一碳代谢路径通路在癌症发生中作用研究进展
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摘要
我国癌症发病群体不断年轻化,发病率不断增加。最近科学研究表明,细胞代谢相关调控基因已成为新的癌症诊断标记和治疗靶点。一碳代谢对于细胞代谢必不可少,一碳代谢需要叶酸、丝氨酸和蛋氨酸等细胞必需的生物代谢物质参与,同时也产生嘌呤、腺苷和胸苷酸等生物代谢物质。一碳代谢包括三类关键反应:叶酸循环、蛋氨酸循环、反硫化途径。在叶酸循环中,叶酸及叶酸循环中间产物可以通过产生嘌呤和胸苷酸调控癌症细胞的生长和增殖。在蛋氨酸循环中产生的多胺和甲基等中间产物也能调控癌症细胞的生长和增值。反硫化途径是谷胱甘肽合成的重要途径,谷胱甘肽能够生成与肿瘤细胞密切相关的活性氧。该研究将简要综述一碳代谢在癌症发生中的作用,概况了近年来一碳代谢通路重要因子及中间产物作为靶点对癌症治疗的意义。
In China, the incidence of cancer is getting higher as well the patients are younger than before.Recently, scientific research shows that the regulation genes relation of cellular metabolism has being as a new target for cancer diagnosis and treatment. One-carbon metabolism is essential for cell metabolism, during this process,not only require folate, serine and methionine, but also can produce the other biological macromolecules, such as purine, adenosine and thymide. Three kinds of key reactions are included in one-carbon metabolism: folate cycle,methionine cycle and trans-sulfuration pathway. In the folate cycle, folate and its intermediates regulate the growth and proliferation of cancer cells by providing purine and thymidine. Moreover, polyamines and DNA methyl groups also regulate the growth and proliferation of cancer cells in the methionine cycle. The tran-sulfurization pathway is an important pathway for the synthesis of glutathione, which can generate reactive oxygen species(ROS) closely related to tumor cells. In this paper, the role of one-carbon metabolism in cancer development is briefly reviewed.And the significance of some important factors and intermediates in one-carbon metabolism is summarized, which might be as the targets for cancer treatment.
In China, the incidence of cancer is getting higher as well the patients are younger than before.Recently, scientific research shows that the regulation genes relation of cellular metabolism has being as a new target for cancer diagnosis and treatment. One-carbon metabolism is essential for cell metabolism, during this process,not only require folate, serine and methionine, but also can produce the other biological macromolecules, such as purine, adenosine and thymide. Three kinds of key reactions are included in one-carbon metabolism: folate cycle,methionine cycle and trans-sulfuration pathway. In the folate cycle, folate and its intermediates regulate the growth and proliferation of cancer cells by providing purine and thymidine. Moreover, polyamines and DNA methyl groups also regulate the growth and proliferation of cancer cells in the methionine cycle. The tran-sulfurization pathway is an important pathway for the synthesis of glutathione, which can generate reactive oxygen species(ROS) closely related to tumor cells. In this paper, the role of one-carbon metabolism in cancer development is briefly reviewed.And the significance of some important factors and intermediates in one-carbon metabolism is summarized, which might be as the targets for cancer treatment.
引文
1 Wishart DS.Is cancer a genetic disease or a metabolic disease.EBioMedicine 2015;2(6):478-9.
2 Newman AC,Maddocks ODK.One-carbon metabolism in cancer.Br J Cancer 2017;116(12):1499-504.
3 Lan X,Field MS,Stover PJ.Cell cycle regulation of folate-mediated one-carbon metabolism.Wiley Interdiscip Rev Syst Biol Med 2018:e1426.
4 Tibbetts AS,Appling DR.Compartmentalization of mammalian folate-mediated one-carbon metabolism.Annu Rev Nutr 2010;30(1):57-81.
5 Gregory S,Duckerand Joshua D,Rabinowitz.One-carbon metabolism in health and disease.Cell Metab 2017;25(1):27-42.
6石汉平.肿瘤是一种代谢性疾病.肿瘤代谢与营养电子杂志(Shi hanping.Tumor is a metabolic disease.Electronic Journal of Metabolism and Nutrition of Cancer)2018;5(02):111-6.
