Hepatocytic Prominin-1 protects against liver fibrosis by stabilizing the SMAD7 protein

Abstract

Background and Aims:Prominin-1 (PROM1) is known to be upregulated in hepatocytic progenitor cells (HPCs) and cholangiocytes of fibrotic livers. To understand the function of upregulated PROM1 during liver fibrosis, we analyzed liver fibrosis from global and liverspecific Prom1 knockout mice and investigated the molecular mechanism of how Prom1 protects the liver against liver fibrosis. Methods:We analyzed PROM1 expression from human liver with mild and severe liver fibrosis (n=4-9). Liver fibrosis was induced by carbon tetrachloride (CCl 4 ) treatment and bile duct ligation (BDL) from wild type and global and liver-specific knockout mice (n=3-13).The severity of liver fibrosis was determined by qRT-PCR, immunostaining and immunoblotting for fibrotic markers such as αSMA, collagen. TGFβ signaling was also analyzed from fibrotic liver and primary hepatocytes of wild type and global and liverspecific knockout mice (n=3-5). Molecular interaction between PROM1 and SMAD7 was determined by endogenous and exogenous co-immunoprecipitation.Results: PROM1 was found in the plasma membranes of both healthy and fibrotic hepatocytes and cholangiocytes. Global Prom1 knockout aggravated BDL-and CCl 4 -induced liver fibrosis. Prom1 -/hepatocytes showed increased TGFβ signaling due to reduced SMAD7 protein expression compared to that in wild-type hepatocytes. PROM1 prevented SMURF2-induced SMAD7 ubiquitination and degradation by interfering with the molecular association of SMAD7 with SMURF2. We also demonstrated that liver-specific Prom 1 knockout aggravated BDL-induced liver fibrosis due to reduced levels of SMAD7. Conclusion:Hepatocytic PROM1 stabilizes SMAD7, preventing TGFβ signaling. Thus, PROM1 is necessary for the negative regulation of TGFβ signaling during liver fibrosis.

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

“…PROM1 is well known as a marker for cancer stem cells and normal stem cells. Recent studies have revealed its ability to regulate various cellular signal transduction pathways by interacting with PI3K, HDAC6, radixin, and SMAD7 [15,16,21,22]. Here, we demonstrated that PROM1 is also necessary for regulating IL-6 signaling during liver regeneration.…”

“…Because hepatocellular PROM1 upregulation is also observed after bile duct ligation (BDL) [16] and a lithogenic diet (data not shown), various liver damages might lead to hepatocellular PROM1 upregulation. Many extracellular and intracellular factors, such as HIF-1, TGF1, p53 and mTOR, regulate the expression of PROM1 [12,23].…”

“…In addition to cancer stem cells, PROM1 is also expressed in normal stem cells, including hematopoietic stem cells and various epithelial cells, in the brain, kidney, digestive track, and liver [12][13][14]. In addition, PROM1 has been known to regulate the glucagon and TGF- signaling pathways in the liver by interacting with radixin and SMAD7, respectively [15,16].…”

“…Because PROM1, a marker for hepatic progenitor cells, is also upregulated in hepatocytes after liver injury [16], the upregulated PROM1 might regulate various signaling pathways related to hepatocyte proliferation. Here, we observed a significant increase in the expression of PROM1 in hepatocytes during liver regeneration after PHx or CCl4 injection.…”

Diamond Nanofilm Normalizes Proliferation and Metabolism in Liver Cancer Cells

“…The diamond surface stimulated the overexpression of several potential oncogenes, such as NUP37, USP17L10, PROM1, MACROH2A1 and LAMTOR1. 79,[98][99][100][101] Overexpression of the nuclear pore structural protein NUP37 in the context of research by Luo et al 98 indicates growth promotion of HepG2 cancer cells by altering signal transduction to the nucleus. Studies on another protein, USP17, have shown that deubiquitination with its participation is a process necessary for the progression of the cell cycle and the G1/S phase transition of cancer cells.…”