Knockout of krüppel-like factor 10 suppresses hepatic cell proliferation in a partially hepatectomized mouse model

Abstract

Abstract. The liver has marked regenerative capabilities, and numerous signaling pathways are involved in liver regeneration. The transforming growth factor-β (TGF-β)/Smad pathway, which is also involved in liver regeneration, regulates numerous biological processes. Krüppel-like factor 10 (KLF10) has been reported to activate the TGF-β/Smad signaling pathway; however, the exact functions of KLF10 under various pathophysiological conditions remain unclear. In the present study, the role of KLF10 in liver regeneration following partial hepatectomy (PH) was investigated using KLF10-knockout (KO) mice. KLF10-KO mice exhibited lower liver/body weight ratios and 5-bromo-2-deoxy-uridine labeling indices compared with wild-type (WT) mice, and significant differences (P= 0.028) were obtained at 72 h after PH. To understand the causes of the gross and histopathological findings, the expression levels of the components of the TGF-β/Smad pathway were examined using reverse transcription-quantitative polymerase chain reaction and western blot analysis. The mRNA and protein levels of Smad3, p15, TGF-β1 and TGF-β receptor 1 were significantly increased, while those of cMyc and cyclin D1 (proliferation-associated genes) were significantly lower in the liver tissues of the KLF10-KO mice compared with those of the WT mice at 72 h post-PH. These results indicated that KLF10-KO may exhibit antiproliferative effects on liver regeneration following PH, through strengthening the TGF-β/Smad signaling pathway in a delayed manner.

Krüppel-like factor 10 modulates stem cell phenotypes of pancreatic adenocarcinoma by transcriptionally regulating notch receptors

“…In the presence of CSL and NICD, Smad 3 could be recruited to CSL (CBF-1/RBP-JK, Su(H), Lag-1)-binding sites on DNA [ 27 ]. KLF10 might also contribute to Smad 3 recruitment in regulating Notch signaling because the levels of phospho-Smad 3 were significantly higher in the tissue of KLF10 L/L mice [ 28 ]. Previous studies, including our own, have revealed that KLF10 transcriptionally suppressed Sirtuin 6 and Slug to modulate EMT in PDAC [ 6 , 7 ].…”

Krüppel-like factor 10 (KLF10) as a critical signaling mediator: Versatile functions in physiological and pathophysiological processes

“… 2 , 51 In addition, although liver had a marked capacity of regeneration in partially hepatectomized mouse model, deletion of Klf10 suppressed the proliferation of hepatocytes as the liver/body weight ratio was significantly lower and the proliferation-associated genes were downregulated in the livers of Klf10 KO mice compared with WT mice, suggesting critical role of KLF10 in liver regeneration. 56 KLF10 is also involved in many other biological processes, which have been reviewed previously. 3 …”

“…But as mentioned earlier, KLF10 has the ability to enhance the proliferation of hepatocytes and is required for liver regeneration in partially hepatectomized mouse model. 56 It is possible that the different tissue microenvironment and cellular context may influence the effect of KLF10 on the capacity of cell proliferation, which needs further exploration. The important roles of KLF10 in the control of tumor development are updated and discussed here.…”

Signaling pathways of liver regeneration: Biological mechanisms and implications

“… 190 According to the studies of Bird, Heo et al., regulating signaling factors like TGF-βR1 and Smad within TGF-β pathway blocked TGF-β signaling pathway, thus inhibiting the termination of LR and promoting hepatocyte proliferation. 191 , 192 Inhibition of TGF-β pathway is an effective therapeutic strategy to promote hepatocyte proliferation and LR. Therefore, the TGF-β signaling pathway deserves further investigations.…”

“… 191 Heo et al. 192 Activin signaling pathway Activin A, as a transcriptional target of KLF2, negatively regulated hepatocyte proliferation and LR. Manavski et al.…”