7 Farber S,Cutler EC,Hawkins Jw,Harrison JH,Peirce EC II,Lenz GG.The action of pteroylglutamic conjugates on man.Science 1947;106(2764):619-21.
8 Farber S,Diamond LK.Temporary remissions in acute leukemia in children produced by folic acid antagonist,4-aminopteroylglutamic acid.N Engl J Med 1948;238(23):787-93.
9 Dhanasekaran S.Augmented cytotoxic effects of paclitaxel by curcumin induced overexpression of folate receptor-αfor enhanced targeted drug delivery in HeLa cells.Phytomedicine2018;56:279-85.
10 Paone A,Marani M,Fiascarelli A,Rinaldo S,Giardina G,Contestabile R,et al.SHMT1 knockdown induces apoptosis in lung cancer cells by causing uracil misincorporation.Cell Death Dis2014;5(11):e1525.
11 Ser Z,Gao X,Johnson C,Mehrmohamadi M,Liu X,Li S,Locasale JW,et al.Targeting one carbon metabolism with an antimetabolite disruptspyrimidine homeostasis and induces nucleotide overflow.Cell Rep 2016;15(11):2367-76.
12 Franchini DM,Petersen-Mahrt SK.Aid and apobec deaminases:balancing DNA damage in epigenetics and immunity.Epigenomics 2014;6(4):427-43.
13 Matherly LH,Hou Z,Gangjee A.The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer.Cancer Chemother Pharmacol2018;81(1):1-15.
14 Bouffard DY,LalibertéJ,Momparler RL.Kinetic studies on 2′,2′-difluorodeoxycytidine(gemcitabine)with purified human deoxycytidine kinase and cytidine deaminase.Biochemical pharmacology 1993;45:1857-61.
15 Ponnaluri VKC,Esteve PO,Ruse,Ruse CI,Pradhan S.S-Adenosylhomocysteine hydrolase participates in DNA methylation inheritance.Mol Biol 2018;430(13):2051-65.
16 Estève PO,Terragni J,Deepti K,Chin HG,Dai N,Espejo A,Corrêa IR,et al.Methyllysine reader plant homeodomain(phd)finger protein 20-Like 1(Phf20l1)antagonizes DNA(cytosine-5)methyltransferase 1(dnmt1)proteasomal degradation.Biol Chem2014;289(12):8277-87.
17 Cohen HM,Griffiths A.D,Tawfik DS,et al.Determinants of cofactor binding to DNA methyltransferases:insights from a systematic series of structural variants of S-adenosylhomocysteine.Org Biomol Chem 2005;3(1):152-61.
18 Zhang B,Denomme MM,White CR,Leung KY,Lee MB,Greene ND,et al.Both the folate cycle and betaine-homocysteine methyltransferase contribute methyl groupsfor DNA methylation in mouse blastocysts.FASEB J 2015;29(3):1069-79.
19 Soda K.The mechanisms by which polyamines accelerate tumor spread.J Exp Clin Cancer Res 2011;30(1):95.
20 Weiss TS,Bernhardt G,Buschauer A,Thasler WE,Dolgner D,Zirngibl H,et al.Polyamine levels of human colorectal adenocarcinomas are correlated with tumor stage and grade.Int J Colorectal Dis 2002;17(6):381-7.
21 Upp JR,Saydjari R,Townsend CM,Singh P,Barranco SC,Thompson JC.Polyamine levels and gastrin receptors in colon cancers.Ann Surg 1988;207(6):662-9.
22 Gallesio C,Colombatt,S,Modica R.free and acetylated polyamines as markers of oral cavity tumors.Oral Surg Oral Med Oral Pathol 1994;77(2):167-71.
23 Becciolini A.Porcian S,Lanini A,Balzi M,Cionini L,Bandettini L.Polyamine levels in healthy and tumor tissues of patients with colon adenocarcinoma.Dis Colon Rectum 1991;34(2):167-73.
