Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts through regulation of the HOXA6/ZBTB12 axis.

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Pub Date : 2023-09-01 DOI:10.2478/acph-2023-0033

Haibo Liu, Shicheng Luo, Xiaofeng Sha, Zhiping Chen, Dongdong Yang

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引用次数: 2

Abstract

Cancer-associated fibroblasts (CAFs) play critical roles in the tumor microenvironment and exert tumor-promoting or tumor-retarding effects on cancer development. Astragaloside IV has been suggested to rescue the pathological impact of CAFs in gastric cancer. This study aimed to investigate the potential mechanism of astragaloside IV in the regulation of CAF pathological functions in gastric cancer development. Homeobox A6 (HOXA6), and Zinc Finger and BTB Domain Containing 12 (ZBTB12) are highly expressed in gastric CAFs compared with normal fibroblasts (NFs) based on the GSE62740 dataset. We found that astragaloside IV-stimulated CAFs suppressed cell growth, migration, and invasiveness of gastric cancer cells. HOXA6 and ZBTB12 were downregulated after astragaloside IV treatment in CAFs. Further analysis revealed that HOXA6 or ZBTB12 knockdown in CAFs also exerted inhibitory effects on the malignant phenotypes of gastric cells. Additionally, HOXA6 or ZBTB12 overexpression in CAFs enhanced gastric cancer cell malignancy, which was reversed after astragaloside IV treatment. Moreover, based on the hTFtarget database, ZBTB12 is a target gene that may be transcriptionally regulated by HOXA6. The binding between HOXA6 and ZBTB12 promoter in 293T cells and CAFs was further confirmed. HOXA6 silencing also induced the downregulation of ZBTB12 mRNA and protein in CAFs. Astragaloside IV was demonstrated to regulate the expression of ZBTB12 by mediating the transcriptional activity of HOXA6. Our findings shed light on the therapeutic value of astragaloside IV for gastric cancer.

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黄芪甲苷通过调控HOXA6/ZBTB12轴抑制胃癌相关成纤维细胞的病理功能。

肿瘤相关成纤维细胞(cancer -associated fibroblasts, CAFs)在肿瘤微环境中发挥重要作用，并在肿瘤发展过程中发挥促瘤或抑瘤作用。黄芪甲苷被认为可以挽救cas在胃癌中的病理影响。本研究旨在探讨黄芪甲苷在胃癌发生发展过程中调控CAF病理功能的可能机制。基于GSE62740数据，与正常成纤维细胞(NFs)相比，在胃CAFs中，Homeobox A6 (HOXA6)、锌指和BTB Domain Containing 12 (ZBTB12)高表达。我们发现黄芪甲苷刺激的CAFs抑制了胃癌细胞的生长、迁移和侵袭性。黄芪甲苷治疗CAFs后，HOXA6和ZBTB12下调。进一步分析发现，cas中HOXA6或ZBTB12的敲低也对胃细胞的恶性表型有抑制作用。此外，HOXA6或ZBTB12在cas中的过表达增强了胃癌细胞的恶性，黄芪甲苷治疗后这种情况被逆转。此外，基于hTFtarget数据库，ZBTB12是一个可能受HOXA6转录调控的靶基因。进一步证实了HOXA6和ZBTB12启动子在293T细胞和CAFs中的结合。HOXA6沉默也诱导了cas中ZBTB12 mRNA和蛋白的下调。黄芪甲苷通过介导HOXA6的转录活性来调节ZBTB12的表达。本研究结果揭示了黄芪甲苷对胃癌的治疗价值。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Pharmaceutica PHARMACOLOGY & PHARMACY-

CiteScore

5.20

自引率

3.60%

发文量

审稿时长

>12 weeks

期刊介绍： AP is an international, multidisciplinary journal devoted to pharmaceutical and allied sciences and contains articles predominantly on core biomedical and health subjects. The aim of AP is to increase the impact of pharmaceutical research in academia, industry and laboratories. With strong emphasis on quality and originality, AP publishes reports from the discovery of a drug up to clinical practice. Topics covered are: analytics, biochemistry, biopharmaceutics, biotechnology, cell biology, cell cultures, clinical pharmacy, drug design, drug delivery, drug disposition, drug stability, gene technology, medicine (including diagnostics and therapy), medicinal chemistry, metabolism, molecular modeling, pharmacology (clinical and animal), peptide and protein chemistry, pharmacognosy, pharmacoepidemiology, pharmacoeconomics, pharmacodynamics and pharmacokinetics, protein design, radiopharmaceuticals, and toxicology.