长链非编码RNA与肿瘤代谢的研究进展
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摘要
长链非编码RNA(long non-coding RNA,lncRNA)是一类长度大于200个核苷酸,不能编码蛋白质的调节性RNA分子,在肿瘤发生和发展中起关键作用。与正常细胞相比,肿瘤细胞表现出不同的代谢特征。LncRNA与肿瘤代谢有关。本文对lncRNA与肿瘤细胞代谢,特别是葡萄糖、谷氨酰胺和脂质代谢的最新进展作简要综述,以期通过更深入地了解lncRNA与肿瘤代谢的关系,为更好地开发靶向肿瘤代谢的新药奠定基础。
Long non-coding RNA(lncRNA) is defined as a large class of non-protein-coding,regulatory RNAs with molecules longer than 200 nucleotides,which play key roles in tumorigenesis and progression. Compared to normal cells,tumor cells exhibit distinct metabolic features,and lncRNAs are involved in tumor metabolism. This article reviews the recent advances in the relationship between lncRNA and tumor metabolism,particularly glucose,glutamine and lipid metabolism;and its application in the development of new drugs targeting tumor metabolism.
Long non-coding RNA(lncRNA) is defined as a large class of non-protein-coding,regulatory RNAs with molecules longer than 200 nucleotides,which play key roles in tumorigenesis and progression. Compared to normal cells,tumor cells exhibit distinct metabolic features,and lncRNAs are involved in tumor metabolism. This article reviews the recent advances in the relationship between lncRNA and tumor metabolism,particularly glucose,glutamine and lipid metabolism;and its application in the development of new drugs targeting tumor metabolism.
引文
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[3]Vander Heiden MG,Cantley LC,Thompson CB.Understanding the Warburg effect:the metabolic requirements of cell proliferation[J].Science,2009,324(5930):1029-1033.
[4]Cairns RA,Harris IS,Mak TW.Regulation of cancer cell metabolism[J].Nat Rev Cancer,2011,11(2):85-95.
[5]Cantor JR,Sabatini DM.Cancer cell metabolism:one hallmark,many faces[J].Cancer Discov,2012,2(10):881-898.
[6]Morris KV,Mattick JS.The rise of regulatory RNA[J].Nat Rev Genet,2014,15(6):423-437.
[7]Mattick JS,Rinn JL.Discovery and annotation of long noncoding RNAs[J].Nat Struct Mol Biol,2015,22(1):5-7.
[8]de Bari L,Atlante A.Including the mitochondrial metabolism of L-lactate in cancer metabolic reprogramming[J].Cell Mol Life Sci(CMLS),2018,75(15):2763-2776.
[9]Quinn JJ,Chang HY.Unique features of long non-coding RNA biogenesis and function[J].Nat Rev Genet,2016,17(1):47-62.
[10]Cabili MN,Trapnell C,Goff L,et al.Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses[J].Genes,2011,25(18):1915-1927.
[11]Iyer MK,Niknafs YS,Malik R,et al.The landscape of long noncoding RNAs in the human transcriptome[J].Nat Genet,2015,47(3):199-208.
[12]Batista PJ,Chang HY.Long noncoding RNAs:cellular address codes in development and disease[J].Cell,2013,152(6):1298-1307.
[13]Guttman M,Rinn JL.Modular regulatory principles of large noncoding RNAs[J].Nature,2012,482(7385):339-346.
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[31]Ellis BC,Graham LD,Molloy PL.CRNDE,a long noncoding RNA responsive to insulin/IGF signaling,regulates genes involved in central metabolism[J].Biochim Biophys Acta,2014,1843(2):372-386.
[32]Li HJ,Li X,Pang H,et al.Long non-coding RNA UCA1promotes glutamine metabolism by targeting miR-16 in human bladder cancer[J].Jpn J Clin Oncol,2015,45(11):1055-1063.
