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ZIP4 Increases Expression of Transcription Factor ZEB1 to Promote Integrin α3β1 Signaling and Inhibit Expression of the Gemcitabine Transporter ENT1 in Pancreatic Cancer Cells.
ZIP4 增加转录因子 ZEB1 的表达,以促进整合素 α 3 β 1 信号传导,并抑制胰腺癌细胞中吉西他滨转运体 ENT1 的表达。

摘要

BACKGROUND & AIMS:Pancreatic tumors undergo rapid growth and progression, become resistant to chemotherapy, and recur after surgery. We studied the functions of the solute carrier family 39 member 4 (SLC39A4, also called ZIP4), which regulates concentrations of intracellular zinc and is increased in pancreatic cancer cells, in cell lines and mice.
METHODS:We obtained 93 pancreatic cancer specimens (tumor and adjacent nontumor tissues) from patients who underwent surgery and gemcitabine chemotherapy and analyzed them by immunohistochemistry. ZIP4 and/or ITGA3 or ITGB1 were overexpressed or knocked down with short hairpin RNAs in AsPC-1 and MIA PaCa-2 pancreatic cancer cells lines, and in pancreatic cells from KPC and KPC-ZEB1-knockout mice, and pancreatic spheroids were established; cells and spheroids were analyzed by immunoblots, reverse transcription polymerase chain reaction, and liquid chromatography tandem mass spectrometry. We studied transcriptional regulation of ZEB1, ITGA3, ITGB1, JNK, and ENT1 by ZIP4 using chromatin precipitation and luciferase reporter assays. Nude mice were given injections of genetically manipulated AsPC-1 and MIA PaCa-2 cells, and growth of xenograft tumors and metastases was measured.
RESULTS:In pancreatic cancer specimens from patients, increased levels of ZIP4 were associated with shorter survival times. MIA PaCa-2 cells that overexpressed ZIP4 had increased resistance to gemcitabine, 5-fluorouracil, and cisplatin, whereas AsPC-1 cells with ZIP4 knockdown had increased sensitivity to these drugs. In mice, xenograft tumors grown from AsPC-1 cells with ZIP4 knockdown were smaller and more sensitive to gemcitabine. ZIP4 overexpression significantly reduced accumulation of gemcitabine in pancreatic cancer cells, increased growth of xenograft tumors in mice, and increased expression of the integrin subunits ITGA3 and ITGB1; expression levels of ITGA3 and ITGB1 were reduced in cells with ZIP4 knockdown. Pancreatic cancer cells with ITGA3 or ITGB1 knockdown had reduced proliferation and formed smaller tumors in mice, despite overexpression of ZIP4; spheroids established from these cells had increased sensitivity to gemcitabine. We found ZIP4 to activate STAT3 to induce expression of ZEB1, which induced expression of ITGA3 and ITGB1 in KPC cells. Increased ITGA3 and ITGB1 expression and subsequent integrin α3β1 signaling, via c-Jun-N-terminal kinase (JNK), inhibited expression of the gemcitabine transporter ENT1, which reduced gemcitabine uptake by pancreatic cancer cells. ZEB1-knockdown cells had increased sensitivity to gemcitabine.
CONCLUSIONS:In studies of pancreatic cancer cell lines and mice, we found that ZIP4 increases expression of the transcription factor ZEB1, which activates expression of ITGA3 and ITGB1. The subsequent increase in integrin α3β1 signaling, via JNK, inhibits expression of the gemcitabine transporter ENT1, so that cells take up smaller amounts of the drug. Activation of this pathway might help mediate resistance of pancreatic tumors to chemotherapeutic agents.

