Published online Dec 28, 2017. doi: 10.3748/wjg.v23.i48.8512
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
To investigate the inhibitory effect of astragaloside IV on the pathological functions of cancer-associated fibroblasts, and to explore the underlying mechanism.
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.
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.
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.
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.