CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Akt/mTOR/SREBP1c and P38/PPARα pathways.
OBJECTIVE
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.


CONCLUSIONS
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.
State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China; State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
Jibin
J
Li
State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
Qichao
Q
Huang
State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
Xiaoyu
X
Long
State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
Jing
J
Zhang
State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
Xiaojun
X
Huang
Laboratory of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 21009, China.
Jiye
J
Aa
Division of Population Science, Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Hushan
H
Yang
State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
Zhinan
Z
Chen
State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China. Electronic address: xingjl@fmmu.edu.cn.
Jinliang
J
Xing
D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D042962:Acyl-CoA Oxidase / Q000235:genetics; D000818:Animals; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D045744:Cell Line, Tumor; D054890:Fatty Acid Synthase, Type I / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D006801:Humans; D050155:Lipogenesis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
C497886:BSG protein, human; D005227:Fatty Acids; D047493:PPAR alpha; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051926:Basigin; D042962:Acyl-CoA Oxidase; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase
EMMPRIN; Fatty acid β-oxidation; HCC; Metabolic reprogramming; de novo lipogenesis