ESE3/EHF, a promising target of rosiglitazone, suppresses pancreatic cancer stemness by downregulating CXCR4

Abstract

Background and aimsThe crosstalk between cancer stem cells (CSCs) and their niche is required for the maintenance of stem cell-like phenotypes of CSCs. Here, we identified E26 transformation-specific homologous factor (EHF) as a key molecule in decreasing the sensitivity of pancreatic cancer (PC) cells to CSCs’ niche stimulus. We also explored a therapeutic strategy to restore the expression of EHF.DesignWe used a LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse model and samples from patients with PC. Immunostaining, flow cytometry, sphere formation assays, anchorage-independent growth assay, in vivo tumourigenicity, reverse transcription PCR, chromatin immunoprecipitation (ChIP) and luciferase analyses were conducted in this study.ResultsCXCL12 derived from pancreatic stellate cells (PSCs) mediates the crosstalk between PC cells and PSCs to promote PC stemness. Tumorous EHF suppressed CSC stemness by decreasing the sensitivity of PC to CXCL12 stimulus and inhibiting the crosstalk between PC and CSC-supportive niches. Mechanically, EHF suppressed the transcription of the CXCL12 receptor CXCR4. EHF had a cell autonomous role in suppressing cancer stemness by inhibiting the transcription of Sox9, Sox2, Oct4 and Nanog. Rosiglitazone suppressed PC stemness and inhibited the crosstalk between PC and PSCs by upregulating EHF. Preclinical KPC mouse cohorts demonstrated that rosiglitazone sensitised PDAC to gemcitabine therapy.ConclusionsEHF decreased the sensitivity of PC to the stimulus from PSC-derived CSC-supportive niche by negatively regulating tumorous CXCR4. Rosiglitazone could be used to target PC stem cells and the crosstalk between CSCs and their niche by upregulating EHF.

The peroxisome proliferator-activated receptor agonist rosiglitazone specifically represses tumour metastatic potential in chromatin inaccessibility-mediated FABP4-deficient gastric cancer

“…Rosiglitazone, an insulin sensitizer, has some side effects, including cardiovascular risk, which limits clinical use of the drug 39 . Recent studies have demonstrated strong therapeutic potential of rosiglitazone for antitumour therapy 40 , and the use of low doses rosiglitazone can avoid known side effects of the drug 41 . Therefore, standardisation of the use of rosiglitazone is extremely important.…”

Down-Regulated miR-130a/b Attenuates Rhabdomyosarcoma Proliferation via PPARG

“…Rosiglitazone maleate has traditionally been widely used to reduce sugar in the blood of patients with diabetes mellitus (Zhao et al, 2021). However, investigators have recently demonstrated that rosiglitazone maleate also has a therapeutic effect on various cancers, including lung cancer, breast cancer, and pancreatic cancer (Dang et al, 2018;Wang et al, 2020;Wu et al, 2020;Wang et al, 2021;Zhou et al, 2021). We found that rosiglitazone maleate had a significant therapeutic effect on RD cells and inhibited RD cell proliferation by mediating the PPARG pathway.…”

Potential to Eradicate Cancer Stemness by Targeting Cell Surface GRP78

“…Without the aim of high throughput results of omics platforms, Takahashi et al defined that “Yamanaka 4 factors”, including Oct3/4, Sox2, c-Myc, and Klf4, were the essential transcription factors required for reprogramming differentiated mouse fibroblasts, from both adult and embryonic, into pluripotent stem cells [ 36 ]. Thereafter, Yamanaka 4 factors became the paradigm of in vitro and in vivo pluripotency studies, and these four molecules have also been studied in the field of cancer stemness [ 7 , 37 , 38 , 39 , 40 , 41 ]. Besides iPSC, stimulus-triggered acquisition of pluripotency (STAP) was another approach that attempted to experimentally manipulate pluripotency.…”