Central role of Prominin-1 in lipid rafts during liver regeneration

Abstract

Prominin-1, a lipid raft protein, is required for maintaining cancer stem cell properties in hepatocarcinoma cell lines, but its physiological roles in the liver have not been well studied. Here, we investigate the role of Prominin-1 in lipid rafts during liver regeneration and show that expression of Prominin-1 increases after 2/3 partial hepatectomy or CCl4 injection. Hepatocyte proliferation and liver regeneration are attenuated in liver-specific Prominin-1 knockout mice compared to wild-type mice. Detailed mechanistic studies reveal that Prominin-1 interacts with the interleukin-6 signal transducer glycoprotein 130, confining it to lipid rafts so that STAT3 signaling by IL-6 is effectively activated. The overexpression of the glycosylphosphatidylinsositol-anchored first extracellular domain of Prominin-1, which is the domain that binds to GP130, rescued the proliferation of hepatocytes and liver regeneration in liver-specific Prominin-1 knockout mice. In summary, Prominin-1 is upregulated in hepatocytes during liver regeneration where it recruits GP130 into lipid rafts and activates the IL6-GP130-STAT3 axis, suggesting that Prominin-1 might be a promising target for therapeutic applications in liver transplantation.

PROM1-mediated cell signal transduction in cancer stem cells and hepatocytes

“…Because PROM1-positive cells possess more TNTs than PROM1-negative cells, PROM1 could be one of the driving forces to generate TNTs in vitro . However, because PROM1 deficiency does not alter the structure of membrane extrusion, such as microvilli in the hepatocytes of mouse liver under electron microscopy ( 14 ), the role of PROM1 in TNT formation remains to be solved in vivo .…”

“…The non-parenchymal cells are composed of various cell types: cholangiocyte, hepatic progenitor cells, hepatic stellate cells, and Kupffer cells ( 49 ). In the liver, PROM1 is mainly known as a hepatic progenitor cell marker, but is also expressed in hepatocytes and cholangiocytes ( 12 - 14 ). The immunofluorescence and electron microscopy of PROM1 show that PROM1 is expressed in microvilli, as well as the plane plasma membrane of mouse hepatocytes.…”

“…The expression of PROM1 in the liver is upregulated by various liver injuries, such as choline-deficient, ethionine-supplemented diet (CDE) ( 50 ), bile duct ligation (BDL)-induced cholestasis ( 13 ), CCl 4 ( 14 , 42 ), and 2/3 partial hepatectomy (PHx) ( 14 ). The immunofluorescence and lineage tracing study of PROM1 show that the expression of PROM1 is increased mainly in hepatocytes rather than in cholangiocytes, progenitor cells, and stellate cells of BDL and PHx liver ( 13 , 14 ).…”

“…Bahn et al . found that PROM1 is required for hepatocyte proliferation during liver regeneration after acute liver injury, such as CCl 4 injection or PHx ( 14 ). Liver-specific Prom1 deficiency delays liver regeneration with reduced hepatocyte proliferation.…”

“…Because of its discovery in CSCs, it has been studied for decades as a target for cancer therapeutics ( 1 - 4 , 10 , 11 ). Recently, PROM1 has been extensively investigated in normal organs, such as liver, intestine, central and peripheral nervous system, eyes, and tooth, using PROM1-deficient mice ( 12 - 19 ). Here, we discuss the precise molecular mechanisms for the physiological functions of PROM1 in different organs.…”