{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T15:22:12Z","timestamp":1793114532889,"version":"4.5.0"},"reference-count":53,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,22]],"date-time":"2020-06-22T00:00:00Z","timestamp":1592784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The oxidative phosphorylation machinery in mitochondria, which generates the main bioenergy pool in cells, includes four enzyme complexes for electron transport and ATP synthase. Among them, the cytochrome c oxidase (COX), which constitutes the fourth complex, has been suggested as the major regulatory site. Recently, abnormalities in COX were linked to tumor progression in several cancers. However, it remains unclear whether COX and its subunits play a role in tumor progression of hepatoma. To search for the key regulatory factor(s) in COX for hepatoma development, in silico analysis using public transcriptomic database followed by validation for postoperative outcome associations using independent in-house patient cohorts was performed. In which, COX5B was highly expressed in hepatoma and associated with unfavorable postoperative prognosis. In addressing the role of COX5B in hepatoma, the loss- and gain-of-function experiments for COX5B were conducted. Consequently, COX5B expression was associated with increased hepatoma cell proliferation, migration and xenograft growth. Downstream effectors searched by cDNA microarray analysis identified UHMK1, an oncogenic protein, which manifested a positively correlated expression level of COX5B. The COX5B-mediated regulatory event on UHMK1 expression was subsequently demonstrated as bioenergetic alteration-dependent activation of AMPK in hepatoma cells. Phosphoproteomic analysis uncovered activation of ERK- and stathmin-mediated pathways downstream of UHMK1. Finally, comprehensive phenotypic assays supported the impacts of COX5B-UHMK1-ERK axis on hepatoma cell growth and migration.<\/jats:p>","DOI":"10.3390\/cancers12061646","type":"journal-article","created":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T07:14:19Z","timestamp":1592982859000},"page":"1646","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["COX5B-Mediated Bioenergetic Alteration Regulates Tumor Growth and Migration by Modulating AMPK-UHMK1-ERK Cascade in Hepatoma"],"prefix":"10.3390","volume":"12","author":[{"given":"Yu-De","family":"Chu","sequence":"first","affiliation":[{"name":"Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6078-1396","authenticated-orcid":false,"given":"Wey-Ran","family":"Lin","sequence":"additional","affiliation":[{"name":"Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan"},{"name":"Department of Hepatology and Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan"},{"name":"Department of Internal Medicine, Chang Gung University College of Medicine, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang-Hsiang","family":"Lin","sequence":"additional","affiliation":[{"name":"Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Hsin","family":"Kuo","sequence":"additional","affiliation":[{"name":"Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-Ju","family":"Tseng","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Chang Gung University College of Medicine, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siew-Na","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Chang Gung University College of Medicine, Taoyuan 333, Taiwan"},{"name":"Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Lin","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Anatomic Pathology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Chiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Anatomic Pathology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Jung","family":"Wu","sequence":"additional","affiliation":[{"name":"Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5649-2222","authenticated-orcid":false,"given":"Kwang-Huei","family":"Lin","sequence":"additional","affiliation":[{"name":"Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chau-Ting","family":"Yeh","sequence":"additional","affiliation":[{"name":"Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan"},{"name":"Department of Hepatology and Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan"},{"name":"Department of Internal Medicine, Chang Gung University College of Medicine, Taoyuan 333, Taiwan"},{"name":"Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1002\/hep.22506","article-title":"Molecular targeted therapies in hepatocellular carcinoma","volume":"48","author":"Llovet","year":"2008","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1136\/gut.48.2.251","article-title":"Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: A cost effectiveness analysis","volume":"48","author":"Bolondi","year":"2001","journal-title":"Gut"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Zhong, J.H., Xiang, B.D., Gong, W.F., Ke, Y., Mo, Q.G., Ma, L., Liu, X., and Li, L.Q. (2013). Comparison of long-term survival of patients with BCLC stage B hepatocellular carcinoma after liver resection or transarterial chemoembolization. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0068193"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1158\/1940-6207.CAPR-08-0166","article-title":"Energy homeostasis and cancer prevention: The AMP-activated protein kinase","volume":"2","author":"Fay","year":"2009","journal-title":"Cancer Prev. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.bbabio.2017.02.006","article-title":"Mitochondrial metabolism and energy sensing in tumor progression","volume":"1858","author":"Iommarini","year":"2017","journal-title":"Biochim Biophys Acta Bioenerg"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e188","DOI":"10.1038\/oncsis.2015.46","article-title":"Energy disruptors: Rising stars in anticancer therapy?","volume":"5","author":"Bost","year":"2016","journal-title":"Oncogenesis"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.ebiom.2019.05.031","article-title":"Dynamic bioenergetic alterations in colorectal adenomatous polyps and adenocarcinomas","volume":"44","author":"Lin","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"32","DOI":"10.2174\/1871524915666150203093656","article-title":"Beyond Mitochondria, What Would be the Energy Source of the Cell?","volume":"15","author":"Herrera","year":"2015","journal-title":"Cent Nerv. Syst. Agents Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e1085120","DOI":"10.1080\/23723556.2015.1085120","article-title":"Mitochondrial respiratory defects promote the Warburg effect and cancer progression","volume":"3","author":"Srinivasan","year":"2016","journal-title":"Mol. Cell Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tibs.2015.12.001","article-title":"The Warburg Effect: How Does it Benefit Cancer Cells?","volume":"41","author":"Liberti","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1158\/1078-0432.CCR-17-3070","article-title":"Oxidative Phosphorylation as an Emerging Target in Cancer Therapy","volume":"24","author":"Ashton","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S0140-6736(06)68970-8","article-title":"Mitochondrial disease","volume":"368","author":"Schapira","year":"2006","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0891-5849(00)00305-1","article-title":"Mitochondrial energy metabolism is regulated via nuclear-coded subunits of cytochrome c oxidase","volume":"29","author":"Kadenbach","year":"2000","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1002\/1439-7633(20010601)2:6<392::AID-CBIC392>3.0.CO;2-N","article-title":"Cytochrome c Oxidase and the Regulation of Oxidative Phosphorylation","volume":"2","author":"Ludwig","year":"2001","journal-title":"Chembiochem"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/j.tem.2017.09.003","article-title":"Regulation of Mammalian 13-Subunit Cytochrome c Oxidase and Binding of other Proteins: Role of NDUFA4","volume":"28","author":"Kadenbach","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s11060-017-2637-z","article-title":"Overexpression of COX7A2 is associated with a good prognosis in patients with glioma","volume":"136","author":"Deng","year":"2018","journal-title":"J. Neurooncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"fon\u20132017\u20130058\u20131719","DOI":"10.2217\/fon-2017-0058","article-title":"High expression of COX5B is associated with poor prognosis in breast cancer","volume":"13","author":"Gao","year":"2017","journal-title":"Future Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1097\/PAI.0000000000000509","article-title":"Differential Expression of Cytochrome C Oxidase Subunit I Along the Colorectal Adenoma: Carcinoma Progression","volume":"26","author":"Hewedi","year":"2018","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1002\/hep.23483","article-title":"The histogenesis of regenerative nodules in human liver cirrhosis","volume":"51","author":"Lin","year":"2010","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.3892\/ol.2014.1966","article-title":"Complex IV subunit 1 defect predicts postoperative survival in hepatocellular carcinoma","volume":"7","author":"Le","year":"2014","journal-title":"Oncol. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"43363","DOI":"10.18632\/oncotarget.6222","article-title":"Loss of COX5B inhibits proliferation and promotes senescence via mitochondrial dysfunction in breast cancer","volume":"6","author":"Gao","year":"2015","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1101\/gad.17420111","article-title":"AMP-activated protein kinase: An energy sensor that regulates all aspects of cell function","volume":"25","author":"Hardie","year":"2011","journal-title":"Genes Dev"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e245","DOI":"10.1038\/emm.2016.81","article-title":"Regulation and function of AMPK in physiology and diseases","volume":"48","author":"Jeon","year":"2016","journal-title":"Exp. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"18623","DOI":"10.1074\/jbc.273.29.18623","article-title":"Identification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase","volume":"273","author":"Favata","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5463","DOI":"10.2147\/OTT.S139243","article-title":"Identification of COX5B as a novel biomarker in high-grade glioma patients","volume":"10","author":"Hu","year":"2017","journal-title":"Onco Targets"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"67117","DOI":"10.18632\/oncotarget.19962","article-title":"Mitochondrial biomarkers predict tumor progression and poor overall survival in gastric cancers: Companion diagnostics for personalized medicine","volume":"8","author":"Sotgia","year":"2017","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ajpath.2017.09.013","article-title":"Immunometabolic Determinants of Chemoradiotherapy Response and Survival in Head and Neck Squamous Cell Carcinoma","volume":"188","author":"Krupar","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1111\/iju.14040","article-title":"Systematic expression analysis of the mitochondrial respiratory chain protein subunits identifies COX5B as a prognostic marker in clear cell renal cell carcinoma","volume":"26","author":"Stein","year":"2019","journal-title":"Int. J. Urol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1038\/onc.2015.227","article-title":"Disruption of cytochrome c oxidase function induces the Warburg effect and metabolic reprogramming","volume":"35","author":"Srinivasan","year":"2016","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9167","DOI":"10.1096\/fj.201900010RR","article-title":"Cytochrome c oxidase dysfunction enhances phagocytic function and osteoclast formation in macrophages","volume":"33","author":"Angireddy","year":"2019","journal-title":"Faseb. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.1093\/emboj\/cdf343","article-title":"A growth factor-dependent nuclear kinase phosphorylates p27(Kip1) and regulates cell cycle progression","volume":"21","author":"Boehm","year":"2002","journal-title":"Embo. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1016\/j.leukres.2008.02.012","article-title":"KIS induces proliferation and the cell cycle progression through the phosphorylation of p27Kip1 in leukemia cells","volume":"32","author":"Nakamura","year":"2008","journal-title":"Leuk. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3082","DOI":"10.1128\/MCB.05565-11","article-title":"AMPK -> ULK1 -> autophagy","volume":"31","author":"Roach","year":"2011","journal-title":"Mol Cell Biol"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1042\/EBC20170021","article-title":"The mammalian ULK1 complex and autophagy initiation","volume":"61","author":"Zachari","year":"2017","journal-title":"Essays Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5541","DOI":"10.1038\/s41388-019-0801-y","article-title":"YAP-dependent induction of UHMK1 supports nuclear enrichment of the oncogene MYBL2 and proliferation in liver cancer cells","volume":"38","author":"Wei","year":"2019","journal-title":"Oncogene"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1074\/jbc.M705792200","article-title":"FoxM1 regulates growth factor-induced expression of kinase-interacting stathmin (KIS) to promote cell cycle progression","volume":"283","author":"Petrovic","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/ncb3113","article-title":"AMPK modulates Hippo pathway activity to regulate energy homeostasis","volume":"17","author":"Wang","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.1073\/pnas.92.8.3100","article-title":"Stathmin interaction with a putative kinase and coiled-coil-forming protein domains","volume":"92","author":"Maucuer","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"28636","DOI":"10.1074\/jbc.271.45.28636","article-title":"Novel Proteins That Interact with the COOH-terminal Cytosolic Routing Determinants of an Integral Membrane Peptide-processing Enzyme","volume":"271","author":"Alam","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"34646","DOI":"10.1074\/jbc.274.49.34646","article-title":"The Novel Kinase Peptidylglycine","volume":"274","author":"Caldwell","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1091\/mbc.12.3.629","article-title":"Signaling Mediated by the Cytosolic Domain of Peptidylglycine \u03b1-Amidating Monooxygenase","volume":"12","author":"Alam","year":"2001","journal-title":"Mol. Biol. Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.bbamcr.2013.02.004","article-title":"The CATS (FAM64A) protein is a substrate of the Kinase Interacting Stathmin (KIS)","volume":"1833","author":"Archangelo","year":"2013","journal-title":"Biochim. Et Biophys. Acta"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1016\/j.bpj.2016.11.007","article-title":"SF1 Phosphorylation Enhances Specific Binding to U2AF(65) and Reduces Binding to 3\u2019-Splice-Site RNA","volume":"111","author":"Chatrikhi","year":"2016","journal-title":"Biophys J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3848","DOI":"10.1172\/JCI33206","article-title":"KIS protects against adverse vascular remodeling by opposing stathmin-mediated VSMC migration in mice","volume":"118","author":"Langenickel","year":"2008","journal-title":"J. Clin. Invest."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.3892\/ol.2016.5110","article-title":"The Ras\/Raf\/MEK\/ERK signaling pathway and its role in the occurrence and development of HCC","volume":"12","author":"Li","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Crowe, A.R., and Yue, W. (2019). Semi-quantitative Determination of Protein Expression using Immunohistochemistry Staining and Analysis: An Integrated Protocol. Bio. Protoc., 9.","DOI":"10.21769\/BioProtoc.3465"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.4161\/cc.29017","article-title":"RACK-1 regulates let-7 microRNA expression and terminal cell differentiation in Caenorhabditis elegans","volume":"13","author":"Chu","year":"2014","journal-title":"Cell Cycle"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/s41419-019-1486-4","article-title":"The methionine salvage pathway-involving ADI1 inhibits hepatoma growth by epigenetically altering genes expression via elevating S-adenosylmethionine","volume":"10","author":"Chu","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1002\/hep.29462","article-title":"Taurine up-regulated gene 1 functions as a master regulator to coordinate glycolysis and metastasis in hepatocellular carcinoma","volume":"67","author":"Lin","year":"2018","journal-title":"Hepatology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e273","DOI":"10.1038\/oncsis.2016.77","article-title":"Hepatocarcinogenesis in transgenic mice carrying hepatitis B virus pre-S\/S gene with the sW172* mutation","volume":"5","author":"Lai","year":"2016","journal-title":"Oncogenesis"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.ydbio.2015.11.011","article-title":"A novel function for the DEAD-box RNA helicase DDX-23 in primary microRNA processing in Caenorhabditis elegans","volume":"409","author":"Chu","year":"2016","journal-title":"Dev. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/(SICI)1097-0258(20000115)19:1<113::AID-SIM245>3.0.CO;2-O","article-title":"Categorizing a prognostic variable: Review of methods, code for easy implementation and applications to decision-making about cancer treatments","volume":"19","author":"Mazumdar","year":"2000","journal-title":"Stat. Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/6\/1646\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:41:31Z","timestamp":1760175691000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/6\/1646"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,22]]},"references-count":53,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["cancers12061646"],"URL":"https:\/\/doi.org\/10.3390\/cancers12061646","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,22]]}}}