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[36]Wang X,Gao Z,Liao J,et al.lncRNA UCA1 inhibits esophageal squamous-cell carcinoma growth by regulating the Wnt signaling pathway[J].J Toxicol Environ Health A,2016,79(9-10):407-418.
[37]Yang L,Venneti S,Nagrath D.Glutaminolysis:a hallmark of cancer metabolism[J].Annu Rev Biomed Eng,2017,19:163-194.
[38]Zeng B,Ye HL,Chen JM,et al.LncRNA TUG1 sponges miR-145 to promote cancer progression and regulate glutamine metabolism via Sirt3/GDH axis[J].Oncotarget,2017,8(89):113650-113661.
[39]Santos CR,Schulze A.Lipid metabolism in cancer[J].FEBS J,2012,279(15):2610-2623.
[40]Liu Y,Zuckier LS,Ghesani NV.Dominant uptake of fatty acid over glucose by prostate cells:a potential new diagnostic and therapeutic approach[J].Anticancer Res,2010,30(2):369-374.
[41]Menendez JA,Lupu R.Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis[J].Nat Rev Cancer,2007,7(10):763-777.
[42]Ong KT,Mashek M,Bu SY,et al.Adipose triglyc-eride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning[J].Hepatology,2011,53(1):116-126.
[43]Cui M,Xiao Z,Wang Y,et al.Long noncoding RNAHULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway[J].Cancer Res,2015,75(5):846-857.
[44]Storch J,Thumser AE.Tissue-specific functions in the fatty acid-binding protein family[J].J Biol Chem,2010,285(43):32679-32683.
[45]Shang C,Wang W,Liao Y,et al.LNMICC promotes nodal metastasis of cervical cancer by reprogramming fatty acid metabolism[J].Cancer Res,2018,78(4):877-890.
[46]Liu S,Xu R,Gerin I,et al.SRA regulates adipogenesis by modulating p38/JNK phosphorylation and stimulating insulin receptor gene expression and downstream signaling[J].PLoS One,2014,9(4):e95416.
[47]Xu B,Gerin I,Miao H,et al.Multiple roles for the noncoding RNA SRA in regulation of adipogenesis and insulin sensitivity[J].PLoS One,2010,5(12):e14199.
[48]Liu S,Sheng L,Miao H,et al.SRA gene knockout protects against diet-induced obesity and improves glucose tolerance[J].J Biol Chem,2014,289(19):13000-13009.
[49]Hardie DG,Ross FA,Hawley SA.AMPK:a nutrient and energy sensor that maintains energy homeostasis[J].Nat Rev Mol Cell Biol,2012,13(4):251-262.
[50]Shackelford DB,Shaw RJ.The LKB1-AMPK pathway:metabolism and growth control in tumour suppression[J].Nat Rev Cancer,2009,9(8):563-575.
[51]Hezel AF,Bardeesy N.LKB1:linking cell structure and tumor suppression[J].Oncogene,2008,27(55):6908-6919.
[52]Liu X,Xiao ZD,Han L,et al.LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress[J].Nat Cell Biol,2016,18(4):431-442.
[53]Xu CF,Brown MA,Nicolai H,et al.Isolation and characterisation of the NBR2 gene which lies head to head with the human BRCA1 gene[J].Hum Mol Genet,1997,6(7):1057-1062.
[54]Xiao ZD,Liu X,Zhuang L,et al.NBR2:a former junk gene emerges as a key player in tumor suppression[J].Mol Cell Oncol,2016,3(4):e1187322.
[55]Beckmann BM,Horos R,Fischer B,et al.The RNAbinding proteomes from yeast to man harbour conserved enigmRBPs[J].Nat Commun,2015,6:10127.
[56]Castello A,Fischer B,Eichelbaum K,et al.Insights into RNA biology from an atlas of mammalian mRNA-binding proteins[J].Cell,2012,149(6):1393-1406.
