Bioinformatics Analysis and Verification of Metabolic Abnormalities in
Esophageal Squamous Carcinoma

Duo      Tang; Guozhen      Wang; Zijia      Liu; Yu Chen      Zheng; Chao      Sheng; Biqi      Wang; Xiaonan      Hou; Yu Chen      Zhang; Mengfei      Yao; Zhixiang      Zhou

doi:10.2174/1386207326666230331083724

Abstract

Background: Although esophageal carcinoma (EC) is one of the most common cancers in the world, details of its pathogenesis remain unclear. Metabolic reprogramming is a main feature of EC. Mitochondrial dysfunction, especially the decrease in mitochondrial complex I (MTCI), plays an important role in the occurrence and development of EC.

Objective: The objective of the study was to analyze and validate the metabolic abnormalities and the role of MTCI in esophageal squamous cell carcinoma.

Methods: In this work, we collected transcriptomic data from 160 esophageal squamous carcinoma samples and 11 normal tissue samples from The Cancer Genome Atlas (TCGA). The OmicsBean and GEPIA2 were used to conduct an analysis of differential gene expression and survival in clinical samples. Rotenone was used to inhibit the MTCI activity. Subsequently, we detected lactate production, glucose uptake, and ATP production.

Results: A total of 1710 genes were identified as being significantly differentially expressed. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis suggested that these differentially expressed genes (DEGs) were significantly enriched in various pathways related to carcinoma tumorigenesis and progression. Moreover, we further identified abnormalities in metabolic pathways, in particular, the significantly low expression of multiple subunits of MTCI genes (ND1, ND2, ND3, ND4, ND4L, ND5, and ND6). Rotenone was used to inhibit the MTCI activity of EC109 cells, and it was found that the decrease in MTCI activity promoted HIF1A expression, glucose consumption, lactate production, ATP production, and cell migration.

Conclusion: Our results indicated the occurrence of abnormal metabolism involving decreased mitochondrial complex I activity and increased glycolysis in esophageal squamous cell carcinoma (ESCC), which might be related to its development and degree of malignancy.

« Previous Next »

Graphical Abstract

[1]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. 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.
 [http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]

[2]
Short, M.W.; Burgers, K.G.; Fry, V.T. Esophageal cancer. Am. Fam. Physician,  2017, 95(1), 22-28.
 [PMID: 28075104]

[3]
Harada, K.; Rogers, J.E.; Iwatsuki, M.; Yamashita, K.; Baba, H.; Ajani, J.A. Recent advances in treating oesophageal cancer. F1000 Res.,  2020, 9, 1189.
 [http://dx.doi.org/10.12688/f1000research.22926.1] [PMID: 33042518]

[4]
Uhlenhopp, D.J.; Then, E.O.; Sunkara, T.; Gaduputi, V. Epidemiology of esophageal cancer: update in global trends, etiology and risk factors. Clin. J. Gastroenterol.,  2020, 13(6), 1010-1021.
 [http://dx.doi.org/10.1007/s12328-020-01237-x] [PMID: 32965635]

[5]
Hochwald, J.; Zhang, J. Glucose oncometabolism of esophageal cancer. Anticancer. Agents Med. Chem.,  2017, 17(3), 385-394.
 [http://dx.doi.org/10.2174/1871520616666160627092716] [PMID: 27357541]

[6]
Kalyanaraman, B.; Cheng, G.; Hardy, M. Therapeutic targeting of tumor cells and tumor immune microenvironment vulnerabilities. Front. Oncol.,  2022, 12, 816504.
 [http://dx.doi.org/10.3389/fonc.2022.816504] [PMID: 35756631]

[7]
Nie, Y.; Yun, X.; Zhang, Y.; Wang, X. Targeting metabolic reprogramming in chronic lymphocytic leukemia. Exp. Hematol. Oncol.,  2022, 11(1), 39.
 [http://dx.doi.org/10.1186/s40164-022-00292-z] [PMID: 35761419]