译文

背景与目的: 胰腺肿瘤经历快速生长和进展,对化疗产生耐药性,并在手术后复发。我们研究了溶质载体家族 39 成员 4 (SLC39A4,也称为 ZIP4) 的功能,它调节细胞内锌的浓度,并在胰腺癌细胞、细胞系和小鼠中增加。
方法: 我们从接受手术和吉西他滨化疗的患者中获得 93 例胰腺癌标本 (肿瘤和癌旁非肿瘤组织),并对其进行免疫组织化学分析。ZIP4 和/或 ITGA3 或 ITGB1 在 AsPC-1 和 MIA PaCa-2 胰腺癌细胞系以及 KPC 和 KPC-ZEB1-knockout 小鼠的胰腺细胞中被短发夹 rna 过度表达或敲除, 并建立了胰腺球体; 通过免疫印迹、逆转录聚合酶链反应和液相色谱串联质谱法分析细胞和球体。我们利用染色质沉淀和荧光素酶报告试验研究了 ZIP4 对 ZEB1 、 ITGA3 、 ITGB1 、 JNK 和 ENT1 的转录调控。给裸小鼠注射基因操纵的 AsPC-1 和 MIA PaCa-2 细胞,并测量异种移植瘤和转移的生长。
结果: 在来自患者的胰腺癌标本中,ZIP4 水平的增加与更短的生存时间相关。MIA PaCa-2 过表达 ZIP4 的细胞对吉西他滨、 5-氟尿嘧啶和顺铂的耐药性增加,而 AsPC-1 的细胞对这些药物的敏感性增加。在小鼠中,ZIP4 敲除的 AsPC-1 细胞生长的异种移植瘤更小,对吉西他滨更敏感。ZIP4 过表达显著减少吉西他滨在胰腺癌细胞中的积累,增加小鼠异种移植瘤的生长,增加整合素亚单位 ITGA3 和 ITGB1 的表达; 在 ZIP4 敲除的细胞中,ITGA3 和 ITGB1 的表达水平降低。尽管 ZIP4 过表达,但 ITGA3 或 ITGB1 敲除的胰腺癌细胞在小鼠体内的增殖减少,并形成较小的肿瘤; 从这些细胞中建立的球体对吉西他滨的敏感性增加。我们发现 ZIP4 激活 STAT3 来诱导 ZEB1 的表达,ZEB1 诱导 KPC 细胞中 ITGA3 和 ITGB1 的表达。通过 c-6月-N-末端激酶 (JNK) 增加 ITGA3 和 ITGB1 的表达和随后的整合素 α 3 β 1 信号,抑制吉西他滨转运体 ENT1 的表达, 这减少了胰腺癌细胞对吉西他滨的摄取。ZEB1-knockdown 细胞对吉西他滨的敏感性增加。
结论: 在对胰腺癌细胞株和小鼠的研究中,我们发现 ZIP4 增加了转录因子 ZEB1 的表达,ZEB1 激活了 ITGA3 和 itgb1 的表达。随后整合素 α 3 β 1 信号的增加,通过 JNK,抑制吉西他滨转运体 ENT1 的表达,从而细胞吸收少量的药物。激活该通路可能有助于介导胰腺肿瘤对化疗药物的耐药性。

Transcription factor

内分泌 蛋白 临床研究术语
概述  :  

在分子生物学中,转录因子(TF)(或序列特异性DNA结合因子)是一种蛋白质,其控制的速率转录的遗传从信息DNA到信使RNA,通过结合特定的DNA序列。 TF的功能是调节(打开和关闭)基因,以确保它们在正确的时间,正确的细胞中表达,并在整个生命周期中以正确的量表达。TF组以协调的方式运作以指导一生中的细胞分裂,细胞生长和细胞死亡;胚胎发育过程中的细胞迁移和组织,并间歇性地响应来自细胞外部的信号(例如激素)。人类基因组中最多有2600个TF 。

transcription   英 /trænˈskrɪpʃn/   美 /trænˈskrɪpʃn/

释    义   n. 抄写;抄本;誊写

例    句   They're sometimes called transcription factors and this is an example of a transcription factor that is itself activated or turned on by the presence of a steroid.它们被称为转录因子,转录因子的一个例子就是,能够自激活或被激素激活。

 

factor   英 /ˈfæktə(r)/  美 /ˈfæktər/

释    义   n. 因素;要素;[物] 因数;代理人

               vi. 做代理商

               vt. 把…作为因素计入;代理经营;把…分解成

例    句   We have to factor that into the calculus.我们要在微积分学中考虑这些因素。

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