Hepatocyte-specific Prominin-1 protects against liver injury-induced fibrosis by stabilizing SMAD7

Abstract

Prominin-1 (PROM1), also known as CD133, is expressed in hepatic progenitor cells (HPCs) and cholangiocytes of the fibrotic liver. In this study, we show that PROM1 is upregulated in the plasma membrane of fibrotic hepatocytes. Hepatocellular expression of PROM1 was also demonstrated in mice (Prom1CreER; R26TdTom) in which cells expressed TdTom under control of the Prom1 promoter. To understand the role of hepatocellular PROM1 in liver fibrosis, global and liver-specific Prom1-deficient mice were analyzed after bile duct ligation (BDL). BDL-induced liver fibrosis was aggravated with increased phosphorylation of SMAD2/3 and decreased levels of SMAD7 by global or liver-specific Prom1 deficiency but not by cholangiocyte-specific Prom1 deficiency. Indeed, PROM1 prevented SMURF2-induced SMAD7 ubiquitination and degradation by interfering with the molecular association of SMAD7 with SMURF2. We also demonstrated that hepatocyte-specific overexpression of SMAD7 ameliorated BDL-induced liver fibrosis in liver-specific Prom1-deficient mice. Thus, we conclude that PROM1 is necessary for the negative regulation of TGFβ signaling during liver fibrosis.

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

“…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 ).…”

“…PROM1 deficiency aggravates BDL-induced liver fibrosis ( 13 ). The first intracellular domain of PROM1 interacts with SMAD7, a negative regulator of the TGFβ-SMAD2/3 signaling, inhibiting SMAD7 ubiquitination ( Fig.…”

“…However, PROM1 is expressed only in the periportal region of the liver and aggravates liver fibrosis in the rhesus rotavirus (RRV) model ( 51 ), challenging the protective role of PROM1 in liver fibrosis. Lee et al ., ( 13 ) showed that PROM1 is upregulated mainly in the hepatocytes of BDL liver by multiple methods, such as immunofluorescence and PROM1 lineage tracing analysis. In addition, they elucidated that the function of PROM1 is predominant in hepatocytes over cholangiocytes by analyzing cholangiocyte-specific Prom1 knockout mice and hepatocyte-specific SMAD7 overexpression mice ( Table 1 ).…”

“…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.…”