脂质代谢重编程与肝细胞癌发生发展研究进展*

doi:10.3969/j.issn.1672-5069.2024.06.040

Abstract

Abstract: Hepatocellular carcinoma (HCC) has complex biological characteristics, highly heterogeneous property and immunosuppressive tumor microenvironment. HCC carries a dismal prognosis. Metabolic reprogramming (MR) is one of the most important features of tumor cells and the lipid metabolism has been an important mechanism underlying HCC growth and metastasis. In this article, we review the roles of common lipid and its metabolism-related molecules in carcinogenesis of HCC and provides new targets for therapy of HCC.

Key words: Hepatocellular carcinoma, Lipid metabolism, Metabolic reprogramming, Carcinogenesis, Targets

Li Xiaobin, Liu Bowen, Hu shiping. Lipid metabolic reprogramming in the carcinogenesis of patients with hepatocellular carcinoma[J]. Journal of Practical Hepatology, 2024, 27(6): 957-960.

References

[1] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin,2021,71(3): 209-249.
[2] Kulik L, Elserag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology,2019,156(2): 477-491.
[3] Calle EE, Rodriguez C, Walker TK, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med,2003, 348(17): 1625-1638.
[4] Pekow JR, Bhan AK, Zheng H, et al. Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis. Cancer,2007,109(12): 2490-2496.
[5] Xu X, Peng Q, Jiang X, et al. Metabolic reprogramming and epigenetic modifications in cancer: from the impacts and mechanisms to the treatment potential. Exp Mol Med,2023,55(7): 1357-1370.
[6] Cheng C, Geng F, Cheng X, et al. Lipid metabolism reprogramming and its potential targets in cancer. Cancer Commun,2018,38(1): 27.
[7] Kuerschner L, Moessinger C, Thiele C. Imaging of lipid biosynthesis: how a neutral lipid enters lipid droplets. Traffic,2008,9(3): 338-352.
[8] Sun D, Zhao T, Long K, et al. Triclosan down-regulates fatty acid synthase through microRNAs in HepG2 cells. Eur J Pharmacol,2021,907: 174261.
[9] Chen SZ, Ling Y, Yu LX, et al. 4-phenylbutyric acid promotes hepatocellular carcinoma via initiating cancer stem cells through activation of PPAR-a. Clin Transl Med,2021,11(4): e379.
[10] Baek AE, Yu YA, He S, et al. The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells. Nat Commun,2017,8(1): 864.
[11] Ward PS, Thompson CB. Metabolic reprogramming: A cancer hallmark even warburg did not anticipate. Cancer Cell,2012,21: 297-308.
[12] Feng XC, Liu FC, Chen WY, et al. Lipid metabolism of hepatocellular carcinoma impacts targeted therapy and immunotherapy. World J Gastrointest Oncol,2023,15(4): 617-631.
[13] Ribatti D, Belloni AS, Nico B,et al. Leptin-leptin receptor are involved in angiogenesis in human hepatocellular carcinoma. Peptides,2008,29(9):1596-1602.
[14] Sharma D, Wang J, Fu PP, et al. Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. Hepatology,2010,52(5): 1713-1722.
[15] Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer,2016,16(11): 732-749.
[16] Currie E, Schulze A, Zechner R, et al. Cellular fatty acid metabolism and cancer. Cell Metab,2013,18(2): 153-161.
[17] Wang M, Han J, Xing H, et al. Dysregulated fatty acid metabolism in hepatocellular carcinoma. Hepat Oncol,2016,3: 241-251.
[18] Verschueren KHG, Blanchet C, Felix J, et al. Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle. Nature,2019,568(7753): 571-575.
[19] Hu C, Xin Z, Sun X, et al. Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate hepatocellular carcinoma metastasis upon endoplasmic reticulum stress. J Exp Clin Cancer Res,2023,42(1): 108.
[20] Wakil SJ, Abuelheiga LA. Fatty acid metabolism: target for metabolic syndrome. J Lipid Res,2009,50: S138-S143.
[21] Wang MD, Wu H, Fu GB, et al. Acetyl-coenzyme A carboxylase alpha promotion of glucose-mediated fatty acid synthesis enhances survival of hepatocellular carcinoma in mice and patients. Hepatology,2016,63(4): 1272-1286.
[22] Flavin R, Peluso S, Nguyen PL, et al. Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol,2010,6(4): 551-562.
[23] Li Y, Yang W, Zheng Y,et al. Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis. J Exp Clin Cancer Res,2023,42(1): 6.