[8]
Zhou, Y.; Zhan, Y.; Jiang, W.; Liu, H.; Wei, S. Long noncoding RNAs and circular RNAs in the metabolic reprogramming of lung cancer: functions, mechanisms, and clinical potential. Oxid. Med. Cell. Longev.,  2022, 2022, 1-17.
 [http://dx.doi.org/10.1155/2022/4802338] [PMID: 35757505]

[9]
Pavlova, N.N.; Thompson, C.B. The emerging hallmarks of cancer metabolism. Cell Metab.,  2016, 23(1), 27-47.
 [http://dx.doi.org/10.1016/j.cmet.2015.12.006] [PMID: 26771115]

[10]
Warburg, O.; Wind, F.; Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol.,  1927, 8(6), 519-530.
 [http://dx.doi.org/10.1085/jgp.8.6.519] [PMID: 19872213]

[11]
Som, P.; Atkins, H.L.; Bandoypadhyay, D.; Fowler, J.S.; MacGregor, R.R.; Matsui, K.; Oster, Z.H.; Sacker, D.F.; Shiue, C.Y.; Turner, H.; Wan, C.N.; Wolf, A.P.; Zabinski, S.V. A fluorinated glucose analog, 2-fluoro-2-deoxy-D-glucose (F-18): nontoxic tracer for rapid tumor detection. J. Nucl. Med.,  1980, 21(7), 670-675.
 [PMID: 7391842]

[12]
Liu, T.; Yin, H. PDK1 promotes tumor cell proliferation and migration by enhancing the Warburg effect in non-small cell lung cancer. Oncol. Rep.,  2017, 37(1), 193-200.
 [http://dx.doi.org/10.3892/or.2016.5253] [PMID: 27878287]

[13]
Sha, L.; Lv, Z.; Liu, Y.; Zhang, Y.; Sui, X.; Wang, T.; Zhang, H. Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer. Mol. Med. Rep.,  2021, 24(2), 560.
 [http://dx.doi.org/10.3892/mmr.2021.12199] [PMID: 34109434]

[14]
Yang, L.; Zhang, W.; Wang, Y.; Zou, T.; Zhang, B.; Xu, Y.; Pang, T.; Hu, Q.; Chen, M.; Wang, L.; Lv, Y.; Yin, K.; Liang, H.; Chen, X.; Xu, G.; Zou, X. Hypoxia-induced miR-214 expression promotes tumour cell proliferation and migration by enhancing the Warburg effect in gastric carcinoma cells. Cancer Lett.,  2018, 414, 44-56.
 [http://dx.doi.org/10.1016/j.canlet.2017.11.007] [PMID: 29129783]

[15]
Ohnishi, T.; Ohnishi, S.T.; Salerno, J.C. Five decades of research on mitochondrial NADH-quinone oxidoreductase (complex I). Biol. Chem.,  2018, 399(11), 1249-1264.
 [http://dx.doi.org/10.1515/hsz-2018-0164] [PMID: 30243012]

[16]
Wirth, C.; Brandt, U.; Hunte, C.; Zickermann, V. Structure and function of mitochondrial complex I. Biochim. Biophys. Acta Bioenerg.,  2016, 1857(7), 902-914.
 [http://dx.doi.org/10.1016/j.bbabio.2016.02.013] [PMID: 26921811]

[17]
Zong, W.X.; Rabinowitz, J.D.; White, E. Mitochondria and Cancer. Mol. Cell,  2016, 61(5), 667-676.
 [http://dx.doi.org/10.1016/j.molcel.2016.02.011] [PMID: 26942671]

[18]
Iommarini, L.; Calvaruso, M.A.; Kurelac, I.; Gasparre, G.; Porcelli, A.M. Complex I impairment in mitochondrial diseases and cancer: Parallel roads leading to different outcomes. Int. J. Biochem. Cell Biol.,  2013, 45(1), 47-63.
 [http://dx.doi.org/10.1016/j.biocel.2012.05.016] [PMID: 22664328]

