Abstract
SummaryLiver progenitor cells (LPCs) have a remarkable contribution to the hepatocytes and ductal cells when normal hepatocyte proliferation is severely impaired. As a biomarker for LPCs, Sry-box 9 (Sox9) plays critical roles in liver homeostasis and repair in response to injury. However, the regulation mechanism of Sox9 in liver physiological and pathological state remains unknown. In this study, we found that miR-126 positively regulated the expression of Sox9, the proliferation and differentiation of SOX9+ LPCs by suppressing the translation of homeobox b6 (Hoxb6). As a transcription factor, HOXB6 directly binds to the promoter of Sox9 to inhibit Sox9 expression, resulting in the destruction of the properties of SOX9+ LPCs in CCl4-induced liver injury. These findings revealed the role of miR-126 in regulating SOX9+ LPCs fate by targeting Hoxb6 in liver injury repair. Our findings suggest the potential role of miR-126 as a nucleic acid therapy drug target for liver failure.
Highlights
MicroRNAs, a class of endogenous, small noncoding RNAs composed of $22 nucleotides, bind to partial complementary sequences in the 3ʹ untranslated region (UTR) of their target transcripts and recruit RNAinduced silencing complex to inhibit the translation of these transcripts, they are involved in the regulation of cellular functions (Bartel, 2018; Mori et al, 2019)
The knockdown of miR-126 in bone marrow stromal cells (BMSCs) accelerated cell aging and inhibited hepatic repair functions of BMSCs (Yan et al, 2019). These results indicated that miR-126 might be involved in hepatic aging through liver stem cells (LSCs) or liver progenitor cells (LPCs)
MiR-126 Promotes SOX9 Expression and Induces SOX9+ Liver progenitor cells (LPCs) Recent investigation has revealed that miRNAs are involved in liver regeneration and might serve as the therapeutic approach to liver fibrosis (John et al, 2014; Tsay et al, 2019)
Summary
MicroRNAs (miRNAs), a class of endogenous, small noncoding RNAs composed of $22 nucleotides, bind to partial complementary sequences in the 3ʹ untranslated region (UTR) of their target transcripts and recruit RNAinduced silencing complex to inhibit the translation of these transcripts, they are involved in the regulation of cellular functions (Bartel, 2018; Mori et al, 2019). A recent study suggests that miRNAs, which are abundant in liver, can modulate a wide range of hepatocellular functions (Su et al, 2018). Our previous research showed that hepatic miR-657 enhanced nuclear factor kB activity to promote hepatocellular carcinoma cell growth and transformation (Zhang et al, 2013). MiR-122 has been identified as a biomarker of acute liver failure in mice and humans (John et al, 2014; Luna et al, 2017). The newly reported miR-221-3p reduced secretion of CCR2 through post-transcription regulation of Gnai, mitigating liver fibrosis (Tsay et al, 2019). The above-mentioned examples indicated that miRNAs play a critical role in liver physiological and pathological regulation. The specific roles of miRNAs in liver regeneration and repair, especially in regulating hepatic stem cell properties remain to be examined
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