[24] Cao D, Song X, Che L, et al. Both de novo synthetized and exogenous fatty acids support the growth of hepatocellular carcinoma cells. Liver Int,2017,37(1): 80-89.
[25] Hulver MW, Berggren JR, Carper MJ, et al. Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans. Cell Metab,2005,2(4): 251-261.
[26] Liu HH, Xu Y, Li CJ, et al. An SCD1-dependent mechanoresponsive pathway promotes HCC invasion and metastasis through lipid metabolic reprogramming. Mol Ther,2022,30(7): 2554-2567.
[27] Goldberg IJ, Eckel RH, Abumrad NA. Regulation of fatty acid uptake into tissues: lipoprotein lipase-and CD36-mediated pathways. J Lipid Res, 2009,50: S86-S90.
[28] Bergers G, Fendt SM. The metabolism of cancer cells during metastasis. Nat Rev Cancer,2021,21(3): 162-180.
[29] Tao L, Ding X, Yan L, et al. CD36 accelerates the progression of hepatocellular carcinoma by promoting FAs absorption. Med Oncol,2022,39(12): 202.
[30] Luo X, Zheng E, Wei L, et al. The fatty acid receptor CD36 promotes HCC progression through activating Src/PI3K/AKT axis-dependent aerobic glycolysis. Cell Death Dis,2021,12(4): 328.
[31] Hong J, Liu J, Zhang Y, et al. MiR-3180 inhibits hepatocellular carcinoma growth and metastasis by targeting lipid synthesis and uptake. Cancer Cell Int, 2023,23(1): 66.
[32] Doege H, Baillie RA, Ortegon AM,et al. Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis. Gastroenterology,2006,130: 1245-1258.
[33] Maxfield FR, Tabas I. Role of cholesterol and lipid organization in disease. Nature,2005,438: 612-621.
[34] Neuschwander‐tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of no triglyceride fatty acid metabolites. Hepatology,2010,52: 774-788.
[35] Hu J, Liu N, Song D,et al. A positive feedback between cholesterol synthesis and the pentose phosphate pathway rather than glycolysis promotes hepatocellular carcinoma. Oncogene,2023,42(39): 2892-2904.
[36] Tang W, Zhou J, Yang W, et al. Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver. Cell Mol Immunol,2022,19(7): 834-847.
[37] Li Z, Wang Y, Xing R, et al. Cholesterol efflux drives the generation of immunosuppressive macrophages to promote the progression of human hepatocellular carcinoma. Cancer Immunol Res,2023,11(10): 1400-1413.
[38] Yuan J, Lyu T, Yang J, et al. The lipid transporter HDLBP promotes hepatocellular carcinoma metastasis through BRAF-dependent epithelial-mesenchymal transition. Cancer Lett,2022,28(549): 215921.
[39] Che L, Chi W, Qiao Y, et al. Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans. Gut,2020,69(1): 177-186.
[40] Zhang F, Gao J, Liu X, et al. LATS-regulated nuclear-cytoplasmic translocation of SREBP2 inhibits hepatocellular carcinoma cell migration and invasion via epithelial-mesenchymal transition. Mol Carcinog,2023,62(7):963-974.
[41] Shao WQ, Zhu WW, Luo MJ, et al. Cholesterol suppresses GOLM1-dependent selective autophagy of RTKs in hepatocellular carcinoma. Cell Rep,2022,39(3): 110712.
[42] Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol,2008,9: 139-150.
[43] Dressler KA, Mathias S, Kolesnick RN. Tumor necrosis factor-α activates the sphingomyelin signal transduction pathway in a cell-free system. Science,1992,255: 1715-1718.
[44] Zhang X, Zhuge J, Liu J, et al. Prognostic signatures of sphingolipids: Understanding the immune landscape and predictive role in immunotherapy response and outcomes of hepatocellular carcinoma. Front Immunol,2023,14: 1153423.
[45] Sasset L, Di LA. Sphingolipid metabolism and signaling in endothelial cell functions. Adv Exp Med Biol,2022,1372: 87-117.
[46] Wang X, Qiu Z, Dong W, et al. S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression. Cell Death Dis,2022,13(9): 768.
[47] Tagaram HR, Divittore NA, Barth BM, et al. Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma. Gut,2011,60(5): 695-701.
[48] Li G, Liu D, Kimchi ET, et al. Nanoliposome C6-ceramide increases the anti-tumor immune response and slows growth of liver tumors in mice. Gastroenterology,2018,154(4): 1024-1036.
