Fentanyl Promotes Breast Cancer Cell Stemness and Epithelial-Mesenchymal Transition by Upregulating α1, 6-Fucosylation via Wnt/β-Catenin Signaling Pathway

Abstract

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.

LncRNA LEF1-AS1/LEF1/FUT8 Axis Mediates Colorectal Cancer Progression by Regulating α1, 6-Fucosylation via Wnt/β-Catenin Pathway

“…Agrawal et al reveal that FUT8 mediates core fucosylation and alters L1CAM proteolytic cleavage and invasion of melanoma cells [14]. In breast cancer, the upregulation of FUT8 and α1, 6-fucosylation induce stemness and EMT by activating Wnt/β-catenin signaling pathway [15]. Our previous study indicates that FUT8 expression is signi cantly up-regulate in high metastatic hepatocellular carcinoma cells and tumor tissues [16].…”

Long non-coding RNA HOTAIR promotes osteoarthritis progression via miR-17-5p/FUT2/β-catenin axis

“…Recently, some researchers reported that aberrant fucosylation and FUTs played an important role in the activation of wnt/β-catenin pathway in various diseases. Yang et al suggested that FUT8 promoted breast cancer cell stemness and epithelial-mesenchymal transition by activating wnt/β-catenin pathway 36 . Zhang et al 37 demonstrated FUT4 promoted embryo adhesion and implantation via wnt/β-catenin signaling pathway.…”

Aberrant glycosylation and cancer biomarker discovery: a promising and thorny journey

“…Fortunately, lectins have been considered as an extremely useful tool for glycomic and glycoproteomic study that can be used alone or in conjunction with other methods such as MS and CE because of the wide availability, affinity and relative specificity [93]. Several approaches based on lectins including lectin blot [94,95], lectin histochemistry/cytochemisty [29,96], lectin-antibody sandwich enzyme-linked immunosorbent assay (ELISA) [33,44,97], lectin affinity chromatography [98,99], lectin microarray [100][101][102] and lectin microfluidics [103] have been applied to capture the specific glycan of the glycoproteins [102,[104][105][106], enhancing the understanding of aberrant glycosylation and carcinogenesis, accelerating biomarkers recognition and quantitative detection. The Gao group has investigated the diagnostic and prognostic value of fucosylated fetuin A in HCC patients by AAL-based ELISA [107].…”