Acta Pharmaceutica, Vol. 73 No. 3, 2023.
Original scientific paper
https://doi.org/10.2478/acph-2023-0033
Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts through regulation of HOXA6/ZBTB12 axis
HAIBO LIU
orcid.org/0009-0008-3845-3247
SHICHENG LUO
; The Affiliated Lianyungang Oriental Hospital of Xuzhou Medical University, Lianyungang, Jiangsu Province, 222042, China
XIAOFENG SHA
; Department of Medical Oncology, Hongze District People's Hospital of Huai'an City, Jiangsu Province, 223100, China
ZHIPING CHEN
orcid.org/0009-0008-3845-3247
; Department of Medical Oncology, Hongze District People's Hospital of Huai'an City, Jiangsu Province, 223100, China
DONGDONG YANG
; Nanjing Jiangbei Hospital, Nanjing, Jiangsu Province, 211500, China
Abstract
haczp1980@163.com, tczyd19881208@163.com
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.
Keywords
astragaloside IV; cancer-associated fibroblasts; HOXA6; ZBTB12
Hrčak ID:
307865
URI
Publication date:
30.9.2023.
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