Loss of Mettl3 enhances liver tumorigenesis by inducing hepatocyte dedifferentiation and hyperproliferation

Hepatocyte-specific METTL3 ablation by Alb-iCre mice (GPT), but not by Alb-Cre mice (JAX), resulted in acute liver failure (ALF) and postnatal lethality

“…As the enhanced compensatory proliferation responses of hepatocytes to liver injury induced through METTL3 Δhep (JAX), these results from this study and other studies [16,20,30] revealed that the increased growth of METTL3 Δhep (JAX) hepatocytes was evidenced by the significant increase of Ki67-positive hepatocytes, accompanied by upregulation of cell-cyclerelated genes. In addition, GO analysis based on the top20 significantly enriched GO terms in "biological process" for up-regulated DEGs obviously revealed that upregulated genes in the livers of METTL3 Δhep mice (JAX) displaying postnatal survival are functionally enriched in terms associated with cell cycle, cell division, mitosis, microtubule cytoskeleton organization, spindle organization, chromatin segregation and organization, and nuclear division [16], consistent with the enhanced compensatory proliferation capacity of METTL3 Δhep hepatocytes (JAX) observed in this study and in other studies from other labs [16,20,30]. However, surprisingly, as the compensatory proliferation responses of hepatocytes to liver injury, we unexpectedly found that the proliferation of METTL3 Δhep hepatocytes (GPT) was not evidenced by the dramatic increase of Ki67-positive hepatocytes, not accompanied by upregulation of cell-cycle-related genes.…”

“…However, these results from this study and others labs [16,17,20,24,30] clearly exhibited that hepatocytespecific METTL3 homozygous ablation in mice by Alb-Cre mice (JAX) [16,20,24,30] induced liver injury, but didn't cause ALF and then postnatal lethality because homozygous METTL3 knockout in mice by Alb-Cre mice (JAX) didn't lead to the severe destruction of liver histological structure of METTL3 Δhep mice (JAX), thereby METTL3 Δhep mice (JAX) still had well-maintained liver function. In addition, hepatocyte-specific METTL3 homozygous disruption in mice by Alb-Cre mice (JAX) [21][22][23] or by AAV-TBG-Cre injection [30,37] didn't also lead to postnatal lethality. Collectively, the above-mentioned data from this study and other labs [16, 20-24, 30, 37] provide strong evidence that ALF and postnatal lethality are not induced via heterozygous or homozygous METTL3 disruption by Alb-Cre mice (JAX).…”

“…Although hepatocyte-specific METTL3 homozygous deficiency by Alb-iCre mice (GPT) or by Alb-Cre mice (JAX) leads to the following same phenotypes: liver injury, abnormal lipid accumulation and apoptosis observed in this study and other studies [16,17,20,24,30], these aforementioned findings from this study and other labs provide very strong evidence AGING that these phenotypes (i.e., ALF and postnatal lethality) of METTL3 Δhep mice (GPT) might be not the real functions of METTL3, and closely related with Alb-iCre mice (GPT). In addition, based on our findings, those from other labs and our in-depth discussion, we remind investigators to apply Alb-iCre mice (GPT) with caution to knockout genes in hepatocytes in vivo.…”

“…In recent years, to examine the roles of METTL3 in the physiological and pathological processes of liver, and underlying mechanisms, the investigators around the world generated mice with hepatocyte-specific METTL3 homozygous knockout (METTL3 Δhep ) by crossing METTL3 fl/fl mice with Alb-Cre mice (JAX) (in this study and in other studies [16,[20][21][22][23][24]30] or Alb-iCre mice (GPT) (in this study and in other study [17]) or with Alb-Cre-ETR 2 mice [17] or by AAV-TBG-Cre injection [30,37]. These results from this study and other studies revealed that hepatocyte-specific METTL3 homozygous knockout in mice by Alb-iCre mice (GPT) (in this study and in other study [17]) or by Alb-Cre mice (JAX) (in this study and in other studies [16,20,24,30] resulted in liver injury, abnormal lipid accumulation and apoptosis.…”

“…With deeply understanding the biochemical processes of m 6 A modification in the past decade, more and more studies have moved forward to examine the functional significance of m 6 A modification in various physiological and pathological processes, including modification plays important roles [10][11][12][13][14][15][16] in liver development [16][17][18], liver regeneration and homeostasis [19][20][21], liver glycogenesis [22], and the development and progression of liver diseases, such as liver injury [17,23,24], NAFLD [18,24,25], hepatic fibrosis [26], and hepatocellular carcinoma (HCC) [27][28][29][30][31][32].…”