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DLL1上调可能促进小细胞肺癌的化疗敏感性

[Up-regulation of DLL1 may promote the chemotherapeutic sensitivity in small cell lung cancer].

作者信息

Liu Huanxin, Peng Juan, Bai Yifeng, Guo Linlang

机构信息

Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.

出版信息

Zhongguo Fei Ai Za Zhi. 2013 Jun;16(6):282-8. doi: 10.3779/j.issn.1009-3419.2013.06.02.

DOI:10.3779/j.issn.1009-3419.2013.06.02
PMID:23769341
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6000567/
Abstract

BACKGROUND

Delta-Like1 (DLL1) can combine with Notch receptor and activate the Notch signal pathway, then made a decision to cell differentiation and regulate the development of many tissues. It is proved that DLL1 was highly correlated with tumor'growth and differentiation, our previously study showed that DLL1 was associated with MDR in small cell lung cancer (SCLC). The aim of this study is to furtherly investigate the role of DLL1 gene in small cell lung multi-drug resistance.

METHODS

Firstly, the analysis of qRT-PCR and Western blot were used to study differential expression of DLL1 from mRNA and protein levels in both the H69 and H69AR cell lines. Then, we developed a stably DDL1 overexpressing H69AR-eGFP-DLL1 subline, by transfection with DLL1-pIRES2-EGFP. Moreover, the sensitivities of cells to chemotherapy drugs such as ADM, DDP, VP-16 were detected by CCK8 assay. The change of cell cycle and apoptosis rate were detected by flow cytometry.

RESULTS

The expression of DLL1 was significantly decreased in H69AR cells than that in the H69 cells. The sensitivities of H69AR cells to chemotherapy drugs were increased when up-regulated the expression of DLL1, enforced DLL1 expression increased cell apoptosis and the cell cycle arrest in G0/G1 and S phase in H69AR cells, the expression of downstream genes HES1 and HEY1 were increased after transfected with DLL1-pIRES2-EGFP.

CONCLUSIONS

Our results suggest that overexpression of DLL1 in small cell lung cancer may increase the sensitivity of cells to chemotherapeutic agents. DLL1 influence drug resistance of small cell lung cancer through activating transcription of downstream genes HES1 and HEY1.

摘要

背景

Delta样蛋白1（DLL1）可与Notch受体结合并激活Notch信号通路，进而决定细胞分化并调节多种组织的发育。已证实DLL1与肿瘤的生长和分化高度相关，我们先前的研究表明DLL1与小细胞肺癌（SCLC）的多药耐药性有关。本研究的目的是进一步探讨DLL1基因在小细胞肺癌多药耐药中的作用。

方法

首先，采用qRT-PCR和蛋白质免疫印迹分析研究DLL1在H69和H69AR细胞系中mRNA和蛋白质水平的差异表达。然后，通过用DLL1-pIRES2-EGFP转染，构建稳定过表达DDL1的H69AR-eGFP-DLL1亚系。此外，通过CCK8法检测细胞对阿霉素、顺铂、依托泊苷等化疗药物的敏感性。通过流式细胞术检测细胞周期和凋亡率的变化。

结果

H69AR细胞中DLL1的表达明显低于H69细胞。上调DLL1表达可增加H69AR细胞对化疗药物的敏感性，增强DLL1表达可增加细胞凋亡，并使H69AR细胞的细胞周期停滞在G0/G1期和S期，转染DLL1-pIRES2-EGFP后下游基因HES1和HEY1的表达增加。

结论

我们的结果表明，小细胞肺癌中DLL1的过表达可能增加细胞对化疗药物的敏感性。DLL1通过激活下游基因HES1和HEY1的转录影响小细胞肺癌的耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ef4/6000567/f84ba7196ec7/zgfazz-16-6-282-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ef4/6000567/48bc6dea4610/zgfazz-16-6-282-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ef4/6000567/ca6bd48a0ce1/zgfazz-16-6-282-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ef4/6000567/e694f9355cb2/zgfazz-16-6-282-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ef4/6000567/88d08817cb99/zgfazz-16-6-282-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ef4/6000567/d888346057a9/zgfazz-16-6-282-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ef4/6000567/f84ba7196ec7/zgfazz-16-6-282-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ef4/6000567/48bc6dea4610/zgfazz-16-6-282-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ef4/6000567/ca6bd48a0ce1/zgfazz-16-6-282-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ef4/6000567/e694f9355cb2/zgfazz-16-6-282-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ef4/6000567/88d08817cb99/zgfazz-16-6-282-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ef4/6000567/d888346057a9/zgfazz-16-6-282-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ef4/6000567/f84ba7196ec7/zgfazz-16-6-282-6.jpg

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本文引用的文献

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Notch pathway is activated by MAPK signaling and influences papillary thyroid cancer proliferation.Notch 通路被 MAPK 信号激活并影响甲状腺乳头状癌的增殖。
Transl Oncol. 2013 Apr;6(2):197-205. doi: 10.1593/tlo.12442. Epub 2013 Apr 1.
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Notch1 is a 5-fluorouracil resistant and poor survival marker in human esophagus squamous cell carcinomas.Notch1 是人类食管鳞癌中氟尿嘧啶耐药和不良生存的标志物。
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The human papillomavirus type 8 E6 protein interferes with NOTCH activation during keratinocyte differentiation.
DLLs在癌症中的作用：一种新型治疗靶点。
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Tumor suppressor genes and their underlying interactions in paclitaxel resistance in cancer therapy.肿瘤抑制基因及其在癌症治疗中对紫杉醇耐药性的潜在相互作用。
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人乳头瘤病毒 8 型 E6 蛋白在角质形成细胞分化过程中干扰 NOTCH 激活。
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Cisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating Notch signaling.顺铂通过激活 Notch 信号通路选择肺腺癌中多药耐药的 CD133+细胞。
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Dll1/Notch activation contributes to bortezomib resistance by upregulating CYP1A1 in multiple myeloma.Dll1/Notch 激活通过上调多发性骨髓瘤中的 CYP1A1 导致硼替佐米耐药。
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Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy.靶向 Notch，一种卵巢癌细胞干关键通路，可提高肿瘤对铂类治疗的敏感性。
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New pathways and mechanisms regulating and responding to Delta-like ligand 4-Notch signalling in tumour angiogenesis.调控和响应 Delta 样配体 4-Notch 信号在肿瘤血管生成中的新途径和机制。
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