Abstract
ABSTRACTThe transcription factor Stat3 is required for proliferation and pluripotency of embryonic stem cells; we have prepared and characterized fluorescent Stat3-reporter zebrafish based on repeats of minimal responsive elements. These transgenic lines mimic in vivo Stat3 expression patterns and are responsive to exogenous Stat3; notably, fluorescence is inhibited by both stat3 knockout and IL6/Jak/STAT inhibitors. At larval stages, Stat3 reporter activity correlates with proliferating regions of the brain, haematopoietic tissue and intestine. In the adult gut, the reporter is active in sparse proliferating cells, located at the base of intestinal folds, expressing the stemness marker sox9b and having the morphology of mammalian crypt base columnar cells; noteworthy, zebrafish stat3 mutants show defects in intestinal folding. Stat3 reporter activity in the gut is abolished with mutation of T cell factor 4 (Tcf7l2), the intestinal mediator of Wnt/β-catenin-dependent transcription. The Wnt/β-catenin dependence of Stat3 activity in the gut is confirmed by abrupt expansion of Stat3-positive cells in intestinal adenomas of apc heterozygotes. Our findings indicate that Jak/Stat3 signalling is needed for intestinal stem cell maintenance and possibly crucial in controlling Wnt/β-catenin-dependent colorectal cancer cell proliferation.
Highlights
Signal transducer and activator of transcription 3 (Stat3), the most prominent member of the STAT family of proteins, is involved in a plethora of cellular processes including development, differentiation, inflammation and metabolism (Levy and Lee, 2002)
No EGFP was detectable in one-cell stage embryos obtained by outcrossing Tg(7xStat3:EGFP) males with wild-type females, indicating that the reporter was maternally activated in the oocyte during oogenesis (Fig. 1B,B′)
High levels of zygotic transgene expression start to be detected during late somitogenesis (22 hpf, hours post fertilization) in the anterior telencephalon (Fig. 1C), in the primordium of the midbrain– hindbrain boundary (MHB) and in cells of the hindbrain region that possibly define the precursors of zebrafish cranial ganglia (Fig. 1D)
Summary
Signal transducer and activator of transcription 3 (Stat3), the most prominent member of the STAT family of proteins, is involved in a plethora of cellular processes including development, differentiation, inflammation and metabolism (Levy and Lee, 2002). Stat phosphorylation is strictly regulated in physiological conditions, over-activation of Stat has been detected in a variety of human cancers, suggesting a key role for this transcription factor in tumour initiation and progression (Huynh et al, 2019). In haematopoietic malignancies and solid tumours, the chronic inflammatory conditions and the maintenance of cancer stem cell properties are reported to be dependent on the IL-6/Stat axis, which stimulates the self-renewal of neoplastic cells (Pattabiraman and Weinberg, 2014; Johnson et al, 2018). IL-6/Stat signalling alters the mucosal barrier in colon adenomas, accelerating the adenocarcinomas transition, it is well known that the Wnt/β-catenin pathway plays an essential role in gut homeostasis (Ahmad et al, 2017). It has been reported that hyperactivated Wnt/β-catenin signalling induces epithelial to mesenchymal transition and promotes CRC (Morin et al, 1997; Vu and Datta, 2017), indicating that the two signalling pathways both act in CRC pathogenesis and progression (Ahmad et al, 2017)
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