Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 28, 2017; 23(48): 8512-8525
Published online Dec 28, 2017. doi: 10.3748/wjg.v23.i48.8512
Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts
Zhen-Fei Wang, Da-Guang Ma, Zhe Zhu, Yong-Ping Mu, Yong-Yan Yang, Li Feng, Hao Yang, Jun-Qing Liang, Yong-Yan Liu, Li Liu, Hai-Wen Lu
Zhen-Fei Wang, Da-Guang Ma, Yong-Ping Mu, Yong-Yan Yang, Hai-Wen Lu, Laboratory for Tumor Molecular Diagnosis, Affiliated People’s Hospital of Inner Mongolia Medical University, Huhhot 010020, Inner Mongolia Autonomous Region, China
Zhe Zhu, Jun-Qing Liang, Yong-Yan Liu, Department of cytotherapy for tumors, Affiliated People’s Hospital of Inner Mongolia Medical University, Huhhot 010020, Inner Mongolia Autonomous Region, China
Li Feng, Department of Abdominal Tumor Surgery, Affiliated People’s Hospital of Inner Mongolia Medical University, Huhhot 010020, Inner Mongolia Autonomous Region, China
Hao Yang, Department of Radiotherapy, Affiliated People’s Hospital of Inner Mongolia Medical University, Huhhot 010020, Inner Mongolia Autonomous Region, China
Li Liu, Central Laboratory, People’s Hospital of Wuhai City, Wuhai 016000, Inner Mongolia Autonomous Region, China
Hai-Wen Lu, Affiliated Hospital of Inner Mongolia Medical University, Huhhot 010050, Inner Mongolia Autonomous Region, China
Author contributions: Wang ZF, Ma DG, Lu HW and Liu L designed the research; Wang ZF, Zhu Z, Mu YP, Yang YY, Yang H and Liang JQ performed the research; Feng L and Liu YY analyzed the data; Liu L and Wang ZF wrote the paper.
Supported by the National Natural Science Foundation of China, No. 81760552; the Program of the Inner Mongolia Natural Science Foundation, No. 2016MS0824 and No. 2015MS0896; the Program of “Keji Baiwan Gongcheng” of Inner Mongolia Medical University, No. YKD2015KJBW008; and the Supporting Program for Outstanding Youth in Science and Technology of Inner Mongolia Autonomous Region, No. NJYT-17-B30.
Institutional review board statement: The study was reviewed and approved by the Affiliated People’s Hospital of Inner Mongolia Medical University.
Conflict-of-interest statement: To the best of our knowledge, no conflict of interest exists.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Hai-Wen Lu, PhD, Professor, Affiliated Hospital, Inner Mongolia Medical University, Huhhot 010050, Inner Mongolia Autonomous Region, China. haiwen_l@yeah.net
Telephone: +86-15548798800 Fax: +86-471-3360302
Received: July 25, 2017
Peer-review started: July 25, 2017
First decision: September 14, 2017
Revised: September 29, 2017
Accepted: November 22, 2017
Article in press: November 22, 2017
Published online: December 28, 2017
Processing time: 154 Days and 23.7 Hours
Abstract
AIM

To investigate the inhibitory effect of astragaloside IV on the pathological functions of cancer-associated fibroblasts, and to explore the underlying mechanism.

METHODS

Paired gastric normal fibroblast (GNF) and gastric cancer-associated fibroblast (GCAF) cultures were established from resected tissues. GCAFs were treated with vehicle control or different concentrations of astragaloside IV. Conditioned media were prepared from GNFs, GCAFs, control-treated GCAFs, and astragaloside IV-treated GCAFs, and used to culture BGC-823 human gastric cancer cells. Proliferation, migration and invasion capacities of BGC-823 cells were determined by MTT, wound healing, and Transwell invasion assays, respectively. The action mechanism of astragaloside IV was investigated by detecting the expression of microRNAs and the expression and secretion of the oncogenic factor, macrophage colony-stimulating factor (M-CSF), and the tumor suppressive factor, tissue inhibitor of metalloproteinase 2 (TIMP2), in different groups of GCAFs. The expression of the oncogenic pluripotency factors SOX2 and NANOG in BGC-823 cells cultured with different conditioned media was also examined.

RESULTS

GCAFs displayed higher capacities to induce BGC-823 cell proliferation, migration, and invasion than GNFs (P < 0.01). Astragaloside IV treatment strongly inhibited the proliferation-, migration- and invasion-promoting capacities of GCAFs (P < 0.05 for 10 μmol/L, P < 0.01 for 20 μmol/L and 40 μmol/L). Compared with GNFs, GCAFs expressed a lower level of microRNA-214 (P < 0.01) and a higher level of microRNA-301a (P < 0.01). Astragaloside IV treatment significantly up-regulated microRNA-214 expression (P < 0.01) and down-regulated microRNA-301a expression (P < 0.01) in GCAFs. Reestablishing the microRNA expression balance subsequently suppressed M-CSF production (P < 0.01) and secretion (P < 0.05), and elevated TIMP2 production (P < 0.01) and secretion (P < 0.05). Consequently, the ability of GCAFs to increase SOX2 and NANOG expression in BGC-823 cells was abolished by astragaloside IV.

CONCLUSION

Astragaloside IV can inhibit the pathological functions of GCAFs by correcting their dysregulation of microRNA expression, and it is promisingly a potent therapeutic agent regulating tumor microenvironment.

Keywords: Astragaloside IV; Gastric cancer-associated fibroblasts; Proliferation; Migration; Invasion; MicroRNA

Core tip: Most of chemotherapeutic agents directly act on cancer cells. However, direct drug attacks on cancer cells have the drawbacks of accelerating cancer evolution, chemoresistance, recurrence, and metastasis. Cancer-associated fibroblasts considerably contribute to cancer initiation and progression by providing nourishment and support for cancer cells. Blocking the pathological functions of cancer-associated fibroblasts can eliminate the conditions suitable for cancer cell survival and expansion, representing a novel effective anti-cancer strategy. Unfortunately, few effective drugs have been found against cancer-associated fibroblasts. Here, astragaloside IV significantly inhibited the pathological functions of gastric cancer-associated fibroblasts, suggesting its valuable therapeutic application in gastric carcinoma.