LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal Adenocarcinoma.
LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal Adenocarcinoma.
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LLGL1 通过调节胰腺导管腺癌中的 ERK-SP1-OSMR 通路来调节吉西他滨耐药性
DOI：
10.1016/j.jcmgh.2020.06.009
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发表时间：
2020
影响因子：
7.2
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Zhu YX;Li CH;Li G;Feng H;Xia T;Wong CH;Fung FKC;Tong JH;To KF;Chen R;Chen Y
胰腺导管腺癌（PDAC）患者迅速获得吉西他滨耐药。预测患者吉西他滨反应和提高吉西他滨化疗敏感性的新方法对提高患者生存率非常重要。我们的目标是鉴定基因作为新的生物标志物来预测吉西他滨反应和治疗靶点，以减轻PDAC细胞的化疗耐药。进行全基因组RNA干扰筛选以鉴定调控吉西他滨化学耐药的基因。采用细胞增殖实验和肿瘤形成实验研究了致死性巨幼虫同源物1 （LLGL1）在吉西他滨化学耐药中的作用。在接受吉西他滨作为单一治疗剂的患者的肿瘤组织中，通过免疫组织化学染色测量LLGL1及其调节靶点的水平。利用基因表达芯片鉴定LLGL1调控的靶标。LLGL1的沉默显著降低了PDAC细胞对吉西他滨的化学敏感性。LLGL1表达水平低的肿瘤患者的生存期（6个月）明显短于LLGL1表达水平高的肿瘤患者（20个月）（风险比，0.1567;95% CI, 0.05966-0.4117）。LLGL1的缺失促进了细胞因子受体肿瘤抑制素M受体（OSMR）在PDAC细胞中的表达，导致吉西他滨耐药，而OSMR的敲低有效地挽救了化疗耐药表型。LLGL1-OSMR调控通路具有重要的临床意义，因为在PDAC组织中经常观察到低LLGL1和高OSMR表达。LLGL1的沉默诱导细胞外信号调节激酶2和特异性蛋白1 （Sp1）的磷酸化，促进Sp1 （pThr453）在OSMR启动子上的结合，并增强OSMR转录。LLGL1通过调节osmr -胞外信号调节的激酶2/Sp1信号通路，具有抑制化疗耐药的肿瘤抑制作用。本研究中生成和分析的数据集可在Gene Expression Omnibus repository （ID: GSE64681）中获得。
Gemcitabine resistance is rapidly acquired by pancreatic ductal adenocarcinoma (PDAC) patients. Novel approaches that predict the gemcitabine response of patients and enhance gemcitabine chemosensitivity are important to improve patient survival. We aimed to identify genes as novel biomarkers to predict the gemcitabine response and the therapeutic targets to attenuate chemoresistance in PDAC cells. Genome-wide RNA interference screening was conducted to identify genes that regulated gemcitabine chemoresistance. A cell proliferation assay and a tumor formation assay were conducted to study the role of lethal giant larvae homolog 1 (LLGL1) in gemcitabine chemoresistance. Levels of LLGL1 and its regulating targets were measured by immunohistochemical staining in tumor tissues obtained from patients who received gemcitabine as a single therapeutic agent. A gene-expression microarray was conducted to identify the targets regulated by LLGL1. Silencing of LLGL1 markedly reduced the gemcitabine chemosensitivity in PDAC cells. Patients had significantly shorter survival (6 months) if they bore tumors expressing low LLGL1 level than tumors with high LLGL1 level (20 months) (hazard ratio, 0.1567; 95% CI, 0.05966–0.4117). Loss of LLGL1 promoted cytokine receptor oncostatin M receptor (OSMR) expression in PDAC cells that led to gemcitabine resistance, while knockdown of OSMR effectively rescued the chemoresistance phenotype. The LLGL1-OSMR regulatory pathway showed great clinical importance because low LLGL1 and high OSMR expressions were observed frequently in PDAC tissues. Silencing of LLGL1 induced phosphorylation of extracellular signal-regulated kinase 2 and specificity protein 1 (Sp1), promoted Sp1 (pThr453) binding at the OSMR promoter, and enhanced OSMR transcription. LLGL1 possessed a tumor-suppressor role as an inhibitor of chemoresistance by regulating OSMR–extracellular signal-regulated kinase 2/Sp1 signaling. The data sets generated and analyzed during the current study are available in the Gene Expression Omnibus repository (ID: GSE64681).
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影响因子：
3.5
作者：
Lin, Yuan-Zhao;Li, Ruei-Nian;Yen, Jeng-Hsien
通讯作者：
Yen, Jeng-Hsien
影响因子：
6.4
作者：
Arao, T;Yanagihara, K;Nishio, K
通讯作者：
Nishio, K
影响因子：
13.5
作者：
Chen, Yangchao;Lin, Marie C.;Kung, Hsiang-fu
通讯作者：
Kung, Hsiang-fu
影响因子：
64.8
作者：
Dollar, GL;Weber, U;Sokol, SY
通讯作者：
Sokol, SY
影响因子：
64.8
作者：
Betschinger, J;Mechtler, K;Knoblich, JA
通讯作者：
Knoblich, JA