E26 transformation-specific homologous factor (EHF) suppresses cancer stemness from intrinsic and extrinsic pathways, and rosiglitazone could be used to target pancreatic cancer stem cells (CSCs) and the crosstalk between those cells and their niche, according to a study in Gut.

Investigators performed an immunohistochemical multiplex assay with archived tissues from a retrospective cohort of 93 patients with pancreatic ductal adenocarcinoma (PDAC). They sought to examine the correlation between the expression of tumorous EHF and the proportion of pancreatic cancer stem cells (PCSCs). In addition, 39 cases of fresh PDAC tissues were prospectively collected from January 2018 to November 2019. The analysis also used LSL-KrasG12D/+, LSL-Trp53 R172H/+, and Pdx1-Cre (KPC) mouse models, which were generated in-house.

The researchers found that tumorous EHF decreased the sensitivity of pancreatic cancer (PC) to the pancreatic stellate cell (PSC)-derived chemokine ligand (CXCL)12 stimulus, which suppressed cancer stemness by inhibiting crosstalk between PC and CSC-supportive niches. EHF repressed the expression of sex-determining region Y-box transcription factor (SOX)9, SOX2, octamer-binding transcription factor (OCT)4, and Nanog in the intrinsic pathway. EHF also decreased the sensitivity of PDACs to the stimulus from the PSC-derived CSC-supportive niche by negatively regulating the tumorous chemokine receptor (CXCR)4 expression in the extrinsic pathway.


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Rosiglitazone, a high-affinity, synthetic agonist for nuclear peroxisome proliferator-activated receptor gamma (PPAR-γ), was the most potent activator of the EHF expression with limited side effects, according to the study authors. On activation with specific ligands, PPAR-γ binds to PPAR-γ response elements, which then mediate the target gene expression.

“Our results suggested that the effects of rosiglitazone on EHF upregulation could be translated into the development of targeted therapy against cancer stemness,” the investigators commented.

Reference

Zhou T, Liu J, Xie Y, et al. ESE3/EHF, a promising target of rosiglitazone, suppresses pancreatic cancer stemness by downregulating CXCR4. Gut. Published online March 5, 2021. doi: 10.1136/gutjnl-2020-321952