肝细胞癌中糖异生代谢异常的研究进展

罗赛芳; 马向明; 曹立瀛

doi:10.3969/j.issn.1001-5256.2022.09.042

肝细胞癌中糖异生代谢异常的研究进展

DOI: 10.3969/j.issn.1001-5256.2022.09.042

华北理工大学附属开滦总医院肝胆外科，河北唐山 063000

基金项目:

河北省2020年度医学科学研究课题计划 (20201285)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：罗赛芳负责资料分析，撰写论文；马向明参与修改论文；曹立瀛负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
曹立瀛，caoliying153@126.com

计量
- 文章访问数: 650
- HTML全文浏览量: 443
- PDF下载量: 72
- 被引次数: 0
出版历程
- 收稿日期: 2022-02-23
- 录用日期: 2022-04-05
- 出版日期: 2022-09-20

Research advances in abnormal gluconeogenesis in hepatocellular carcinoma

Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology, Tangshan, Hebei 063000, China

Research funding:

2020 Medical Science Research Project Plan of Hebei Province (20201285)

More Information

Corresponding author: CAO Liying, caoliying153@126.com(ORCID: 0000-0003-3662-5961)

摘要

摘要: 肿瘤在有氧环境中仍然进行糖酵解以加速对肿瘤微环境中的葡萄糖摄取和产生大量乳酸，为肿瘤细胞增殖提供所需的核苷酸、脂质和蛋白质的生物分子前体，以及可抑制免疫细胞的功能而促进肿瘤细胞的转移。糖异生代谢作为糖酵解的逆反应在肝细胞癌中处于抑制状态，尤其是丙酮酸羧化酶、磷酸烯醇式丙酮酸羧激酶、果糖-1, 6-二磷酸酶1和葡萄糖-6-磷酸酶4个关键限速酶的表达下调，通过促进有氧糖酵解及其分支途径而促进肝细胞癌的生长和增殖，同时也与肝细胞癌患者的总生存期和预后相关，被认为是肝细胞癌的抑制因子。基于此，本文总结了糖异生代谢关键酶在肝细胞癌发生发展中的变化及其作用机制，并分析了其在肝细胞癌中相关研究的不足和未来方向，期望为肝细胞癌的治疗提供新思路。
- 癌, 肝细胞 /
- 糖原异生 /
- 代谢
Abstract: Tumors still perform glycolysis in the aerobic environment to accelerate the uptake of glucose and produce a large amount of lactic acid in tumor microenvironment, provide biomolecular precursors of nucleotides, lipids, and proteins for tumor cell proliferation, and inhibit the function of immune cells and promote the metastasis of tumor cells in acidic environment. Gluconeogenesis, as the reverse reaction of glycolysis, is inhibited in hepatocellular carcinoma, especially the downregulated expression of the four key rate-limiting enzymes pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-diphosphate 1, and glucose-6-phosphatase 4, which promotes the growth and proliferation of hepatocellular carcinoma by promoting aerobic glycolysis and its branched pathways, and meanwhile, it is also associated with the overall survival time and prognosis of patients with hepatocellular carcinoma and is considered an inhibitor for hepatocellular carcinoma. Therefore, this review summarizes the changes and mechanism of action of the key enzymes of gluconeogenesis in the development and progression of hepatocellular carcinoma and analyzes the shortcomings and future directions of related research in hepatocellular carcinoma, so as to provide new ideas for the treatment of hepatocellular carcinoma.
- Carcinoma, Hepatocellular /
- Gluconeogenesis /
- Metabolism

HTML全文

图 1 肿瘤代谢中的糖酵解和糖异生

Figure 1. Glycolysis and gluconeogenesis in tumor metabolism

下载: 全尺寸图片幻灯片

图 2 PEPCK与肝细胞癌

Figure 2. PEPCK and hepatocellular carcinoma

下载: 全尺寸图片幻灯片

图 3 FBP1与肝细胞癌

Figure 3. FBP1 and hepatocellular carcinoma

下载: 全尺寸图片幻灯片

参考文献(54)