[57]Cheng Z,Ristow M.Mitochondria and metabolic homeostasis[J].Antioxid Redox Signal,2013,19(3):240-242.
[58]Leucci E,Vendramin R,Spinazzi M,et al.Melanoma addiction to the long non-coding RNA SAMMSON[J].Nature,2016,531(7595):518-522.
[59]Noh JH,Kim KM,Abdelmohsen K,et al.HuR and GRSF1modulate the nuclear export and mitochondrial localization of the lncRNA RMRP[J].Genes Dev,2016,30(10):1224-1239.
[60]Kumarswamy R,Bauters C,Volkmann I,et al.Circulating long noncoding RNA,LIPCAR,predicts survival in patients with heart failure[J].Circ Res,2014,114(10):1569-1575.
[61]Li HJ,Sun XM,Li ZK,et al.LncRNA UCA1 promotes mitochondrial function of bladder cancer via the MiR-195/ARL2 signaling pathway[J].Cell Physiol Biochem,2017,43(6):2548-2561.
[62]Handschin C,Spiegelman BM.Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators,energy homeostasis,and metabolism[J].Endocr Rev,2006,27(7):728-735.
[63]Long J,Badal SS,Ye Z,et al.Long noncoding RNA Tug1regulates mitochondrial bioenergetics in diabetic nephropathy[J].J Clin Invest,2016,126(11):4205-4218.
[64]MiaoW T,Gang L.long non-coding RNA MEG3 induces renal cell carcinoma cells apoptosis by activating the mitochondrial pathway[J].J Huazhoung Univ Sci Technol,2015,35:541-545.
[65]Kong LZX,Wu Y.Targeting HOTAIR induces mitochondria related apoptosis and inhibits tumor growth in head and neck aquamous cell carcinoma in vitro and in vivo[J].Curr Mol Med,2015,15:952-960.
[66]Wei YF,Yu ST,Zhang YP,et al.NDRG2 promotes adriamycin sensitivity through a Bad/p53 complex at the mitochondria in breast cancer[J].Oncotarget,2017,8(17):29038-29047.
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[70]Christensen LL,True K,Hamilton MP,et al.SNHG16 is regulated by the Wnt pathway in colorectal cancer and affects genes involved in lipid metabolism[J].Mol Oncol,2016,10(8):1266-1282.
[71]Khan MR,Xiang S,Song Z,et al.The p53-inducible long noncoding RNA TRINGS protects cancer cells from necrosis under glucose starvation[J].EMBO J,2017,36(23):3483-3500.
[72]Xiao ZD,Han L,Lee H,et al.Energy stressinduced lncR-NA FILNC1 represses c-Myc-mediated energy metabolism and inhibits renal tumor development[J].Nat Commun,2017,8(1):783.
[73]Yang B,Zhang L,Cao Y,et al.Overexpression of lncRNAIGFBP4-1 reprograms energy metabolism to promote lung cancer progression[J].Mol Cancer,2017,16(1):154.
[74]Wei S,Fan Q,Yang L,et al.Promotion of glycolysis by HOTAIR through GLUT1 upregulation via mTOR signaling[J].Oncol Rep,2017,38(3):1902-1908.
[75]Shang C,Wang W,Liao Y,et al.LNMICC promotes nodal metastasis of cervical cancer by reprogramming fatty acid metabolism[J].Cancer Res,2018,78(4):877-890.
[76]Song J,Wu X,Liu F,et al.Long non-coding RNA PVT1promotes glycolysis and tumor progression by regulating miR-497/HK2 axis in osteosarcoma[J].Biochem Biophys Res Commun,2017,490(2):217-224.
[77]Zhao L,Ji G,Le X,et al.Long noncoding RNA LINC00092acts in cancer-associated fibroblasts to drive glycolysis and progression of ovarian cancer[J].Cancer Res,2017,77(6):1369-1382.
