Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts through regulation of the HOXA6/ZBTB12 axis
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 pote...
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2023-09-01
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| Series: | Acta Pharmaceutica |
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| Online Access: | https://doi.org/10.2478/acph-2023-0033 |
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| author | Liu Haibo Luo Shicheng Sha Xiaofeng Chen Zhiping Yang Dongdong |
| author_facet | Liu Haibo Luo Shicheng Sha Xiaofeng Chen Zhiping Yang Dongdong |
| author_sort | Liu Haibo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-db0d0fe01040443bbde894678e461656 |
| institution | Kabale University |
| issn | 1846-9558 |
| language | English |
| publishDate | 2023-09-01 |
| publisher | Sciendo |
| record_format | Article |
| series | Acta Pharmaceutica |
| spelling | doaj-art-db0d0fe01040443bbde894678e4616562025-02-03T02:26:14ZengSciendoActa Pharmaceutica1846-95582023-09-0173342343910.2478/acph-2023-0033Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts through regulation of the HOXA6/ZBTB12 axisLiu Haibo0Luo Shicheng1Sha Xiaofeng2Chen Zhiping3Yang Dongdong4The Affiliated Lianyungang Oriental Hospital of Xuzhou Medical University, Lianyungang Jiangsu Province, 222042, ChinaThe Affiliated Lianyungang Oriental Hospital of Xuzhou Medical University, Lianyungang Jiangsu Province, 222042, ChinaDepartment of Medical Oncology Hongze District People’s Hospital of Huai’an City, Jiangsu Province223100, ChinaDepartment of Medical Oncology Hongze District People’s Hospital of Huai’an City, Jiangsu Province223100, ChinaNanjing Jiangbei Hospital Nanjing, Jiangsu Province, 211500ChinaCancer-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.https://doi.org/10.2478/acph-2023-0033astragaloside ivcancer-associated fibroblastshoxa6zbtb12 |
| spellingShingle | Liu Haibo Luo Shicheng Sha Xiaofeng Chen Zhiping Yang Dongdong Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts through regulation of the HOXA6/ZBTB12 axis Acta Pharmaceutica astragaloside iv cancer-associated fibroblasts hoxa6 zbtb12 |
| title | Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts through regulation of the HOXA6/ZBTB12 axis |
| title_full | Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts through regulation of the HOXA6/ZBTB12 axis |
| title_fullStr | Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts through regulation of the HOXA6/ZBTB12 axis |
| title_full_unstemmed | Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts through regulation of the HOXA6/ZBTB12 axis |
| title_short | Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts through regulation of the HOXA6/ZBTB12 axis |
| title_sort | astragaloside iv inhibits pathological functions of gastric cancer associated fibroblasts through regulation of the hoxa6 zbtb12 axis |
| topic | astragaloside iv cancer-associated fibroblasts hoxa6 zbtb12 |
| url | https://doi.org/10.2478/acph-2023-0033 |
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