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Ahnak depletion accelerates liver regeneration by modulating the TGF-β/Smad signaling pathway
Insook Yang,Yeri Son,Jae Hoon Shin,Il Yong Kim,Je Kyung Seong 생화학분자생물학회 2022 BMB Reports Vol.55 No.8
Ahnak, a large protein first identified as an inhibitor of TGF-βsignaling in human neuroblastoma, was recently shown to promoteTGF-β in some cancers. The TGF-β signaling pathway regulatescell growth, various biological functions, and cancergrowth and metastasis. In this study, we used Ahnak knockout(KO) mice that underwent a 70% partial hepatectomy (PH) toinvestigate the function of Ahnak in TGF-β signaling during liverregeneration. At the indicated time points after PH, we analyzedthe mRNA and protein expression of the TGF -β/Smad signalingpathway and cell cycle-related factors, evaluated the cell cyclethrough proliferating cell nuclear antigen (PCNA) immunostaining,analyzed the mitotic index by hematoxylin and eosinstaining. We also measured the ratio of liver tissue weight tobody weight. Activation of TGF-β signaling was confirmed byanalyzing the levels of phospho-Smad 2 and 3 in the liver atthe indicated time points after PH and was lower in Ahnak KOmice than in WT mice. The expression levels of cyclin B1, D1,and E1; proteins in the Rb/E2F transcriptional pathway, whichregulates the cell cycle; and the numbers of PCNA-positive cellswere increased in Ahnak KO mice and showed tendencies oppositethat of TGF-β expression. During postoperative regeneration,the liver weight to body weight ratio tended to increasefaster in Ahnak KO mice. However, 7 days after PH, both groupsof mice showed similar rates of regeneration, following whichtheir active regeneration stopped. Analysis of hepatocytes undergoingmitosis showed that there were more mitotic cells inAhnak KO mice, consistent with the weight ratio. Our findingssuggest that Ahnak enhances TGF-β signaling during postoperativeliver regeneration, resulting in cell cycle disruption; thishighlights a novel role of Ahnak in liver regeneration. Theseresults provide new insight into liver regeneration and potentialtreatment targets for liver diseases that require surgicaltreatment.
Insook Yang,Seung Yeon Oh,Suin Jang,Il Yong Kim,You Me Sung,성제경 생화학분자생물학회 2022 BMB Reports Vol.55 No.12
Liver regeneration is a well-known systemic homeostatic phenomenon. The N6-methyladenosine (m6A) modification pathwayhas been associated with liver regeneration and hepatocellularcarcinoma. m6A methyltransferases, such as methyltransferase 3(METTL3) and methyltransferase 14 (METTL14), are involvedin the hepatocyte-specific-regenerative pathway. To illustratethe role of METTL14, secreted from non-parenchymal liver cells,in the initiation phase of liver regeneration, we performed 70%partial hepatectomy (PH) in Mettl14 heterozygous (HET) andwild-type (WT) mice. Next, we analyzed the ratio of liver weightto body weight and the expression of mitogenic stimulatorsderived from non-parenchymal liver cells. Furthermore, weevaluated the expression of cell cycle-related genes and thehepatocyte proliferation rate via MKI67-immunostaining. Duringregeneration after PH, the weight ratio was lower in Mettl14HET mice compared to WT mice. The expressions of hepatocytegrowth factor (HGF) and tumor necrosis factor (TNF)-α,mitogens derived from non-parenchymal liver cells that stimulatethe cell cycle, as well as the expressions of cyclin B1 andD1, which regulate the cell cycle, and the number of MKI67-positive cells, which indicate proliferative hepatocyte in the lateG1-M phase, were significantly reduced in Mettl14 HET mice72 h after PH. Our findings demonstrate that global Mettl14mutation may interrupt the homeostasis of liver regenerationafter an acute injury like PH by restraining certain mitogens,such as HGF and TNF-α, derived from sinusoidal endothelialcells, stellate cells, and Kupffer cells. These results providenew insights into the role of METTL14 in the clinical treatmentstrategies of liver disease.