24 Pegg AE.Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy.Cancer Res 1988;48(4):759-74.
25 Gerner EW,Meyskens FL Jr.Polyamines and cancer:old molecules,new understanding.Nat Rev Cancer 2004;4(10):781-92.
26 Casero RA,Marton LJ.Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases.Nat Rev Drug discov 2007;6(5):373-90.
27 Gupta S,Ahmad N,Marengo SR,MacLennan GT,Greenberg NM,Mukhtar H.Chemoprevention of prostate carcinogenesis by alpha-difluoromethylornithine in TRAMP mice.Cancer Res2000;60(18):5125-33.
28 Gilmour SK.Polyamines and nonmelanoma skin cancer.Toxicol Appl Pharmacol 2007;224(3):249-56.
29 Soda K,Kano Y,Chiba F,Koizumi K,Miyaki Y.Increased polyamine intake inhibits age-associated alteration in global DNAmethylation and 1,2-dimethylhydrazine-induced tumorigenesis.PLoS ONE 2013;8(5):e64357.
30 Konno M,Koseki J,Kawamoto K,Nishida N,Matsui H,Dewi DL,et al.Embryonic microRNA-369 controls metabolic splicing factors and urges cellular reprograming.PLoS One 2015;10(7):e0132789.
31 Hamabe A,Konno M,Tanuma N,Shima H,Tsunekuni K,Kawamoto K,et al.Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition.Proc Natl Acad Sci USA 2014;111(43):15526-31.
32 Hayashi K,Tamari K,Ishii H,Konno M,Nishida N,Kawamoto K,et al.Visualization and characterization of cancer stem-like cells in cervical cancer.Int J Oncol 2014;45(6):2468-74.
33 Kano Y,Konno M,Kawamoto K,Tamari K,Hayashi K,Fukusumi T,et al.Novel drug discovery system for cancer stem cells in human squamous cell carcinoma of the esophagus.Oncol Rep 2014;31(1):1133-8.
34 Tamari K,Hayashi K,Ishii H,Kano Y,Konno M,Kawamoto K,et al.Identification of chemoradiation-resistant osteosarcoma stem cells using an imaging system for proteasome activity.Int JOncol 2014;45(6):2349-54.
35 Kulis M,Esteller M.DNA methylation and cancer.Adv Genet2010;70:27-56.
36 Kottakis F,Nicolay BN,Roumane A,Karnik R,Gu H,Nagle JM,et al.LKB1 loss links serine metabolism to DNA methylation andtumorigenesis.Nature 2016;539(7629):390-5.
37 Shridhar K,Walia GK,Aggarwal A,Gulati S,Geetha AV,Prabhakaran D,et al.DNA methylation markers for oral pre-cancer progression:A critical review.Oral Oncol 2015;53:1-9.
38 Nojima D,Li LC,Dharia A,Perinchery G,Ribeiro-Filho L,Yen TS,et al.CpG hypermethylation of the promoter region inactivates the estrogen receptor-βgene in patients with prostate carcinoma.Cancer 2001;92(8):2076-83.
39 Kojima K,Nakamura T,Ooizumi Y,Igarashi K,Tanaka T,Yokoi K,et al.Clinical significance of cancer specific methylation of the CDO1 gene in small bowel cancer.PLoS One 2019;14(1):e0211108.
40 Rampersaud GC,Kauwell GP,Hutson AD,Cerda JJ,Bailey LB.Genomic DNA methylation decreases in response to moderate folate depletion in elderly women.Am J clin Nutr 2000;72(4):998-1003.
41 Cui S,Li W,Lv X,Wang P,Gao Y,Huang G.Folic acid supplementation delays atherosclerotic lesion development by modulating MCP1 and VEGF DNA methylation levels in vivo and in vitro.Int J Mol Sci 2017;18(5):990.
42 Schiebe M,Chandel NS.ROS function in redox signaling and oxidative stress.Curr Biol 2014;4(10):R453-62.
43 Giannoni E,buricchi F,Raugei G,Ramponi G,Chiarugi P.Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth.Mol Cell Biol 2005;25(10):6391-403.
