通过新型肿瘤干性生物标记物 NANOG 预测胰腺癌吉西他滨联合治疗的协同作用

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jiongjia Cheng, Ting Zhu, Shaoxian Liu, Jiayu Zhou, Xiaofeng Wang and Guangxiang Liu
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引用次数: 0

摘要

吉西他滨仍然是治疗胰腺癌的一流化疗药物。然而,由于吉西他滨在胰腺癌中的耐药性发展迅速,吉西他滨单药或与其他抗癌药物联用在临床上的疗效有限。如何切实有效地确定最佳用药方案极具挑战性。因此,鉴定适当的预测生物标志物对于合理设计基于吉西他滨的治疗方案至关重要。在此,我们使用了一种对吉西他滨具有化疗抗性的胰腺癌干细胞(PCSC)模型来测试临床抗癌药物在有或没有吉西他滨的情况下的活性。通过组合治疗确定,几种类型的药物可使吉西他滨耐药的PCSC对吉西他滨重新敏感,其中索拉非尼(表皮生长因子受体抑制剂)/吉西他滨和舒尼替尼(TBK1抑制剂)/吉西他滨药物组合是治疗PCSC的首选药物。通过对干性生物标志物的15个基因表达进行抗体阵列测试,对PCSC模型进行了验证,结果显示,与亲代细胞相比,NANOG在PCSC中的表达明显不同。通过对干细胞指数与组合指数的综合分析,成功构建了干性相关模型,证明了NANOG表达与协同作用之间的相关性。研究发现,癌细胞干性与NANOG的过表达高度相关,而NANOG的过表达可通过吉西他滨药物组合的协同作用而减弱。因此,NANOG可作为一种治疗生物标志物,用于预测吉西他滨对胰腺癌的高效联合治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Prediction of synergistic gemcitabine-based combination treatment through a novel tumor stemness biomarker NANOG in pancreatic cancer

Prediction of synergistic gemcitabine-based combination treatment through a novel tumor stemness biomarker NANOG in pancreatic cancer

Prediction of synergistic gemcitabine-based combination treatment through a novel tumor stemness biomarker NANOG in pancreatic cancer

Gemcitabine remains a first-class chemotherapeutic drug for pancreatic cancer. However, due to the rapid development of gemcitabine resistance in pancreatic cancer, gemcitabine alone or in combination with other anti-cancer drugs only showed limited effect in the clinic. It is extremely challenging to effectively and efficiently determine the optimal drug regimens. Thus, identification of appropriate prediction biomarkers is critical for the rational design of gemcitabine-based therapeutic options. Herein, a pancreatic cancer stem cell (PCSC) model exhibiting chemoresistance to gemcitabine was used to test the activity of clinical cancer drugs in the presence or absence of gemcitabine. As determined by combinatorial treatment, several types of drugs resensitized gemcitabine-resistant PCSCs to gemcitabine, with sorafenib (EGFR inhibitor)/gemcitabine and sunitinib (TBK1 inhibitors)/gemcitabine drug combinations being the most preferred treatments for PCSCs. Following the validation of the PCSC model by an antibody array test of 15-gene expression of stemness biomarkers, NANOG showed markedly different expression in PCSCs compared to the parental cells. From comprehensive analysis of stem cell index versus combination index, a stemness-related correlation model was successfully constructed to demonstrate the correlation between NANOG expression and synergism. Cancer cell stemness was ascertained to be highly relevant to NANOG overexpression that can be abrogated by synergized gemcitabine-drug combinations. Therefore, NANOG works as a therapeutic biomarker for predicating efficient combinatorial treatment of gemcitabine in pancreatic cancer.

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来源期刊
CiteScore
5.80
自引率
2.40%
发文量
129
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