Cancer pain is a common and severe complication of human
breast cancer, and relieving
pain is fundamental strategy in the treatment.
Fentanyl, as an
opioid analgesic, is widely used in
breast cancer patients. However, little is known about its effects on stemness and epithelial-mesenchymal transition (EMT) of
breast cancer cells. Aberrant protein glycosylation is involved in
cancer malignancy. The α1, 6-fucosylation is an important type of glycosylation, and the elevated α1, 6-fucosylation catalyzed by
fucosyltransferase VIII (FUT8) is found in many
tumors. However, whether 1, 6-fucosylation is involved in regulating stemness and EMT, and stimulated by
fentanyl is not clear. In this study, we found that
fentanyl induced stemness and EMT in MCF-7 and MDA-MB-231
breast cancer cells by analysis of sphere formation, expression of stemness markers (Sox2, Oct4) and EMT markers (
N-cadherin,
E-cadherin and
Vimentin). Results also showed that
fentanyl upregulated FUT8 gene and
protein expression by qPCR, Western blot and immunofluorescent staining, as well as α1, 6-fucosylation level by
Lectin blot and
Lectin fluorescent staining. Furthermore, decreased or blocked α1, 6-fucosylation by FUT8
siRNA transfection or LCA
Lectin blockage reduced stemness and EMT. Additionally,
fentanyl activated the key molecules and target genes in Wnt/β-
catenin signaling pathway.
LGK-974 (an inhibitor of Wnt
ligands) suppressed
fentanyl-mediated upregulation of α1, 6-fucosylation, stemness and EMT. The results of
tumor xenograft demonstrated that
fentanyl enhanced
tumor growth, α1, 6-fucosylation, stemness and EMT. Taken together, our study reveals that
fentanyl upregulated FUT8 expression, which increased α1, 6-fucosylation level through activation of Wnt/β-
catenin signaling pathway, thereby, induce stemness and EMT of
breast cancer cells. This study suggest a potential side effect of
fentanyl in the treatment of
cancer, which may guide the safety of
fentanyl in the clinical application.