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Background & Aims Activated hepatic stellate cells (HSCs) located in the Disse's space play a crucial role in liver fibrosis. HAb18G/CD147, a tumor-related glycoprotein, is highly expressed in hepatocellular carcinoma cells and fibroblasts. Whether HAb18G/CD147 plays an important role in the hepatic fibrogenesis is unknown. Methods Immunohistochemistry for HAb18G/CD147 and α-smooth muscle actin expression in diseased liver tissues was used for correlation analysis. The function of HAb18G/CD147 in fibrogenesis was evaluated with the human HSCs LX-2 cell line and carbon tetrachloride-induced mouse liver fibrosis model. The specific antibody HAb18 targeting HAb18G/CD147 was injected intravenously into the mouse to investigate whether HAb18G/CD147 could be a potential target for liver fibrosis treatment. Results HAb18G/CD147 is highly expressed on activated HSCs in the sinusoid. The positive rates of HAb18G/CD147 expression in human HBV-related liver cirrhosis, liver biopsy with HBV and liver adjacent to hemangioma were 95.6% (65/68), 14.8% (8/54) and 6.4% (8/125), respectively. HAb18G/CD147 expression was significantly correlated with the Child–Pugh grade (r=0.2848, p =0.0186) and with the expression of α-smooth muscle actin in HSCs (r=0.4434, p =0.0002) in liver cirrhosis. Transforming growth factor-β1 upregulated HAb18G/CD147 expression in LX-2 cells. Transfection of HAb18G/CD147 promoted the profibrogenic genes expression. In mouse liver fibrosis model, HAb18G/CD147 expression increased with the development of fibrogenesis and decreased during the liver fibrosis spontaneous recovery. The HAb18 targeting HAb18G/CD147 could attenuate liver fibrosis. Conclusions These data suggest that HAb18G/CD147 plays a role in HSC activation and is a potential therapeutic target in fibrosis/cirrhosis.

Background & Aims CD147 is a transmembrane glycoprotein which is highly expressed in various human cancers including hepatocellular carcinoma (HCC). A drug Licartin developed with 131 Iodine-labeled antibody against CD147 has been approved by the Chinese Food and Drug Administration (FDA) and enters into clinical use for HCC treatment. Increasing lines of evidence indicate that CD147 is implicated in the metabolism of cancer cells, especially glycolysis. However, the molecular mechanism underlying the relationship between CD147 and aberrant tumor lipid metabolism remains elusive. Methods We systematically investigated the role of CD147 in the regulation of lipid metabolism, including de novo lipogenesis and fatty acid β-oxidation, in HCC cells and explored the underlying molecular mechanisms. Results Bioinformatic analysis and experimental evidence demonstrated that CD147 significantly contributed to the reprogramming of fatty acid metabolism in HCC cells mainly through two mechanisms. On one hand, CD147 upregulated the expression of sterol regulatory element binding protein 1c (SREBP1c) by activating the Akt/mTOR signaling pathway, which in turn directly activated the transcription of major lipogenic genes FASN and ACC1 to promote de novo lipogenesis. On the other hand, CD147 downregulated peroxisome proliferator-activated receptor alpha (PPARα) and its transcriptional target genes CPT1A and ACOX1 by activating the p38 MAPK signaling pathway to inhibit fatty acid β-oxidation. Moreover, in vitro and in vivo assays indicated that the CD147-mediated reprogramming of fatty acid metabolism played a critical role in the proliferation and metastasis of HCC cells. Conclusion Our findings demonstrate that CD147 is a critical regulator of fatty acid metabolism, which provides a strong line of evidence for this molecule to be used as a drug target in cancer treatment.

Background & Aims Cancer cells exhibit the reprogrammed metabolism characterized by high level of glycolysis even in the presence of oxygen. Aerobic glycolysis, known as the Warburg effect, supplies cancer cells with the substrates required for biomass generation. To date, several intracellular signaling mediators have been identified in metabolic regulation of cancer cells. However, it remains largely ambiguous how molecules on the cell surface are involved in regulation of cancer metabolism. Methods In the current study, we established several HCC cell lines differing in their CD147 (a typical transmembrane glycoprotein) expression status by zinc-finger nuclease and RNAi techniques. Then, we systematically investigated the role of CD147 in the regulation of the Warburg effect in HCC cells and explored the underlying mechanism. Results We found that CD147 significantly contributed to the reprogramming of glucose metabolism in HCC cells through a p53-dependent way. CD147 facilitated the cell surface expression of MCT1 and lactate export, which led to activation of the PI3K/Akt/MDM2 pathway and thus increased p53 degradation. The gain/loss-of-function studies demonstrated that while CD147 promoted glycolysis, mediated by p53-dependent upregulation of GLUT1 and activation of PFKL, it inhibited mitochondrial biogenesis and functions, mediated by p53-dependent downregulation of PGC1α, TFAM, and p53R2. Additionally, proliferation of HCC cells was suppressed by blocking CD147 and/or MCT1, which resulted in down-regulation of glucose metabolism. Conclusions We demonstrate that CD147 is a crucial regulator of glucose metabolism.