[19]
Calabrese, C.; Iommarini, L.; Kurelac, I.; Calvaruso, M.A.; Capristo, M.; Lollini, P.L.; Nanni, P.; Bergamini, C.; Nicoletti, G.; De Giovanni, C.; Ghelli, A.; Giorgio, V.; Caratozzolo, M.F.; Marzano, F.; Manzari, C.; Betts, C.M.; Carelli, V.; Ceccarelli, C.; Attimonelli, M.; Romeo, G.; Fato, R.; Rugolo, M.; Tullo, A.; Gasparre, G.; Porcelli, A.M. Respiratory complex I is essential to induce a Warburg profile in mitochondria-defective tumor cells. Cancer Metab.,  2013, 1(1), 11.
 [http://dx.doi.org/10.1186/2049-3002-1-11] [PMID: 24280190]

[20]
Vatrinet, R.; Iommarini, L.; Kurelac, I.; De Luise, M.; Gasparre, G.; Porcelli, A.M. Targeting respiratory complex I to prevent the Warburg effect. Int. J. Biochem. Cell Biol.,  2015, 63, 41-45.
 [http://dx.doi.org/10.1016/j.biocel.2015.01.017] [PMID: 25668477]

[21]
Chen, C.; Chen, H.; Zhang, Y.; Thomas, H.R.; Frank, M.H.; He, Y.; Xia, R. TBtools: An integrative toolkit developed for interactive analyses of big biological data. Mol. Plant,  2020, 13(8), 1194-1202.
 [http://dx.doi.org/10.1016/j.molp.2020.06.009] [PMID: 32585190]

[22]
Kishore Kumar, S.N.; Deepthy, J.; Saraswathi, U.; Thangarajeswari, M.; Yogesh Kanna, S.; Ezhil, P.; Kalaiselvi, P. Morinda citrifolia mitigates rotenone-induced striatal neuronal loss in male Sprague-Dawley rats by preventing mitochondrial pathway of intrinsic apoptosis. Redox Rep.,  2017, 22(6), 418-429.
 [http://dx.doi.org/10.1080/13510002.2016.1253449] [PMID: 27882828]

[23]
Li, N.; Ragheb, K.; Lawler, G.; Sturgis, J.; Rajwa, B.; Melendez, J.A.; Robinson, J.P. Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J. Biol. Chem.,  2003, 278(10), 8516-8525.
 [http://dx.doi.org/10.1074/jbc.M210432200] [PMID: 12496265]

[24]
Liu, A.; Xu, J. Circ_03955 promotes pancreatic cancer tumorigenesis and Warburg effect by targeting the miR-3662/HIF-1α axis. Clin. Transl. Oncol.,  2021, 23(9), 1905-1914.
 [http://dx.doi.org/10.1007/s12094-021-02599-5] [PMID: 33864618]

[25]
Meng, F.; Luo, X.; Li, C.; Wang, G. LncRNA LINC00525 activates HIF-1α through miR-338-3p / UBE2Q1 / β-catenin axis to regulate the Warburg effect in colorectal cancer. Bioengineered,  2022, 13(2), 2552-2565.
 [http://dx.doi.org/10.1080/21655979.2021.2018538] [PMID: 35156520]

[26]
Kotlyar, A.B.; Vinogradov, A.D. Slow active/inactive transition of the mitochondrial NADH-ubiquinone reductase. Biochim. Biophys. Acta Bioenerg.,  1990, 1019(2), 151-158.
 [http://dx.doi.org/10.1016/0005-2728(90)90137-S] [PMID: 2119805]

[27]
Kahlhöfer, F.; Gansen, M.; Zickermann, V. Accessory subunits of the matrix arm of mitochondrial complex I with a Focus on Subunit NDUFS4 and its role in complex I function and assembly. Life,  2021, 11(5), 455.
 [http://dx.doi.org/10.3390/life11050455] [PMID: 34069703]

