This is a preview and has not been published.

Integrated Analysis of Glutamine Metabolism-related Genes Associated with Clinical Prognosis in Hepatocellular Carcinoma

Glutamine Metabolism-related Genes in HCC

Authors

  • Zhou Xi a:1:{s:5:"en_US";s:62:"Affiliated Hospital of North Sichuan Medical College, Nanchong";}
  • Xiaowu Zhong Affiliated Hospital of North Sichuan Medical College, Nanchong
  • Chuanli Gao Affiliated Hospital of North Sichuan Medical College, Nanchong
  • Yan Zhou School of Basic Medical Sciences, North Sichuan Medical College, Nanchong 637000, P.R.China
  • Xin Chen Department of Rehabilitation Medicine, Affiliated Hospital of North Sichuan Medicine College,
  • Jibing Cheng Department of Laboratory Medicine, North Sichuan Medical College, Nanchong 637000, P.R.China
  • Qingrong Li Department of Laboratory Medicine, North Sichuan Medical College, Nanchong 637000, P.R.China
  • Ru Sun Department of Laboratory Medicine, North Sichuan Medical College, Nanchong 637000, P.R.China
  • Lei Xu Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, P.R.China
  • Miyuan Yang Department of Laboratory Medicine, North Sichuan Medical College, Nanchong 637000, P.R.China
  • Qiang Ma Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, P.R.China
  • Xiaolan Guo

Keywords:

Hepatocellular carcinoma (HCC), Glutamine, SLC1A5, GLS, GLUD1

Abstract

Abstract

Background: Glutamine metabolism-related genes play an indispensable role in a variety of human cancers, while the gene expression profiles, prognostic value, and potential mechanism in Hepatocellular carcinoma (HCC) are yet unclear.

Methods: The expression and roles of SLC1A5, GLS, and GLUD1 in HCC were investigated using a series of bioinformatics databases and tools. The protein expression of SLC1A5, GLS, and GLUD1 between HCC with the corresponding adjacent tissues was validated using western blot.

Results: The expression of SLC1A5 and GLS were up-regulated, and the expression of GLUD1 was down-regulated in HCC tissues. SLC1A5, GLS, and GLUD1 were also related to the clinicopathological parameters of the patients. The protein expression level of SLC1A5 and GLS in HCC tissues was significantly higher than that in para-cancerous tissues, while the protein expression of GLUD1 was significantly lower, which was validated by western blot. Higher expression of SLC1A5, higher expression of GLS, and lower expression of GLUD1 was associated with poor prognosis in HCC patients. Gene expression of SLC1A5, GLS, and GLUD1 in HCC were potentially correlated with promoter methylation level and immune cell infiltration. Functional enrichment analysis of SLC1A5, GLS, and GLUD1 related genes showed that they were mainly concentrated in pyruvate metabolism, tricarboxylic acid cycle, glutamine metabolism, and so on.

Conclusions: Our study broadly elucidated the expressions and prognostic values of SLC1A5, GLS, and GLUD1 in HCC patients, and provided a potential regulatory mechanism for these genes on HCC tumorigenesis.

Keywords: Hepatocellular carcinoma (HCC); Glutamine; SLC1A5; GLS; GLUD1;

Downloads

Download data is not yet available.

##submission.authorBiographies##

##submission.authorWithAffiliation##

1Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, P.R.China  

2Department of Laboratory Medicine, North Sichuan Medical College, Nanchong 637000, P.R.China

3Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, P.R.China 

##submission.authorWithAffiliation##

Department of Laboratory Medicine, North Sichuan Medical College, Nanchong 637000, P.R.China

##submission.authorWithAffiliation##

 School of Basic Medical Sciences, North Sichuan Medical College, Nanchong 637000, P.R.China 

##submission.authorWithAffiliation##

Department of Rehabilitation Medicine, Affiliated Hospital of North Sichuan Medicine College,

##submission.authorWithAffiliation##

Department of Laboratory Medicine, North Sichuan Medical College, Nanchong 637000, P.R.China

##submission.authorWithAffiliation##

Department of Laboratory Medicine, North Sichuan Medical College, Nanchong 637000, P.R.China

##submission.authorWithAffiliation##

Department of Laboratory Medicine, North Sichuan Medical College, Nanchong 637000, P.R.China

##submission.authorWithAffiliation##

Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, P.R.China 

##submission.authorWithAffiliation##

Department of Laboratory Medicine, North Sichuan Medical College, Nanchong 637000, P.R.China

##submission.authorWithAffiliation##

 

Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, P.R.China  

##submission.citations##

Guo Z, Zhong J H, Jiang J H, Zhang J, Xiang B D, Li L Q. Comparison of survival of patients with BCLC stage A hepatocellular carcinoma after hepatic resection or transarterial chemoembolization: a propensity score-based analysis. Ann Surg Oncol, 2014, 21(9): 3069-3076.