[2]Reitman ZJ,Yan H.Isocitrate dehydrogenase 1 and 2 mutations in cancer:alterations at a crossroads of cellular metabolism[J].J Natl Cancer Inst,2010,102(13):932-941.
[3]Vander Heiden MG,Cantley LC,Thompson CB.Understanding the Warburg effect:the metabolic requirements of cell proliferation[J].Science,2009,324(5930):1029-1033.
[4]Cairns RA,Harris IS,Mak TW.Regulation of cancer cell metabolism[J].Nat Rev Cancer,2011,11(2):85-95.
[5]Cantor JR,Sabatini DM.Cancer cell metabolism:one hallmark,many faces[J].Cancer Discov,2012,2(10):881-898.
[6]Morris KV,Mattick JS.The rise of regulatory RNA[J].Nat Rev Genet,2014,15(6):423-437.
[7]Mattick JS,Rinn JL.Discovery and annotation of long noncoding RNAs[J].Nat Struct Mol Biol,2015,22(1):5-7.
[8]de Bari L,Atlante A.Including the mitochondrial metabolism of L-lactate in cancer metabolic reprogramming[J].Cell Mol Life Sci(CMLS),2018,75(15):2763-2776.
[9]Quinn JJ,Chang HY.Unique features of long non-coding RNA biogenesis and function[J].Nat Rev Genet,2016,17(1):47-62.
[10]Cabili MN,Trapnell C,Goff L,et al.Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses[J].Genes,2011,25(18):1915-1927.
[11]Iyer MK,Niknafs YS,Malik R,et al.The landscape of long noncoding RNAs in the human transcriptome[J].Nat Genet,2015,47(3):199-208.
[12]Batista PJ,Chang HY.Long noncoding RNAs:cellular address codes in development and disease[J].Cell,2013,152(6):1298-1307.
[13]Guttman M,Rinn JL.Modular regulatory principles of large noncoding RNAs[J].Nature,2012,482(7385):339-346.
[14]Salmena L,Poliseno L,Tay Y,et al.A ceRNA hypothesis:the rosetta stone of a hidden RNA language?[J].Cell,2011,146(3):353-358.
[15]Hensley CT,Wasti AT,DeBerardinis RJ.Glutamine and cancer:cell biology,physiology,and clinical opportunities[J].J Clin Invest,2013,123(9):3678-3684.
[16]Mishra P,Tang W,Putluri V,et al.ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming[J].J Clin Investig,2018,128(1):323-340.
[17]Yan W,Wu X,Zhou W,et al.Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells[J].Nat Cell Biol,2018,20(5):597-609.
[18]Zhu X,Wu YB,Zhou J,et al.Upregulation of lncRNAMEG3 promotes hepatic insulin resistance via increasing FoxO1 expression[J].Biochem Biophys Res Commun,2016,469(2):319-325.
[19]Balon TW.SGLT and GLUT:are they teammates?Focus on“mouse SGLT3a generates proton-activated currents but does not transport sugar”[J].Am J Physiol Cell Phy-siol,2012,302(8):C1071-C1072.
[20]Zou ZW,Ma C,Medoro L.LncRNA ANRIL is up-regulated in nasopharyngeal carcinoma and promotes the cancer progression via increasing proliferation,reprograming cell glucose metabolism and inducing side-population stem like cancer cells[J].Oncotarget,2016,7:38.
[21]Wong N,Ojo D,Yan J,et al.PKM2 contributes to cancer metabolism[J].Cancer Lett,2015,356(2 Pt A):184-191.
[22]Zhao L,Ji G,Le X,et al.Long noncoding RNALINC00092 acts in cancer-associated fibroblasts to drive glycolysis and progression of ovarian cancer[J].Cancer Res,2017,77(6):1369-1382.
[23]Robey RB,Hay N.Mitochondrial hexokinases,novel mediators of the antiapoptotic effects of growth factors and Akt[J].Oncogene,2006,25(34):4683-4696.