[28]
Ishikawa, K.; Takenaga, K.; Akimoto, M.; Koshikawa, N.; Yamaguchi, A.; Imanishi, H.; Nakada, K.; Honma, Y.; Hayashi, J.I. ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science,  2008, 320(5876), 661-664.
 [http://dx.doi.org/10.1126/science.1156906] [PMID: 18388260]

[29]
Sharma, L.K.; Fang, H.; Liu, J.; Vartak, R.; Deng, J.; Bai, Y. Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation. Hum. Mol. Genet.,  2011, 20(23), 4605-4616.
 [http://dx.doi.org/10.1093/hmg/ddr395] [PMID: 21890492]

[30]
Sun, W.; Zhou, S.; Chang, S.S.; McFate, T.; Verma, A.; Califano, J.A. Mitochondrial mutations contribute to HIF1alpha accumulation via increased reactive oxygen species and up-regulated pyruvate dehydrogenease kinase 2 in head and neck squamous cell carcinoma. Clin. Cancer Res.,  2009, 15(2), 476-484.
 [http://dx.doi.org/10.1158/1078-0432.CCR-08-0930] [PMID: 19147752]

[31]
Guan, Q.; Wang, X.; Jiang, Y.; Zhao, L.; Nie, Z.; Jin, L. RNA-Seq expression analysis of enteric neuron cells with rotenone treatment and prediction of regulated pathways. Neurochem. Res.,  2017, 42(2), 572-582.
 [http://dx.doi.org/10.1007/s11064-016-2112-9] [PMID: 27900601]

[32]
Khadrawy, Y.A.; Mourad, I.M.; Mohammed, H.S.; Noor, N.A.; Aboul, H.S. Cerebellar neurochemical and histopathological changes in rat model of Parkinson’s disease induced by intrastriatal injection of rotenone. Gen. Physiol. Biophys.,  2017, 36(1), 99-108.
 [http://dx.doi.org/10.4149/gpb_2016031] [PMID: 27901474]

[33]
Zhang, Z.N.; Zhang, J.S.; Xiang, J.; Yu, Z.H.; Zhang, W.; Cai, M.; Li, X.T.; Wu, T.; Li, W.W.; Cai, D.F. Subcutaneous rotenone rat model of Parkinson’s disease: Dose exploration study. Brain Res.,  2017, 1655, 104-113.
 [http://dx.doi.org/10.1016/j.brainres.2016.11.020] [PMID: 27876560]

[34]
Noser, A.A.; Abdelmonsef, A.H.; El-Naggar, M.; Salem, M.M. New amino acid schiff bases as anticancer agents via potential mitochondrial complex I-Associated hexokinase inhibition and targeting AMP-protein kinases/mTOR signaling pathway. Molecules,  2021, 26(17), 5332.
 [http://dx.doi.org/10.3390/molecules26175332] [PMID: 34500765]

[35]
DeBerardinis, R.J.; Chandel, N.S. Fundamentals of cancer metabolism. Sci. Adv.,  2016, 2(5), e1600200.
 [http://dx.doi.org/10.1126/sciadv.1600200] [PMID: 27386546]

[36]
Desquiret-Dumas, V.; Leman, G.; Wetterwald, C.; Chupin, S.; Lebert, A.; Khiati, S.; Le Mao, M.; Geffroy, G.; Kane, M.S.; Chevrollier, A.; Goudenege, D.; Gadras, C.; Tessier, L.; Barth, M.; Leruez, S.; Amati-Bonneau, P.; Henrion, D.; Bonneau, D.; Procaccio, V.; Reynier, P.; Lenaers, G.; Gueguen, N. Warburg-like effect is a hallmark of complex I assembly defects. Biochim. Biophys. Acta Mol. Basis Dis.,  2019, 1865(9), 2475-2489.
 [http://dx.doi.org/10.1016/j.bbadis.2019.05.011] [PMID: 31121247]