Villanueva A, Hoshida Y, Battiston C, Tovar V, Sia D, Alsinet C, Cornella H, Liberzon A, Kobayashi M, Kumada H, Thung S N, Bruix J, Newell P, April C, Fan J B, Roayaie S, Mazzaferro V, Schwartz M E, Llovet J M. Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carci noma. Gastroenterology, 2011, 140(5): 1501-1512.

Portolani N, Coniglio A, Ghidoni S, Giovanelli M, Benetti A, Tiberio G A, Giulini S M. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeu tic implications. Ann Surg, 2006, 243(2): 229-235.

Ward P S, Thompson C B. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell, 2012, 21(3): 297-308.

Altman B J, Stine Z E, Dang C V. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer, 2016, 16(10): 619-634.

Deberardinis R J, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson C B. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requ irement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A., 2007, 104(49): 19345-19350.

Curthoys N P, Watford M. Regulation of glutaminase activity and glutamine metabolism. Annu Rev Nutr, 1995, 15: 133-159.

Craze M L, El-Ansari R, Aleskandarany M A, Cheng K W, Alfarsi L, Masisi B, Diez-Rodriguez M, Nolan C C, Ellis I O, Rakha E A, Green A R. Glutamate dehydrogenase (GLUD1) expression in breast cancer. Breast Cancer Res Treat, 2019, 174(1): 79-91.

Hassanein M, Hoeksema M D, Shiota M, Qian J, Harris B K, Chen H, Clark J E, Alborn W E, Eisenberg R, Massion P P. SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival. Clin Cancer Res, 2013, 19(3): 560-570.

Gao P, Tchernyshyov I, Chang T C, Lee Y S, Kita K, Ochi T, Zeller K I, De Marzo A M, Van Eyk J E, Mendell J T, Dang C V. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature, 2009, 458(7239): 762-765.

Szeliga M, Obara-Michlewska M. Glutamine in neoplastic cells: focus on the expression and roles of glutaminases. Neurochem Int, 2009, 55(1-3): 71-75.

van Geldermalsen M, Wang Q, Nagarajah R, Marshall A D, Thoeng A, Gao D, Ritchie W, Feng Y, Bailey C G, Deng N, Harvey K, Beith J M, Selinger C I, O'Toole S A, Rasko J E, Holst J. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene, 2016, 35(24): 3201-3208.

Sun H W, Yu X J, Wu W C, Chen J, Shi M, Zheng L, Xu J. GLUT1 and ASCT2 as Predictors for Prognosis of Hepatocellular Carcinoma. PLoS One., 2016, 11(12): e168907.

Huang F, Zhao Y, Zhao J, Wu S, Jiang Y, Ma H, Zhang T. Upregulated SLC1A5 promotes cell growth and survival in colorectal cancer. Int J Clin Exp Pathol, 2014, 7(9): 6006-6014.

Xi J, Sun Y, Zhang M, Fa Z, Wan Y, Min Z, Xu H, Xu C, Tang J. GLS1 promotes proliferation in hepatocellular carcinoma cells via AKT/GSK3¦Â/CyclinD1 pathway. Exp Cell Res, 2019, 381(1): 1-9.

Cao J, Zhang C, Jiang G Q, Jin S J, Gao Z H, Wang Q, Yu D C, Ke A W, Fan Y Q, Li D W, Wang A Q, Bai D S. Expression of GLS1 in intrahepatic cholangiocarcinoma and its clinical significance. Mol Med Rep, 2019, 20(2): 1915-1924.

Huang X, Gan G, Wang X, Xu T, Xie W. The HGF-MET axis coordinates liver cancer metabolism and autophagy for chemotherapeutic resistance. Autophagy, 2019, 15(7): 1258-1279.