[24]Li Z,Li X,Wu S,et al.Long non-coding RNA UCA1 promotes glycolysis by upregulating hexokinase 2 through the m TORSTAT3/microRNA143 pathway[J].Cancer Sci,2014,105(8):951-955.
[25]Hung CL,Wang LY,Yu YL,et al.A long noncoding RNAconnects c-Myc to tumor metabolism[J].Proc Natl Acad Sci U S A,2014,111(152):18697-18702.
[26]Huarte M,Guttman M,Feldser D,et al.A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response[J].Cell,2010,142(3):409-419.
[27]Yang F,Zhang H,Mei Y,et al.Reciprocal regulation of HIF-1alpha and lincRNA-p21 modulates the Warburg effect[J].Mol Cell,2014,53(1):88-100.
[28]Choudhry H,Schodel J,Oikonomopoulos S,et al.Extensive regulation of the non-coding transcriptome by hypoxia:role of HIF in releasing paused RNApol2[J].EMBO Rep,2014,15(1):70-76.
[29]Rupaimoole R,Lee J,Haemmerle M,et al.Long noncoding RNA ceruloplasmin promotes cancer growth by altering glycolysis[J].Cell Rep,2015,13(11):2395-2402.
[30]Graham LD,Pedersen SK,Brown GS,et al.Colorectal neoplasia differentially expressed(CRNDE),a novel gene with elevated expression in colorectal adenomas and adenocarcinomas[J].Genes Cancer,2011,2(8):829-840.
[31]Ellis BC,Graham LD,Molloy PL.CRNDE,a long noncoding RNA responsive to insulin/IGF signaling,regulates genes involved in central metabolism[J].Biochim Biophys Acta,2014,1843(2):372-386.
[32]Li HJ,Li X,Pang H,et al.Long non-coding RNA UCA1promotes glutamine metabolism by targeting miR-16 in human bladder cancer[J].Jpn J Clin Oncol,2015,45(11):1055-1063.
[33]Redis RS,Vela LE,Lu W,et al.Allelespecific reprogramming of cancer metabolism by the long non-coding RNACCAT2[J].Mol Cell,2016,61(4):520-534.
[34]Jones RG,Thompson CB.Tumor suppressors and cell metabolism:a recipe for cancer growth[J].Genes Dev,2009,23(5):537-548.
[35]Xu XY,Li JY,Sun X,et al.Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression[J].Oncotarget,2015,6(28):26161-26176.
[36]Wang X,Gao Z,Liao J,et al.lncRNA UCA1 inhibits esophageal squamous-cell carcinoma growth by regulating the Wnt signaling pathway[J].J Toxicol Environ Health A,2016,79(9-10):407-418.
[37]Yang L,Venneti S,Nagrath D.Glutaminolysis:a hallmark of cancer metabolism[J].Annu Rev Biomed Eng,2017,19:163-194.
[38]Zeng B,Ye HL,Chen JM,et al.LncRNA TUG1 sponges miR-145 to promote cancer progression and regulate glutamine metabolism via Sirt3/GDH axis[J].Oncotarget,2017,8(89):113650-113661.
[39]Santos CR,Schulze A.Lipid metabolism in cancer[J].FEBS J,2012,279(15):2610-2623.
[40]Liu Y,Zuckier LS,Ghesani NV.Dominant uptake of fatty acid over glucose by prostate cells:a potential new diagnostic and therapeutic approach[J].Anticancer Res,2010,30(2):369-374.
[41]Menendez JA,Lupu R.Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis[J].Nat Rev Cancer,2007,7(10):763-777.
[42]Ong KT,Mashek M,Bu SY,et al.Adipose triglyc-eride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning[J].Hepatology,2011,53(1):116-126.
[43]Cui M,Xiao Z,Wang Y,et al.Long noncoding RNAHULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway[J].Cancer Res,2015,75(5):846-857.