[49] Miura K, Nagahashi M, Prasoon P,et al. Dysregulation of sphingolipid metabolic enzymes leads to high levels of sphingosine-1-phosphate and ceramide in human hepatocellular carcinoma. Hepatol Res,2021,51(5): 614-626.
[50] Cheng JC, Wang EY, Yi Y, et al. S1P stimulates proliferation by upregulating CTGF expression through S1PR2-mediated YAP activation. Mol Cancer Res,2018,16(10): 1543-1555.
[51] Li M, Tang Y, Wang D, et al. Sphingosine-1-phosphate transporter spinster homolog 2 is essential for iron-regulated metastasis of hepatocellular carcinoma. Mol Ther,2022,30(2): 703-713.
[52] Liu H, Ma Y, He HW, et al. SPHK1 (sphingosine kinase 1) induces epithelial-mesenchymal transition by promoting the autophagy-linked lysosomal degradation of CDH1/E-cadherin in hepatoma cells. Autophagy,2017,13(5): 900-913.
[53] Tallima H, Azzazy HME, El RR. Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion. Lipids Health Dis,2021,20(1): 150.
[54] Li Z, Guan M, Lin Y, et al. Aberrant lipid metabolism in hepatocellular carcinoma revealed by liver lipidomics. Int J Mol Sci,2017,18(12): 2550.
[55] Lin M, Liao W, Dong M, et al. Exosomal neutral sphingomyelinase 1 suppresses hepatocellular carcinoma via decreasing the ratio of sphingomyelin/ceramide. FEBS J,2018,285(20): 3835-3848.
[56] D’angelo G, Moorthi S, Luberto C. Role and function of sphingomyelin biosynthesis in the development of cancer. Adv Cancer Res,2018,140: 61-96.
[57] Lu H, Zhou L, Zuo H, et al. Overriding sorafenib resistance via blocking lipid metabolism and Ras by sphingomyelin synthase 1 inhibition in hepatocellular carcinoma. Cancer Chemother Pharmacol,2021,87(2): 217-228.
[58] Schnaar RL. Glycosphingolipids in cell surface recognition. Glycobiology,1991,1: 477-485.
[59] Schömel N, Geisslinger G, Wegner MS. Influence of glycosphingolipids on cancer cell energy metabolism. Prog Lipid Res,2020,79: 101050.
[60] Jennemann R, Federico G, Mathow D, et al. Inhibition of hepatocellular carcinoma growth by blockade of glycosphingolipid synthesis. Oncotarget,2017,8(65): 109201-109216.
[61] Su T, Qin XY, Dohmae N,et al. Inhibition of ganglioside synthesis suppressed liver cancer cell proliferation through targeting kinetochore metaphase signaling. Metabolites,2021,11(3): 167.
[62] Zhu J, Wang Y, Yu Y, et al. Aberrant fucosylation of glycosphingolipids in human hepatocellular carcinoma tissues. Liver Int,2014,34(1): 147-160.
[63] Zhong WX, Honke K, Long ZY, et al. Lactosylsulfatide expression in hepatocellular carcinoma cells enhances cell adhesion to vitronectin and intrahepatic metastasis in nude mice. Int J Cancer,2004,110(4): 504-510.
[64] Makide K, Kitamura H, Sato Y, et al. Emerging lysophospholipid mediators, lysophosphatidylserine, lysophosphatidylthreonine, lysophosphatidylethanolamine and lysophosphatidylglycerol. Prostaglandins Other Lipid Mediat,2009,89(3-4): 135-139.
[65] Grzelczyk A, Gendaszewska-darmach E. Novel bioactive glycerol-based lysophospholipids: new data --new insight into their function. Biochimie,2013,95(4): 667-679.
[66] Ouben AJ, Moolenaar WH. Autotaxin and LPA receptor signaling in cancer. Cancer Metastasis Rev,2011,30(3-4): 557-565.
[67] Guri Y, Colombi M, Dazert E, et al. mTORC2 promotes tumorigenesis via lipid synthesis. Cancer Cell,2017,32(6): 807-823.
[68] Zhong H, Xiao M, Zarkovic K, et al. Mitochondrial control of apoptosis through modulation of cardiolipin oxidation in hepatocellular carcinoma: A novel link between oxidative stress and cancer. Free Radic Biol Med,2017,102: 67-76.
[69] Guan Y, Chen X, Wu M, et al. The phosphatidylethanolamine biosynthesis pathway provides a new target for cancer chemotherapy. J Hepatol,2020,72(4): 746-760.
[70] Cheng X, Li L, Thorpe PE, et al. Antibody-mediated blockade of phosphatidylserine enhances the antitumor effect of sorafenib in hepatocellular carcinomas xenografts. Ann Surg Oncol,2016,23: 583-591.
[71] Mokdad AA, Zhu H, Beg MS, et al. Efficacy and safety of bavituximab in combination with sorafenib in advanced hepatocellular carcinoma: A single-arm, open-label, phase II clinical trial. Target Oncol,2019,14(5): 541-550.