Wu Y J, Hu Z L, Hu S D, Li Y X, Xing X W, Yang Y, Du X H. Glutamate dehydrogenase inhibits tumor growth in gastric cancer through the Notch signaling pathway. Cancer Biomark, 2019, 26(3): 303-312.

Rhodes D R, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan A M. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia, 2004, 6(1): 1-6.

Chandrashekar D S, Bashel B, Balasubramanya S A H, Creighton C J, Ponce-Rodriguez I, Chakravarthi B, Varambally S. UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia, 2017, 19(8): 649-658.

Thul P J, Kesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, Alm T, Asplund A, Bj Rk L, Breckels L M, B Ckstr M A, Danielsson F, Fagerberg L, Fall J, Gatto L, Gnann C, Hober S, Hjelmare M, Johansson F, Lee S, Lindskog C, Mulder J, Mulvey C M, Nilsson P, Oksvold P, Rockberg J, Schutten R, Schwenk J M, Sivertsson, Sj Stedt E, Skogs M, Stadler C, Sullivan D P, Tegel H, Winsnes C, Zhang C, Zwahlen M, Mardinoglu A, Pont N F, von Feilitzen K, Lilley K S, Uhl N M, Lundberg E. A subcellular map of the human proteome. Science, 2017, 356(6340).

Nagy, L Nczky A, Menyh Rt O, Gy Rffy B. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep, 2018, 8(1): 9227.

Gao J, Aksoy B A, Dogrusoz U, Dresdner G, Gross B, Sumer S O, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal, 2013, 6(269): l1.

Koch A, De Meyer T, Jeschke J, Van Criekinge W. MEXPRESS: visualizing expression, DNA methylation and clinical TCGA data. Bmc Genomics, 2015, 16: 636.

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu J S, Li B, Liu X S. TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res, 2017, 77(21): e108-e110.

Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, Lin J, Minguez P, Bork P, von Mering C, Jensen L J. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res, 2013, 41(Database issue): D808-D815.

Huang D W, Sherman B T, Lempicki R A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc, 2009, 4(1): 44-57.

Yang L, Venneti S, Nagrath D. Glutaminolysis: A Hallmark of Cancer Metabolism. Annu Rev Biomed Eng, 2017, 19: 163-194.

Wang C Y, Chiao C C, Phan N N, Li C Y, Sun Z D, Jiang J Z, Hung J H, Chen Y L, Yen M C, Weng T Y, Chen W C, Hsu H P, Lai M D. Gene signatures and potential therapeutic targets of amino acid metabolism in estrogen receptor-posit ive breast cancer. Am J Cancer Res, 2020, 10(1): 95-113.

Lu J, Chen M, Tao Z, Gao S, Li Y, Cao Y, Lu C, Zou X. Effects of targeting SLC1A5 on inhibiting gastric cancer growth and tumor development in vitro and in vivo. Oncotarget, 2017, 8(44): 76458-76467.

Yuan L, Sheng X, Willson A K, Roque D R, Stine J E, Guo H, Jones H M, Zhou C, Bae-Jump V L. Glutamine promotes ovarian cancer cell proliferation through the mTOR/S6 pathway. Endocr Relat Cancer, 2015, 22(4): 577-591.

He J, Mao Y, Huang W, Li M, Zhang H, Qing Y, Lu S, Xiao H, Li K. Methylcrotonoyl-CoA Carboxylase 2 Promotes Proliferation, Migration and Invasion and Inhibits Apoptos is of Prostate Cancer Cells Through Regulating GLUD1-P38 MAPK Signaling Pathway. Onco Targets Ther, 2020, 13: 7317-7327.

Li B, Cao Y, Meng G, Qian L, Xu T, Yan C, Luo O, Wang S, Wei J, Ding Y, Yu D. Targeting glutaminase 1 attenuates stemness properties in hepatocellular carcinoma by increasing reac tive oxygen species and suppressing Wnt/beta-catenin pathway. Ebiomedicine, 2019, 39: 239-254.

Rebouissou S, Nault J C. Advances in molecular classification and precision oncology in hepatocellular carcinoma. J Hepatol., 2020, 72(2): 215-229.

Long J, Chen P, Lin J, Bai Y, Yang X, Bian J, Lin Y, Wang D, Yang X, Zheng Y, Sang X, Zhao H. DNA methylation-driven genes for constructing diagnostic, prognostic, and recurrence models for hepat ocellular carcinoma. Theranostics, 2019, 9(24): 7251-7267.

