN, and ARID1A were selected for further studies. In GAC samples, TP53 was upregulated, whereas PTEN and ARID1A were downregulated. Mutations in these TSGs led to a consistent alteration in the expression of their target genes. AGS cells exhibited TSG expression profiles like those observed in GAC, which supports their suitability as an in vitro model. Knocking-out ARID1A (ARID1AKO) enhanced cell chemosensitivity. In contrast, silencing TP53 (p53KO) or PTEN (PTENKO) led to increased resistance to platinum-based drugs, doxorubicin, epirubicin, and docetaxel. Characterization of the resistome was performed using TaqMan Low-Density Arrays. In p53KO and PTENKO cells, the expression of UGT1A and CD44 was altered. Additional silencing of CD44 in these cells partially reversed their chemoresistance. Moreover, pharmacological inhibition of CD44 with verbascoside sensitized p53KO and PTENKO cells to anticancer drugs. In conclusion, dysfunctional TP53 and PTEN contribute to altered drug responses of GAC. Moreover, we identified pharmacological vulnerabilities that could be useful to chemosensitize these tumors.
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来源期刊
CiteScore
11.90
自引率
2.70%
发文量
1621
审稿时长
48 days
期刊介绍: Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.
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