[37]
Bai, M.L.; Li, H.J.; Zhang, L.X. Effects of deguelin on the proliferation and apoptosis of human esophageal cancer cell Ec-109: An experimental research. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih,  2013, 33(3), 397-400.
 [PMID: 23713258]

[38]
Yu, X.; Liang, Q.; Liu, W.; Zhou, L.; Li, W.; Liu, H. Deguelin, an Aurora B kinase inhibitor, exhibits potent anti-tumor effect in human esophageal squamous cell carcinoma. EBioMedicine,  2017, 26, 100-111.
 [http://dx.doi.org/10.1016/j.ebiom.2017.10.030] [PMID: 29129699]

[39]
Levine, A.J.; Puzio-Kuter, A.M. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science,  2010, 330(6009), 1340-1344.
 [http://dx.doi.org/10.1126/science.1193494] [PMID: 21127244]

[40]
Doe, M.R.; Ascano, J.M.; Kaur, M.; Cole, M.D. Myc posttranscriptionally induces HIF1 protein and target gene expression in normal and cancer cells. Cancer Res.,  2012, 72(4), 949-957.
 [http://dx.doi.org/10.1158/0008-5472.CAN-11-2371] [PMID: 22186139]

[41]
Elzakra, N.; Kim, Y. HIF-1α metabolic pathways in human cancer. Adv. Exp. Med. Biol.,  2021, 1280, 243-260.
 [http://dx.doi.org/10.1007/978-3-030-51652-9_17] [PMID: 33791987]

[42]
Hayashi, M.; Sakata, M.; Takeda, T.; Yamamoto, T.; Okamoto, Y.; Sawada, K.; Kimura, A.; Minekawa, R.; Tahara, M.; Tasaka, K.; Murata, Y. Induction of glucose transporter 1 expression through hypoxia-inducible factor 1α under hypoxic conditions in trophoblast-derived cells. J. Endocrinol.,  2004, 183(1), 145-154.
 [http://dx.doi.org/10.1677/joe.1.05599] [PMID: 15525582]

[43]
Liu, Y.; Li, Y.; Tian, R.; Liu, W.; Fei, Z.; Long, Q.; Wang, X.; Zhang, X. The expression and significance of HIF-1α and GLUT-3 in glioma. Brain Res.,  2009, 1304, 149-154.
 [http://dx.doi.org/10.1016/j.brainres.2009.09.083] [PMID: 19782666]

[44]
Jing, S.; Wang, J.; Liu, Q.; Cheng, Y.; Yang, C.; Wang, Y.; Cao, F.; Wen, B.; Jiao, W.; Guo, Y. Relationship between hypoxia inducible factor-1α and esophageal squamous cell carcinoma: a meta analysis. Zhonghua Bing Li Xue Za Zhi,  2014, 43(9), 593-599.
 [PMID: 25471499]

[45]
Li, W.; Xue, D.; Xue, M.; Zhao, J.; Liang, H.; Liu, Y.; Sun, T. Fucoidan inhibits epithelial to mesenchymal transition via regulation of the HIF-1α pathway in mammary cancer cells under hypoxia. Oncol. Lett.,  2019, 18(1), 330-338.
 [http://dx.doi.org/10.3892/ol.2019.10283] [PMID: 31289504]

[46]
Peng, J. Shen, S.; Wang, J.; Jiang, H.; Wang, Y. Ηypoxia-inducible factor -1α promotes colon cell proliferation and migration by upregulating AMPK-related protein kinase 5 under hypoxic conditions. Oncol. Lett.,  2018, 15(3), 3639-3645.
 [http://dx.doi.org/10.3892/ol.2018.7748] [PMID: 29467884]

Rights & Permissions Print Cite

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1386207326666230331083724	Print ISSN 1386-2073
Publisher Name Bentham Science Publisher	Online ISSN 1875-5402

Combinatorial Chemistry & High Throughput Screening

Bioinformatics Analysis and Verification of Metabolic Abnormalities in Esophageal Squamous Carcinoma

Abstract Play Pause

Graphical Abstract

Related Journals

Abstract