Claudin1 decrease induced by 1,25-dihydroxy-vitamin D3 potentiates gefitinib resistance therapy through inhibiting AKT activation-mediated cancer stem-like properties in NSCLC cells.
Claudin1 decrease induced by 1,25-dihydroxy-vitamin D3 potentiates gefitinib resistance therapy through inhibiting AKT activation-mediated cancer stem-like properties in NSCLC cells.
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DOI：
10.1038/s41420-022-00918-5
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发表时间：
2022-03-18
影响因子：
7
通讯作者：
Ding X
中科院分区：
文献类型：
--
作者：
Jia Z;Wang K;Duan Y;Hu K;Zhang Y;Wang M;Xiao K;Liu S;Pan Z;Ding X
紧密连接蛋白是一种调节细胞旁通透性和细胞极性的完整紧密连接蛋白，在癌症中经常失调;然而，它们在调节非小细胞肺癌（NSCLC）中EGFR酪氨酸激酶抑制剂（EGFR-TKI）耐药性方面的作用尚不清楚。为此，我们进行了GEO数据集分析，并确定了claudin 1是NSCLC细胞中EGFR-TKI耐药性的关键调节因子。我们还发现，在EGFR-TKI耐药NSCLC细胞中，由连续吉非替尼治疗高度诱导的claudin 1显著上调。通过敲低细胞系和异种移植模型中的claudin 1，我们确定吉非替尼耐药性降低。此外，claudin 1敲低抑制多能性标志物（Oct 4、Nanog、Sox 2、CD 133和ALDH 1A 1）的表达水平。Claudin 1缺失抑制磷酸化AKT（p-AKT）表达，并通过抑制AKT活化降低癌细胞的干细胞性。此外，β-连环蛋白激动剂SKL 2001上调了claudin 1、p-AKT和多能性标志物的表达水平，1，25-二羟基维生素D3（1，25（OH）2D 3）通过抑制β-连环蛋白降低了claudin 1表达、AKT活化和癌细胞干细胞性，并抑制了claudin 1/AKT通路介导的癌干细胞样特性和吉非替尼耐药性。总的来说，通过1，25（OH）2D 3抑制claudin 1介导的癌干细胞样特性可能通过AKT途径降低吉非替尼耐药性，这可能是抑制EGFR突变型肺腺癌吉非替尼耐药性的有前景的治疗策略。
Claudins, the integral tight junction proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their roles in regulating EGFR tyrosine kinase inhibitors (EGFR-TKIs) resistance in non-small cell lung cancer (NSCLC) are unknown. To this end, we performed GEO dataset analysis and identified that claudin1 was a critical regulator of EGFR-TKI resistance in NSCLC cells. We also found that claudin1, which was highly induced by continuous gefitinib treatment, was significantly upregulated in EGFR-TKI-resistant NSCLC cells. By knocking down claudin1 in cell lines and xenograft models, we established that gefitinib resistance was decreased. Moreover, claudin1 knockdown suppressed the expression levels of pluripotency markers (Oct4, Nanog, Sox2, CD133, and ALDH1A1). Claudin1 loss inhibited phosphorylated AKT (p-AKT) expression and reduced cancer cell stemness by suppressing AKT activation. Furthermore, SKL2001, a β-catenin agonist, upregulated the expression levels of claudin1, p-AKT, and pluripotency markers, and 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) reduced claudin1 expression, AKT activation, and cancer cell stemness by inhibiting β-catenin, and suppressed claudin1/AKT pathway mediated cancer stem-like properties and gefitinib resistance. Collectively, inhibition of claudin1-mediated cancer stem-like properties by 1,25(OH)2D3 may decrease gefitinib resistance through the AKT pathway, which may be a promising therapeutic strategy for inhibiting gefitinib resistance in EGFR-mutant lung adenocarcinoma.
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DOI：
10.1158/1078-0432.ccr-14-2437
发表时间：
2015-02-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Li Z;Jia Z;Gao Y;Xie D;Wei D;Cui J;Mishra L;Huang S;Zhang Y;Xie K
通讯作者：
Xie K
影响因子：
5.6
作者：
Kwon MJ
通讯作者：
Kwon MJ
1 α,25-二羟基维生素 D3 通过增强维生素 D 受体和抑制 CD44 抑制卵巢癌细胞的干细胞样特性
影响因子：
4.2
作者：
Ji, Mintao;Liu, Lizhi;Li, Bingyan
通讯作者：
Li, Bingyan
DOI：
10.1016/s0140-6736(17)33326-3
发表时间：
2018-03-17
期刊：
Lancet (London, England)
影响因子：
--
作者：
Allemani C;Matsuda T;Di Carlo V;Harewood R;Matz M;Nikšić M;Bonaventure A;Valkov M;Johnson CJ;Estève J;Ogunbiyi OJ;Azevedo E Silva G;Chen WQ;Eser S;Engholm G;Stiller CA;Monnereau A;Woods RR;Visser O;Lim GH;Aitken J;Weir HK;Coleman MP;CONCORD Working Group
通讯作者：
CONCORD Working Group
二甲双胍通过抑制 IL-6 信号传导和 EMT 逆转，在体外和体内使 EGFR-TKI 耐药的人肺癌细胞变得敏感
影响因子：
11.5
作者：
Li, Li;Han, Rui;He, Yong
通讯作者：
He, Yong