44 Hoeijmakers JH.DNA damage,aging,and cancer.N Engl J Med2009;361(15):1475-85.
45 Yee C,Yang W,Hekimi S.The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C.elegans.Cell 2014;157(4):897-909.
46 Du MQ,Carmichael PI,Phillip DH.Induction of activating mutations in the human c-Ha-ras-aproto-oncogene by oxygen free radicals.Mol.Carcinog 1994;11:170-5.
47 Ushijima T.Detection and interpretation of altered methylation patterns in cancer cells.Nat Rev Cancer 2005;5(3):223-31.
48 Toyokuni,S.Molecular mechanisms of oxidative stress-induced carcinogenesis:From epidemiology to oxygenomics.IUBMBLife 2008;60(7):441-7.
49 Le KH,Kim SW,Kim JR.Reactive oxygen species regulate urokinase plasminogen activator expressionand cell invasion via mitogen-activated protein kinase pathways after treatment with hepatocyte growthfactor in stomach cancer cells.J Exp Clin Cancer Res 2009;28:73.
50 Liou GY,Storz P.Reactive oxygen species in cancer.Free Radic Res 2010;44(5):479-96.
51 Li Q,Engelhardt JF.Interleukin-1beta induction of NFkappaB is partially regulated by H2O2-mediated activation of NFkappaB-inducing kinase.Biol Chem 2006;281(3):1495-505.
52 Fresno Vara JA.,Casado E,de Castro J,Cejas P,Belda-Iniesta C,González-Barón M.PI3K/Akt signaling pathway and cancer.Cancer Treat Rev 2004;30(2):193-204.
53 Dou C,Xu Q,Liu J,Wang Y,Zhou Z,Yao W,et al.SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROSproduction.J Exp Clin Cancer Res 2019;38(1):70.
2 Newman AC,Maddocks ODK.One-carbon metabolism in cancer.Br J Cancer 2017;116(12):1499-504.
3 Lan X,Field MS,Stover PJ.Cell cycle regulation of folate-mediated one-carbon metabolism.Wiley Interdiscip Rev Syst Biol Med 2018:e1426.
4 Tibbetts AS,Appling DR.Compartmentalization of mammalian folate-mediated one-carbon metabolism.Annu Rev Nutr 2010;30(1):57-81.
5 Gregory S,Duckerand Joshua D,Rabinowitz.One-carbon metabolism in health and disease.Cell Metab 2017;25(1):27-42.
6石汉平.肿瘤是一种代谢性疾病.肿瘤代谢与营养电子杂志(Shi hanping.Tumor is a metabolic disease.Electronic Journal of Metabolism and Nutrition of Cancer)2018;5(02):111-6.
7 Farber S,Cutler EC,Hawkins Jw,Harrison JH,Peirce EC II,Lenz GG.The action of pteroylglutamic conjugates on man.Science 1947;106(2764):619-21.
8 Farber S,Diamond LK.Temporary remissions in acute leukemia in children produced by folic acid antagonist,4-aminopteroylglutamic acid.N Engl J Med 1948;238(23):787-93.
9 Dhanasekaran S.Augmented cytotoxic effects of paclitaxel by curcumin induced overexpression of folate receptor-αfor enhanced targeted drug delivery in HeLa cells.Phytomedicine2018;56:279-85.
10 Paone A,Marani M,Fiascarelli A,Rinaldo S,Giardina G,Contestabile R,et al.SHMT1 knockdown induces apoptosis in lung cancer cells by causing uracil misincorporation.Cell Death Dis2014;5(11):e1525.
11 Ser Z,Gao X,Johnson C,Mehrmohamadi M,Liu X,Li S,Locasale JW,et al.Targeting one carbon metabolism with an antimetabolite disruptspyrimidine homeostasis and induces nucleotide overflow.Cell Rep 2016;15(11):2367-76.
12 Franchini DM,Petersen-Mahrt SK.Aid and apobec deaminases:balancing DNA damage in epigenetics and immunity.Epigenomics 2014;6(4):427-43.
13 Matherly LH,Hou Z,Gangjee A.The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer.Cancer Chemother Pharmacol2018;81(1):1-15.