[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[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660.
[2]	VIBERT E, SCHWARTZ M, OLTHOFF KM. Advances in resection and transplantation for hepatocellular carcinoma[J]. J Hepatol, 2020, 72(2): 262-276. DOI: 10.1016/j.jhep.2019.11.017.
[3]	WARBURG O. On the origin of cancer cells[J]. Science, 1956, 123(3191): 309-314. DOI: 10.1126/science.123.3191.309.
[4]	VANDER HEIDEN MG, CANTLEY LC, THOMPSON CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation[J]. Science, 2009, 324(5930): 1029-1033. DOI: 10.1126/science.1160809.
[5]	DEBERARDINIS RJ, LUM JJ, HATZIVASSILIOU G, et al. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation[J]. Cell Metab, 2008, 7(1): 11-20. DOI: 10.1016/j.cmet.2007.10.002.
[6]	QIAO WJ, LIU XJ. Research progress on reprogramming of T cell glycometabolism and anti-tumor immunotherapy[J]. Chin J Cancer Biother, 2022, 29(1): 75-79. https://www.cnki.com.cn/Article/CJFDTOTAL-ZLSW202201012.htm 乔万佳, 刘小军. T细胞糖代谢重编程与抗肿瘤免疫治疗的研究进展[J]. 中国肿瘤生物治疗杂志, 2022, 29(1): 75-79. https://www.cnki.com.cn/Article/CJFDTOTAL-ZLSW202201012.htm
[7]	FISCHER K, HOFFMANN P, VOELKL S, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells[J]. Blood, 2007, 109(9): 3812-3819. DOI: 10.1182/blood-2006-07-035972.
[8]	FENG J, LI J, WU L, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma[J]. J Exp Clin Cancer Res, 2020, 39(1): 126. DOI: 10.1186/s13046-020-01629-4.
[9]	SMOLLE E, LEKO P, STACHER-PRIEHSE E, et al. Distribution and prognostic significance of gluconeogenesis and glycolysis in lung cancer[J]. Mol Oncol, 2020, 14(11): 2853-2867. DOI: 10.1002/1878-0261.12780.
[10]	LEITHNER K, TRIEBL A, TRÖTZMVLLER M, et al. The glycerol backbone of phospholipids derives from noncarbohydrate precursors in starved lung cancer cells[J]. Proc Natl Acad Sci U S A, 2018, 115(24): 6225-6230. DOI: 10.1073/pnas.1719871115.
[11]	VINCENT EE, SERGUSHICHEV A, GRISS T, et al. Mitochondrial phosphoenolpyruvate carboxykinase regulates metabolic adaptation and enables glucose-independent tumor growth[J]. Mol Cell, 2015, 60(2): 195-207. DOI: 10.1016/j.molcel.2015.08.013.
[12]	LU C, REN C, YANG T, et al. Fructose-1, 6-bisphosphatase 1 interacts with NF-κB p65 to regulate breast tumorigenesis via PIM2 induced phosphorylation[J]. Theranostics, 2020, 10(19): 8606-8618. DOI: 10.7150/thno.46861.
[13]	LI K, YING M, FENG D, et al. Fructose-1, 6-bisphosphatase is a novel regulator of Wnt/β-Catenin pathway in breast cancer[J]. Biomed Pharmacother, 2016, 84: 1144-1149. DOI: 10.1016/j.biopha.2016.10.050.
[14]	WANG Z, DONG C. Gluconeogenesis in cancer: Function and regulation of PEPCK, FBPase, and G6Pase[J]. Trends Cancer, 2019, 5(1): 30-45. DOI: 10.1016/j.trecan.2018.11.003.
[15]	WANG B, HSU SH, FRANKEL W, et al. Stat3-mediated activation of microRNA-23a suppresses gluconeogenesis in hepatocellular carcinoma by down-regulating glucose-6-phosphatase and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha[J]. Hepatology, 2012, 56(1): 186-197. DOI: 10.1002/hep.25632.
[16]	ZOU J, ZHU X, XIANG D, et al. LIX1-like protein promotes liver cancer progression via miR-21-3p-mediated inhibition of fructose-1, 6-bisphosphatase[J]. Acta Pharm Sin B, 2021, 11(6): 1578-1591. DOI: 10.1016/j.apsb.2021.02.005.
[17]	LIU MX, JIN L, SUN SJ, et al. Metabolic reprogramming by PCK1 promotes TCA cataplerosis, oxidative stress and apoptosis in liver cancer cells and suppresses hepatocellular carcinoma[J]. Oncogene, 2018, 37(12): 1637-1653. DOI: 10.1038/s41388-017-0070-6.
[18]	GRASMANN G, SMOLLE E, OLSCHEWSKI H, et al. Gluconeogenesis in cancer cells - Repurposing of a starvation-induced metabolic pathway?[J]. Biochim Biophys Acta Rev Cancer, 2019, 1872(1): 24-36. DOI: 10.1016/j.bbcan.2019.05.006.
