Regulation of ABCG2 expression by Wnt5a through FZD7 in human pancreatic cancer cells

Abstract

ATP-binding cassette subfamily G member 2 (ABCG2), a member of the ABC transporter superfamily, has been implicated in the development of chemotherapeutic drug resistance in cancer cells. However, the regulators of ABCG2 expression and their roles in anticancer drug resistance have not been fully characterized, especially in the context of pancreatic cancer. The aim of the present study was to investigate whether ABCG2 contributed to drug resistance in pancreatic cancer and to elucidate its regulatory molecular pathways. Using immunohistochemical analysis of pancreatic ductal adenocarcinoma and adjacent healthy tissue samples, the present study identified a positive correlation between ABCG2 and Wnt5a, a member of the Wnt family of secreted proteins. It was also determined that treatment with recombinant human Wnt5a protein could upregulate the expression of ABCG2 in the Capan-2 human pancreatic cancer cell line and enhance its resistance to gemcitabine. The upregulation of ABCG2 by Wnt5a was inhibited by small interfering RNA silencing of Frizzled class receptor 7 (FZD7) or by FZD7 inhibitors. Moreover, both FZD7 silencing or inhibition of its function attenuated gemcitabine resistance induced by Wnt5a in Capan-2 cells. Therefore, the present findings suggested that Wnt5a and FZD7 acted as upstream regulators of ABCG2 expression and that FZD7 may be an essential factor for Wnt5a-induced gemcitabine resistance in pancreatic cancer cells.

Engineered extracellular matrices reveal stiffness-mediated chemoresistance in patient-derived pancreatic cancer organoids

“…CSCs are a population of malignant cells within a tumor that exhibit a de-differentiated phenotype and increased chemoresistance through a broad range of mechanisms 11 . In PDAC, CSCs are often identified by the expression of several cell-surface markers, including CD44, ABCG2, CD9, CD24, and CD133, each of which has been previously associated with poor prognosis in pancreatic cancer 6,[40][41][42][43][44] . To corroborate the potential correlation between these CSC markers and PDAC patient survival, we evaluated data from The Cancer Genome Atlas and quantified overall survival for patients stratified by upper and lower quartile gene expression of each CSC marker (Fig.…”

Understanding pancreatic cancer stem cells and their role in carcinogenesis: a narrative review

“…It facilitates pancreatic cancer progression by mediating the interaction between PCSCs and stromal pancreatic stellate cells (PSCs) (36). Although ABCG2 and Lgr5 have also been implicated in the development of PDACs, very little is known about their precise role in development of pancreatic cancer tumorigenesis (37,38).…”

Macrophages-Related Genes Biomarkers in the Deterioration of Atherosclerosis

“…Frizzled class receptor 7 (FZD7), as the membrane receptor of Wnt/b-catenin signal pathway, controlled both vaso-obliteration and neovascular phases in oxygen-induced retinopathy and single intravitreal microinjection of a monoclonal antibody against Fzd7 or a soluble Fzd7 receptor reduced retinal neovascularization ( 48 ). Wnt5a/FZD7 can regulate ABCG2 expression and YTHDF1 promoted translation of FZD7 in an m6A-dependent manner and mutated YTHDF1 enhanced FZD7 expression, resulting in the Wnt/β-catenin pathway over-activation ( 49 , 50 ). FZD7-mediated PCP signaling increased YAP expression by activating RhoA, which may also act as a potential target for macrophages in CVD ( 51 ).…”