Lipid metabolic reprogramming in the carcinogenesis of patients with hepatocellular carcinoma

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	Zhang Shaobo, Zhang Shugeng, Liu Lianxin. Immunotherapy in hepatocellular carcinoma patients after liver transplantation:Current knowledge and future perspectives [J]. Journal of Practical Hepatology, 2024, 27(6): 801-803.
[2]	Zheng Hao, Zhang Shugeng, Wang Jiabei, et al. Therapeutic strategies for patients with recurrent hepatocellular carcinoma after liver transplantation [J]. Journal of Practical Hepatology, 2024, 27(6): 804-807.
[3]	Zhu Zebin, Zhang Shugeng, Liu Lianxin. Targeted therapy and immunotherapy in downstaging of patients with hepatocellular carcinoma before liver transplantation [J]. Journal of Practical Hepatology, 2024, 27(6): 808-811.
[4]	Zeng Wang, Cai Xiaoman, Ge Shang. Enhanced MRI manifestation feature in differential diagnosis of ICC and HCC: A single center study [J]. Journal of Practical Hepatology, 2024, 27(6): 907-910.
[5]	Danba Yuzhen, Cheng Pan. Gd-EOB-DTPA-enhanced MRI scan in diagnosis of patients with hepatocellular carcinoma [J]. Journal of Practical Hepatology, 2024, 27(6): 911-914.
[6]	Yang Jiaxin, Yang Zijun, Chen Wei. Image quality and diagnostic efficacy of dual-source CT dual-energy TNC technique in patients with hepatocellular carcinoma [J]. Journal of Practical Hepatology, 2024, 27(6): 915-918.
[7]	Wang Lingling, Yao Min, Yao Dengfu. Abnormal expressions of Krüppel-like factors in progression of hepatocellular carcinoma [J]. Journal of Practical Hepatology, 2024, 27(6): 953-956.
[8]	Zhang Weiping, Ge Hongyan. Pyroptosis and its roles in hepatocellular carcinogenesis [J]. Journal of Practical Hepatology, 2024, 27(5): 797-800.
[9]	Luo Ke, Ding Li, Liu Mei. Cancerous expression of TTF-1, p53 and p63 proteins in patients with hepatocellular carcinoma [J]. Journal of Practical Hepatology, 2024, 27(3): 434-437.
[10]	Yan Zhen, Zhao Bowen, Lin Guoying, et al. Clinical application of imaging three-dimensional visualization technique in guidance of hepatectomy in patients with hepatocellular carcinoma [J]. Journal of Practical Hepatology, 2024, 27(3): 438-441.
[11]	Wei Ye, Wang Shiyu, Ge Gaohua, et al.. Is the magnetic resonance imaging superior to CT scan in the differential diagnosis of hepatic hemangioma and hepatocellular carcinoma? [J]. Journal of Practical Hepatology, 2024, 27(2): 279-282.
[12]	Ye Mengmeng, Deng Zerun, Zhang Tao. Improved benefit of camrelizumab and apatinib combination in the treatment of patients with advanced hepatocellular carcinoma [J]. Journal of Practical Hepatology, 2024, 27(1): 96-100.
[13]	Zhou Li, Ding Yunqing, Yuan Fengying, et al. Diagnostic performance of contrast-enhanced ultrasound in determining qualitatively intrahepatic space-occupying lesions in patients with hepatitis B liver cirrhosis [J]. Journal of Practical Hepatology, 2023, 26(6): 903-906.
[14]	Han Shishan, Zhao Caiyan. Perspective of betatrophin in the development of nonalcoholic fatty liver diseases [J]. Journal of Practical Hepatology, 2023, 26(6): 930-933.
[15]	Su Peihua, Song Meifang, Zhao Caiyan. Is the incidence of hepatocellular carcinoma increased in patients with chronic hepatitis B and nonalcoholic fatty liver diseases? [J]. Journal of Practical Hepatology, 2023, 26(3): 445-448.