[44]Storch J,Thumser AE.Tissue-specific functions in the fatty acid-binding protein family[J].J Biol Chem,2010,285(43):32679-32683.
[45]Shang C,Wang W,Liao Y,et al.LNMICC promotes nodal metastasis of cervical cancer by reprogramming fatty acid metabolism[J].Cancer Res,2018,78(4):877-890.
[46]Liu S,Xu R,Gerin I,et al.SRA regulates adipogenesis by modulating p38/JNK phosphorylation and stimulating insulin receptor gene expression and downstream signaling[J].PLoS One,2014,9(4):e95416.
[47]Xu B,Gerin I,Miao H,et al.Multiple roles for the noncoding RNA SRA in regulation of adipogenesis and insulin sensitivity[J].PLoS One,2010,5(12):e14199.
[48]Liu S,Sheng L,Miao H,et al.SRA gene knockout protects against diet-induced obesity and improves glucose tolerance[J].J Biol Chem,2014,289(19):13000-13009.
[49]Hardie DG,Ross FA,Hawley SA.AMPK:a nutrient and energy sensor that maintains energy homeostasis[J].Nat Rev Mol Cell Biol,2012,13(4):251-262.
[50]Shackelford DB,Shaw RJ.The LKB1-AMPK pathway:metabolism and growth control in tumour suppression[J].Nat Rev Cancer,2009,9(8):563-575.
[51]Hezel AF,Bardeesy N.LKB1:linking cell structure and tumor suppression[J].Oncogene,2008,27(55):6908-6919.
[52]Liu X,Xiao ZD,Han L,et al.LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress[J].Nat Cell Biol,2016,18(4):431-442.
[53]Xu CF,Brown MA,Nicolai H,et al.Isolation and characterisation of the NBR2 gene which lies head to head with the human BRCA1 gene[J].Hum Mol Genet,1997,6(7):1057-1062.
[54]Xiao ZD,Liu X,Zhuang L,et al.NBR2:a former junk gene emerges as a key player in tumor suppression[J].Mol Cell Oncol,2016,3(4):e1187322.
[55]Beckmann BM,Horos R,Fischer B,et al.The RNAbinding proteomes from yeast to man harbour conserved enigmRBPs[J].Nat Commun,2015,6:10127.
[56]Castello A,Fischer B,Eichelbaum K,et al.Insights into RNA biology from an atlas of mammalian mRNA-binding proteins[J].Cell,2012,149(6):1393-1406.
[57]Cheng Z,Ristow M.Mitochondria and metabolic homeostasis[J].Antioxid Redox Signal,2013,19(3):240-242.
[58]Leucci E,Vendramin R,Spinazzi M,et al.Melanoma addiction to the long non-coding RNA SAMMSON[J].Nature,2016,531(7595):518-522.
[59]Noh JH,Kim KM,Abdelmohsen K,et al.HuR and GRSF1modulate the nuclear export and mitochondrial localization of the lncRNA RMRP[J].Genes Dev,2016,30(10):1224-1239.
[60]Kumarswamy R,Bauters C,Volkmann I,et al.Circulating long noncoding RNA,LIPCAR,predicts survival in patients with heart failure[J].Circ Res,2014,114(10):1569-1575.
[61]Li HJ,Sun XM,Li ZK,et al.LncRNA UCA1 promotes mitochondrial function of bladder cancer via the MiR-195/ARL2 signaling pathway[J].Cell Physiol Biochem,2017,43(6):2548-2561.
[62]Handschin C,Spiegelman BM.Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators,energy homeostasis,and metabolism[J].Endocr Rev,2006,27(7):728-735.
[63]Long J,Badal SS,Ye Z,et al.Long noncoding RNA Tug1regulates mitochondrial bioenergetics in diabetic nephropathy[J].J Clin Invest,2016,126(11):4205-4218.
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