Zheng C, Zheng L, Yoo J K, Guo H, Zhang Y, Guo X, Kang B, Hu R, Huang J Y, Zhang Q, Liu Z, Dong M, Hu X, Ouyang W, Peng J, Zhang Z. Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. 2017, 169(7): 1342-1356.

Rumping L, B Ttner B, Maier O, Rehmann H, Lequin M, Schlump J U, Schmitt B, Schiebergen-Bronkhorst B, Prinsen H, Losa M, Fingerhut R, Lemke J R, Zwartkruis F J T, Houwen R H J, Jans J J M, Verhoeven-Duif N M, van Hasselt P M, Jamra R. Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal E pileptic Encephalopathy. Jama Neurol, 2019, 76(3): 342-350.

Lakshminarasimhan R, Liang G. The Role of DNA Methylation in Cancer. Adv Exp Med Biol, 2016, 945: 151-172.

Zhang H, Cui K, Yao S, Yin Y, Liu D, Huang Z. Comprehensive molecular and clinical characterization of SLC1A5 in human cancers. Pathol Res Pract, 2021, 224: 153525.

Hanahan D, Weinberg R A. Hallmarks of cancer: the next generation. Cell, 2011, 144(5): 646-674.

O'Sullivan D, Sanin D E, Pearce E J, Pearce E L. Metabolic interventions in the immune response to cancer. Nat Rev Immunol, 2019, 19(5): 324-335.

Karinch A M, Pan M, Lin C M, Strange R, Souba W W. Glutamine metabolism in sepsis and infection. J Nutr, 2001, 131(9 Suppl): 2535S-2538S, 2550S-2551S.

Nachef M, Ali A K, Almutairi S M, Lee S H. Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the T umor Microenvironment. Front Immunol, 2021, 12: 624324.

Nakaya M, Xiao Y, Zhou X, Chang J H, Chang M, Cheng X, Blonska M, Lin X, Sun S C. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake a nd mTORC1 kinase activation. Immunity, 2014, 40(5): 692-705.

Edwards D N, Ngwa V M, Raybuck A L, Wang S, Hwang Y, Kim L C, Cho S H, Paik Y, Wang Q, Zhang S, Manning H C, Rathmell J C, Cook R S, Boothby M R, Chen J. Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer. J Clin Invest, 2021, 131(4).

Shang M, Cappellesso F, Amorim R, Serneels J, Virga F, Eelen G, Carobbio S, Rincon M Y, Maechler P, De Bock K, Ho P C, Sandri M, Ghesqui Re B, Carmeliet P, Di Matteo M, Berardi E, Mazzone M. Macrophage-derived glutamine boosts satellite cells and muscle regeneration. Nature, 2020, 587(7835): 626-631.

Liu G Y, Sabatini D M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol, 2020, 21(4): 183-203.

Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer V E, Mackeigan J P, Porter J A, Wang Y K, Cantley L C, Finan P M, Murphy L O. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell, 2009, 136(3): 521-534.

Lin J, Yang T, Peng Z, Xiao H, Jiang N, Zhang L, Ca D, Wu P, Pan Q. SLC1A5 Silencing Inhibits Esophageal Cancer Growth via Cell Cycle Arrest and Apoptosis. Cell Physiol Biochem, 2018, 48(1): 397.

Lampa M, Arlt H, He T, Ospina B, Reeves J, Zhang B, Murtie J, Deng G, Barberis C, Hoffmann D, Cheng H, Pollard J, Winter C, Richon V, Garcia-Escheverria C, Adrian F, Wiederschain D, Srinivasan L. Glutaminase is essential for the growth of triple-negative breast cancer cells with a deregulated glu tamine metabolism pathway and its suppression synergizes with mTOR inhibition. Plos One, 2017, 12(9): e185092.

Dang C V, Le A, Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res, 2009, 15(21): 6479-6483.

P Rez-Escuredo J, Dadhich R K, Dhup S, Cacace A, Van H E V F, De Saedeleer C J, Sboarina M, Rodriguez F, Fontenille M J, Brisson L, Porporato P E, Sonveaux P. Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. Cell Cycle, 2016, 15(1): 72-83.

Section

Original articles