[19]	HAMMOND KD, BALINSKY D. Activities of key gluconeogenic enzymes and glycogen synthase in rat and human livers, hepatomas, and hepatoma cell cultures[J]. Cancer Res, 1978, 38(5): 1317-1322. http://hwmaint.cancerres.aacrjournals.org/cgi/reprint/38/5/1317.pdf
[20]	LEE MH, DEBERARDINIS RJ, WEN X, et al. Active pyruvate dehydrogenase and impaired gluconeogenesis in orthotopic hepatomas of rats[J]. Metabolism, 2019, 101: 153993. DOI: 10.1016/j.metabol.2019.153993.
[21]	HIRATA H, SUGIMACHI K, KOMATSU H, et al. Decreased expression of fructose-1, 6-bisphosphatase associates with glucose metabolism and tumor progression in hepatocellular carcinoma[J]. Cancer Res, 2016, 76(11): 3265-3276. DOI: 10.1158/0008-5472.CAN-15-2601.
[22]	CHENG L, HU S, MA J, et al. Long noncoding RNA RP11-241J12.3 targeting pyruvate carboxylase promotes hepatocellular carcinoma aggressiveness by disrupting pyruvate metabolism and the DNA mismatch repair system[J]. Mol Biomed, 2022, 3(1): 4. DOI: 10.1186/s43556-021-00065-w.
[23]	XU D, WANG Z, XIA Y, et al. The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis[J]. Nature, 2020, 580(7804): 530-535. DOI: 10.1038/s41586-020-2183-2.
[24]	PAN XM. The gluconeogenic enzyme FBP1 and PCK1 inhibit HCC tumorigenesis[D]. Chongqing: ChongQing Medical University, 2020. 潘璇明. 糖异生关键酶FBP1和PCK1调控肝细胞癌发生的实验研究[D]. 重庆: 重庆医科大学, 2020.
[25]	GAO Y, WANG X, SANG Z, et al. Quantitative proteomics by SWATH-MS reveals sophisticated metabolic reprogramming in hepatocellular carcinoma tissues[J]. Sci Rep, 2017, 7: 45913. DOI: 10.1038/srep45913.
[26]	TUO L, XIANG J, PAN X, et al. PCK1 negatively regulates cell cycle progression and hepatoma cell proliferation via the AMPK/p27Kip1 axis[J]. J Exp Clin Cancer Res, 2019, 38(1): 50. DOI: 10.1186/s13046-019-1029-y.
[27]	CAI Z, CHEHAB NH, PAVLETICH NP. Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase[J]. Mol Cell, 2009, 35(6): 818-829. DOI: 10.1016/j.molcel.2009.09.007.
[28]	CARLONI V, LULLI M, MADIAI S, et al. CHK2 overexpression and mislocalisation within mitotic structures enhances chromosomal instability and hepatocellular carcinoma progression[J]. Gut, 2018, 67(2): 348-361. DOI: 10.1136/gutjnl-2016-313114.
[29]	XIANG J, CHEN C, LIU R, et al. Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation[J]. J Clin Invest, 2021, 131(8): e144703. DOI: 10.1172/JCI144703.
[30]	ZHANG P, TU B, WANG H, et al. Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion[J]. Proc Natl Acad Sci U S A, 2014, 111(29): 10684-10689. DOI: 10.1073/pnas.1411026111.
[31]	KHAN MW, BISWAS D, GHOSH M, et al. mTORC2 controls cancer cell survival by modulating gluconeogenesis[J]. Cell Death Discov, 2015, 1: 15016. DOI: 10.1038/cddiscovery.2015.16.
[32]	SHI H, FANG R, LI Y, et al. The oncoprotein HBXIP suppresses gluconeogenesis through modulating PCK1 to enhance the growth of hepatoma cells[J]. Cancer Lett, 2016, 382(2): 147-156. DOI: 10.1016/j.canlet.2016.08.025.
[33]	LATORRE-MURO P, BAEZA J, ARMSTRONG EA, et al. Dynamic acetylation of phosphoenolpyruvate carboxykinase toggles enzyme activity between gluconeogenic and anaplerotic reactions[J]. Mol Cell, 2018, 71(5): 718-732. DOI: 10.1016/j.molcel.2018.07.031.
[34]	LI M, LUO RZ, CHEN JW, et al. High expression of transcriptional coactivator p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma[J]. J Transl Med, 2011, 9: 5. DOI: 10.1186/1479-5876-9-5.
[35]	TOMASI ML, TOMASI I, RAMANI K, et al. S-adenosyl methionine regulates ubiquitin-conjugating enzyme 9 protein expression and sumoylation in murine liver and human cancers[J]. Hepatology, 2012, 56(3): 982-993. DOI: 10.1002/hep.25701.
[36]	YOKOMIZO C, YAMAGUCHI K, ITOH Y, et al. High expression of p300 in HCC predicts shortened overall survival in association with enhanced epithelial mesenchymal transition of HCC cells[J]. Cancer Lett, 2011, 310(2): 140-147. DOI: 10.1016/j.canlet.2011.06.030.