14 Bouffard DY,LalibertéJ,Momparler RL.Kinetic studies on 2′,2′-difluorodeoxycytidine(gemcitabine)with purified human deoxycytidine kinase and cytidine deaminase.Biochemical pharmacology 1993;45:1857-61.
15 Ponnaluri VKC,Esteve PO,Ruse,Ruse CI,Pradhan S.S-Adenosylhomocysteine hydrolase participates in DNA methylation inheritance.Mol Biol 2018;430(13):2051-65.
16 Estève PO,Terragni J,Deepti K,Chin HG,Dai N,Espejo A,Corrêa IR,et al.Methyllysine reader plant homeodomain(phd)finger protein 20-Like 1(Phf20l1)antagonizes DNA(cytosine-5)methyltransferase 1(dnmt1)proteasomal degradation.Biol Chem2014;289(12):8277-87.
17 Cohen HM,Griffiths A.D,Tawfik DS,et al.Determinants of cofactor binding to DNA methyltransferases:insights from a systematic series of structural variants of S-adenosylhomocysteine.Org Biomol Chem 2005;3(1):152-61.
18 Zhang B,Denomme MM,White CR,Leung KY,Lee MB,Greene ND,et al.Both the folate cycle and betaine-homocysteine methyltransferase contribute methyl groupsfor DNA methylation in mouse blastocysts.FASEB J 2015;29(3):1069-79.
19 Soda K.The mechanisms by which polyamines accelerate tumor spread.J Exp Clin Cancer Res 2011;30(1):95.
20 Weiss TS,Bernhardt G,Buschauer A,Thasler WE,Dolgner D,Zirngibl H,et al.Polyamine levels of human colorectal adenocarcinomas are correlated with tumor stage and grade.Int J Colorectal Dis 2002;17(6):381-7.
21 Upp JR,Saydjari R,Townsend CM,Singh P,Barranco SC,Thompson JC.Polyamine levels and gastrin receptors in colon cancers.Ann Surg 1988;207(6):662-9.
22 Gallesio C,Colombatt,S,Modica R.free and acetylated polyamines as markers of oral cavity tumors.Oral Surg Oral Med Oral Pathol 1994;77(2):167-71.
23 Becciolini A.Porcian S,Lanini A,Balzi M,Cionini L,Bandettini L.Polyamine levels in healthy and tumor tissues of patients with colon adenocarcinoma.Dis Colon Rectum 1991;34(2):167-73.
24 Pegg AE.Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy.Cancer Res 1988;48(4):759-74.
25 Gerner EW,Meyskens FL Jr.Polyamines and cancer:old molecules,new understanding.Nat Rev Cancer 2004;4(10):781-92.
26 Casero RA,Marton LJ.Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases.Nat Rev Drug discov 2007;6(5):373-90.
27 Gupta S,Ahmad N,Marengo SR,MacLennan GT,Greenberg NM,Mukhtar H.Chemoprevention of prostate carcinogenesis by alpha-difluoromethylornithine in TRAMP mice.Cancer Res2000;60(18):5125-33.
28 Gilmour SK.Polyamines and nonmelanoma skin cancer.Toxicol Appl Pharmacol 2007;224(3):249-56.
29 Soda K,Kano Y,Chiba F,Koizumi K,Miyaki Y.Increased polyamine intake inhibits age-associated alteration in global DNAmethylation and 1,2-dimethylhydrazine-induced tumorigenesis.PLoS ONE 2013;8(5):e64357.
30 Konno M,Koseki J,Kawamoto K,Nishida N,Matsui H,Dewi DL,et al.Embryonic microRNA-369 controls metabolic splicing factors and urges cellular reprograming.PLoS One 2015;10(7):e0132789.
31 Hamabe A,Konno M,Tanuma N,Shima H,Tsunekuni K,Kawamoto K,et al.Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition.Proc Natl Acad Sci USA 2014;111(43):15526-31.
32 Hayashi K,Tamari K,Ishii H,Konno M,Nishida N,Kawamoto K,et al.Visualization and characterization of cancer stem-like cells in cervical cancer.Int J Oncol 2014;45(6):2468-74.
