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A Combined Bioinformatic and Nanoparticle-Based Study Reveal the Role of ABCG2 in the Drug Resistant Breast Cancer
Recent Patents on Anti-Cancer Drug Discovery ( IF 2.8 ) Pub Date : 2021-07-31 , DOI: 10.2174/1574892816666210218220531
Qin, Huo

Background: ATP-Binding Cassette subfamily G member 2 (ABCG2) is a semi-transport protein that plays a key role in human diseases, including bladder cancer and lung cancer, and maybe resistant to chemotherapy drugs.

Objective: The present study aimed to determine the role and underlying mechanisms of breast cancer resistance protein (ABCG2) in breast cancer and to study the reversal effect of inhibiting ABCG2 expression on the drug resistance of breast cancer cells and provide new ideas for gene-targeted therapy of breast cancer.

Methods: The structure and genomic alterations of ABCG2 were systematically investigated using GeneCards and cBioPortal to reveal the genetic alterations (including amplification and deep deletions) of ABCG2. We performed the correlation between ABCG2 expression and clinicopathological parameters using the data in bc-GenExMiner 4.4. Then, the protein-protein interaction and functional enrichment analysis of ABCG2 were performed based on the STRING, bc-GenExMiner 4.4, and Enrichr databases. Besides, we analyzed the pathway activity of genes that interact with ABCG2 using GSCALite and PharmGKB. Using magnetic nanoparticles polyMAG as the carrier of ABCG2-siRNA, polyMAG-ABCG2-siRNA was transfected into the Doxorubicin (DOX)-resistant breast cancer cell line MCF-7/ADR and directly into the tumors in nude mice. Patent US20150328485 points out that magnetic nanoparticles can be attached to an anti-cancer drug, such as an antibody-based anti-cancer drug.

Results: We found a statistically significant correlation between ABCG2 expression and clinicopathological parameters, such as Estrogen Receptor (ER), Progesterone Receptor (PR), and human epidermal growth factor receptor-2 (HER2), and nodal status in breast cancer patients. ABCG2 is closely related to SLC2A9, KIT, ABCG1, and MRPS7, which suggests that these proteins may be functional partners of breast cancer. The expression of ABCG2 is correlated with the activation or inhibition of multiple oncogenic pathways. Moreover, we found that ABCG2 is involved in the DOX signaling pathway. The small interfering RNA (siRNA) carried by magnetic nanoparticles can reduce the expression of ABCG2, thereby significantly improving the therapeutic effect of DOX on tumors.

Conclusion: Our findings provide a more in-depth understanding of ABCG2 as a biomarker for predicting DOX-resistance and insights into the development of related therapeutic targets in breast cancer.



中文翻译:

一项基于生物信息学和纳米粒子的联合研究揭示了 ABCG2 在耐药性乳腺癌中的作用

背景:ATP-Binding Cassette subfamily G member 2 (ABCG2) 是一种半转运蛋白,在包括膀胱癌和肺癌在内的人类疾病中起关键作用,并且可能对化疗药物产生耐药性。

目的:本研究旨在明确乳腺癌耐药蛋白(ABCG2)在乳腺癌中的作用及其潜在机制,研究抑制ABCG2表达对乳腺癌细胞耐药性的逆转作用,为基因靶向治疗提供新思路。乳腺癌的治疗。

方法:使用 GeneCards 和 cBioPortal 系统研究 ABCG2 的结构和基因组改变,以揭示 ABCG2 的遗传改变(包括扩增和深度缺失)。我们使用 bc-GenExMiner 4.4 中的数据进行了 ABCG2 表达和临床病理学参数之间的相关性。然后,基于 STRING、bc-GenExMiner 4.4 和 Enrichr 数据库进行 ABCG2 的蛋白质-蛋白质相互作用和功能富集分析。此外,我们使用 GSCALite 和 PharmGKB 分析了与 ABCG2 相互作用的基因的通路活性。使用磁性纳米粒子polyMAG作为ABCG2-siRNA的载体,将polyMAG-ABCG2-siRNA转染到耐多柔比星(DOX)的乳腺癌细胞系MCF-7/ADR中,并直接转染到裸鼠肿瘤中。

结果:我们发现,乳腺癌患者的 ABCG2 表达与临床病理参数(如雌激素受体 (ER)、孕激素受体 (PR) 和人表皮生长因子受体-2 (HER2))和淋巴结状态之间存在统计学显着相关性。ABCG2与SLC2A9、KIT、ABCG1和MRPS7密切相关,提示这些蛋白可能是乳腺癌的功能伙伴。ABCG2 的表达与多种致癌途径的激活或抑制相关。此外,我们发现ABCG2参与了DOX信号通路。磁性纳米粒子携带的小干扰RNA(siRNA)可以降低ABCG2的表达,从而显着提高DOX对肿瘤的治疗效果。

结论:我们的研究结果提供了对 ABCG2 作为预测 DOX 耐药性的生物标志物的更深入理解,并为乳腺癌相关治疗靶点的发展提供了见解。

更新日期:2021-07-31
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