[37]	BIAN XL, CHEN HZ, YANG PB, et al. Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation[J]. Nat Commun, 2017, 8: 14420. DOI: 10.1038/ncomms14420.
[38]	JING Z, GAO J, LI J, et al. Acetylation-induced PCK isoenzyme transition promotes metabolic adaption of liver cancer to systemic therapy[J]. Cancer Lett, 2021, 519: 46-62. DOI: 10.1016/j.canlet.2021.06.016.
[39]	DZUGAJ A. Localization and regulation of muscle fructose-1, 6-bisphosphatase, the key enzyme of glyconeogenesis[J]. Adv Enzyme Regul, 2006, 46: 51-71. DOI: 10.1016/j.advenzreg.2006.01.021.
[40]	YANG J, WANG C, ZHAO F, et al. Loss of FBP1 facilitates aggressive features of hepatocellular carcinoma cells through the Warburg effect[J]. Carcinogenesis, 2017, 38(2): 134-143. DOI: 10.1093/carcin/bgw109.
[41]	LI F, HUANGYANG P, BURROWS M, et al. FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome[J]. Nat Cell Biol, 2020, 22(6): 728-739. DOI: 10.1038/s41556-020-0511-2.
[42]	LIU GM, LI Q, ZHANG PF, et al. Restoration of FBP1 suppressed snail-induced epithelial to mesenchymal transition in hepatocellular carcinoma[J]. Cell Death Dis, 2018, 9(11): 1132. DOI: 10.1038/s41419-018-1165-x.
[43]	YANG J, JIN X, YAN Y, et al. Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression[J]. Sci Rep, 2017, 7: 43864. DOI: 10.1038/srep43864.
[44]	PAN D, MAO C, WANG YX. Suppression of gluconeogenic gene expression by LSD1-mediated histone demethylation[J]. PLoS One, 2013, 8(6): e66294. DOI: 10.1371/journal.pone.0066294.
[45]	LEITHNER K. Epigenetic marks repressing gluconeogenesis in liver and kidney cancer[J]. Cancer Res, 2020, 80(4): 657-658. DOI: 10.1158/0008-5472.CAN-19-3953.
[46]	LIAO K, DENG S, XU L, et al. A feedback circuitry between polycomb signaling and fructose-1, 6-bisphosphatase enables hepatic and renal tumorigenesis[J]. Cancer Res, 2020, 80(4): 675-688. DOI: 10.1158/0008-5472.CAN-19-2060.
[47]	WATTANAVANITCHAKORN S, ROJVIRAT P, CHAVALIT T, et al. CCAAT-enhancer binding protein-α (C/EBPα) and hepatocyte nuclear factor 4α (HNF4α) regulate expression of the human fructose-1, 6-bisphosphatase 1 (FBP1) gene in human hepatocellular carcinoma HepG2 cells[J]. PLoS One, 2018, 13(3): e0194252. DOI: 10.1371/journal.pone.0194252.
[48]	YANG LN, NING ZY, WANG L, et al. HSF2 regulates aerobic glycolysis by suppression of FBP1 in hepatocellular carcinoma[J]. Am J Cancer Res, 2019, 9(8): 1607-1621. http://www.ncbi.nlm.nih.gov/pubmed/31497345/
[49]	JIN X, PAN Y, WANG L, et al. MAGE-TRIM28 complex promotes the Warburg effect and hepatocellular carcinoma progression by targeting FBP1 for degradation[J]. Oncogenesis, 2017, 6(4): e312. DOI: 10.1038/oncsis.2017.21.
[50]	RAMADOSS P, UNGER-SMITH NE, LAM FS, et al. STAT3 targets the regulatory regions of gluconeogenic genes in vivo[J]. Mol Endocrinol, 2009, 23(6): 827-837. DOI: 10.1210/me.2008-0264.
[51]	LIANG J, LIU C, QIAO A, et al. MicroRNA-29a-c decrease fasting blood glucose levels by negatively regulating hepatic gluconeogenesis[J]. J Hepatol, 2013, 58(3): 535-542. DOI: 10.1016/j.jhep.2012.10.024.
[52]	PICCININ E, VILLANI G, MOSCHETTA A. Metabolic aspects in NAFLD, NASH and hepatocellular carcinoma: the role of PGC1 coactivators[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(3): 160-174. DOI: 10.1038/s41575-018-0089-3.
[53]	MA R, ZHANG W, TANG K, et al. Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma[J]. Nat Commun, 2013, 4: 2508. DOI: 10.1038/ncomms3508.
[54]	SHANG F, LIU M, LI B, et al. The anti-angiogenic effect of dexamethasone in a murine hepatocellular carcinoma model by augmentation of gluconeogenesis pathway in malignant cells[J]. Cancer Chemother Pharmacol, 2016, 77(5): 1087-1096. DOI: 10.1007/s00280-016-3030-x.