Suppression of lethal‐7b and miR‐125a/b Maturation by Lin28b Enables Maintenance of Stem Cell Properties in Hepatoblasts

Abstract

In liver development, hepatoblasts that act as hepatic stem/progenitor cells proliferate and differentiate into both hepatocytes and cholangiocytes to form liver tissues. Although numerous factors contribute to this event, little is known about the roles of microRNAs in hepatoblast proliferation and differentiation. In this study, we focused on the lineage-28 (Lin28) family proteins, which are required for microRNA regulation in pluripotent stem cells and cancer cells, and investigated their roles as regulatory factors for the properties of hepatoblasts. Conclusion: Lin28b was specifically expressed in hepatoblasts, and its suppression induced growth arrest and cholangiocyte differentiation of hepatoblasts; mechanistically, Lin28b positively regulates the expression of Lin28b itself and cell cycle-related proteins in hepatoblasts by suppressing the maturation of target microRNAs, lethal-7b and miR-125a/b, enabling maintenance of the stem cell properties of hepatoblasts, such as their capabilities for proliferation and bi-lineage differentiation, during liver development. (HEPATOLOGY 2016;64:245-260) M icroRNAs (miRNAs), which are composed of 20-25 nucleotides of RNA, bind to partial complementary sequences in the 3 0 -untranslated region (UTR) of their target transcripts, recruit RNA-induced silencing complex to inhibit the translation of these transcripts, and are involved in the regulation of many aspects of cellular function. (1)(2)(3)(4)(5)(6) Regarding the involvement of miRNAs in liver development, miR-122 is highly expressed in the liver after embryonic day (E) 11.5 and contributes to the progression of liver development by suppressing Cut-like homeobox 1 (also known as CCAAT displacement protein), which acts as a transcriptional repressor against terminal differentiation of hepatocytes. (7) It was also reported that miR-23b interferes with the differentiation of cholangiocytes through suppression of the transforming growth factor-b signaling pathway by targeting Smad3/4/5 in the liver of E16.5-E17.5 mouse embryos. (8) Moreover, miR-346 and miR-500 are highly expressed in the developing liver, and their expression gradually decreases in accordance with the progression of liver development. (9) Conversely, miR-30 is specifically expressed in cholangiocytes between E18.5 and neonatal stages and contributes to bile duct formation by targeting trinucleotide repeat containing 6a, which is a subunit of the RNA-induced silencing

The miR-125a/HK2 axis regulates cancer cell energy metabolism reprogramming in hepatocellular carcinoma

“…Previous studies have shown that miR-125a plays a tumor-suppressive role in various cancers through negatively regulating tumor oncogenes 33–36 . For example, miR-125a was found to be an independent prognostic factor and inhibit proliferation of gastric cancer 37 and miR-125a function as tumor suppressor by regulating abnormal activity of SIRT7 in human HCC tumorigenesis 38 .…”

Involvement of inflammation and its related microRNAs in hepatocellular carcinoma

“…Meanwhile, signaling pathways that regulate the LPCs/CSCs fate have been suggested, such as bone morphogenetic protein (BMP), fibroblast growth factor (FGF), Wnt, oncostatin M (OSM), TGF-β, Jagged1/Notch, IL-6/STAT3, and hepatocyte growth factor (HGF)/c-Met [3, 31]. Moreover, expression patterns of miRNAs in EpCAM + hepatic CSCs differ from that in LPCs, and miRNAs such as Let-7 family members, miR-125a/b and miR-452 are also involved in determination and maintenance of LPCs/CSCs [79–81]. It is worth noting that a series of intriguing questions have not been addressed.…”

Lowered expression of microRNA-125a-5p in human hepatocellular carcinoma and up-regulation of its oncogenic targets sirtuin-7, matrix metalloproteinase-11, and c-Raf

“…Today, it is present in all animals with bilateral symmetry and its nucleotide sequence is very well conserved, with an 11 nucleotide stretch encompassing the seed region that is identical in all species analyzed [24]. This microRNA plays a fundamental role in downregulating Lin-28 protein, thus promoting phase transitions in development and/or cell differentiation in nematodes, insects and mammals [36–39]. In mammalians, miR-125a appears to be expressed in most tissues, mainly targeting membrane receptors or intracellular signal transductors of mitogenic signals, thus limiting cell proliferation.…”