33 Kano Y,Konno M,Kawamoto K,Tamari K,Hayashi K,Fukusumi T,et al.Novel drug discovery system for cancer stem cells in human squamous cell carcinoma of the esophagus.Oncol Rep 2014;31(1):1133-8.
34 Tamari K,Hayashi K,Ishii H,Kano Y,Konno M,Kawamoto K,et al.Identification of chemoradiation-resistant osteosarcoma stem cells using an imaging system for proteasome activity.Int JOncol 2014;45(6):2349-54.
35 Kulis M,Esteller M.DNA methylation and cancer.Adv Genet2010;70:27-56.
36 Kottakis F,Nicolay BN,Roumane A,Karnik R,Gu H,Nagle JM,et al.LKB1 loss links serine metabolism to DNA methylation andtumorigenesis.Nature 2016;539(7629):390-5.
37 Shridhar K,Walia GK,Aggarwal A,Gulati S,Geetha AV,Prabhakaran D,et al.DNA methylation markers for oral pre-cancer progression:A critical review.Oral Oncol 2015;53:1-9.
38 Nojima D,Li LC,Dharia A,Perinchery G,Ribeiro-Filho L,Yen TS,et al.CpG hypermethylation of the promoter region inactivates the estrogen receptor-βgene in patients with prostate carcinoma.Cancer 2001;92(8):2076-83.
39 Kojima K,Nakamura T,Ooizumi Y,Igarashi K,Tanaka T,Yokoi K,et al.Clinical significance of cancer specific methylation of the CDO1 gene in small bowel cancer.PLoS One 2019;14(1):e0211108.
40 Rampersaud GC,Kauwell GP,Hutson AD,Cerda JJ,Bailey LB.Genomic DNA methylation decreases in response to moderate folate depletion in elderly women.Am J clin Nutr 2000;72(4):998-1003.
41 Cui S,Li W,Lv X,Wang P,Gao Y,Huang G.Folic acid supplementation delays atherosclerotic lesion development by modulating MCP1 and VEGF DNA methylation levels in vivo and in vitro.Int J Mol Sci 2017;18(5):990.
42 Schiebe M,Chandel NS.ROS function in redox signaling and oxidative stress.Curr Biol 2014;4(10):R453-62.
43 Giannoni E,buricchi F,Raugei G,Ramponi G,Chiarugi P.Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth.Mol Cell Biol 2005;25(10):6391-403.
44 Hoeijmakers JH.DNA damage,aging,and cancer.N Engl J Med2009;361(15):1475-85.
45 Yee C,Yang W,Hekimi S.The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C.elegans.Cell 2014;157(4):897-909.
46 Du MQ,Carmichael PI,Phillip DH.Induction of activating mutations in the human c-Ha-ras-aproto-oncogene by oxygen free radicals.Mol.Carcinog 1994;11:170-5.
47 Ushijima T.Detection and interpretation of altered methylation patterns in cancer cells.Nat Rev Cancer 2005;5(3):223-31.
48 Toyokuni,S.Molecular mechanisms of oxidative stress-induced carcinogenesis:From epidemiology to oxygenomics.IUBMBLife 2008;60(7):441-7.
49 Le KH,Kim SW,Kim JR.Reactive oxygen species regulate urokinase plasminogen activator expressionand cell invasion via mitogen-activated protein kinase pathways after treatment with hepatocyte growthfactor in stomach cancer cells.J Exp Clin Cancer Res 2009;28:73.
50 Liou GY,Storz P.Reactive oxygen species in cancer.Free Radic Res 2010;44(5):479-96.
51 Li Q,Engelhardt JF.Interleukin-1beta induction of NFkappaB is partially regulated by H2O2-mediated activation of NFkappaB-inducing kinase.Biol Chem 2006;281(3):1495-505.
52 Fresno Vara JA.,Casado E,de Castro J,Cejas P,Belda-Iniesta C,González-Barón M.PI3K/Akt signaling pathway and cancer.Cancer Treat Rev 2004;30(2):193-204.
53 Dou C,Xu Q,Liu J,Wang Y,Zhou Z,Yao W,et al.SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROSproduction.J Exp Clin Cancer Res 2019;38(1):70.
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