File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: NDUFA4L2 Fine-tunes Oxidative Stress in Hepatocellular Carcinoma

TitleNDUFA4L2 Fine-tunes Oxidative Stress in Hepatocellular Carcinoma
Authors
Issue Date2016
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://clincancerres.aacrjournals.org/
Citation
Clinical Cancer Research, 2016, v. 22 n. 12, p. 3105-3117 How to Cite?
AbstractPURPOSE: Hepatocellular carcinoma (HCC) lacks effective curative therapy. Hypoxia is commonly found in HCC. Hypoxia elicits a series of protumorigenic responses through hypoxia-inducible factor-1 (HIF1). Better understanding of the metabolic adaptations of HCC cells during hypoxia is essential to the design of new therapeutic regimen. EXPERIMENTAL DESIGN: Expressions of genes involved in the electron transport chain (ETC) in HCC cell lines (20% and 1% O2) and human HCC samples were analyzed by transcriptome sequencing. Expression of NDUFA4L2, a less active subunit in complex I of the ETC, in 100 pairs of HCC and nontumorous liver tissues were analyzed by qRT-PCR. Student t test and Kaplan-Meier analyses were used for clinicopathologic correlation and survival studies. Orthotopic HCC implantation model was used to evaluate the efficiency of HIF inhibitor. RESULTS: NDUFA4L2 was drastically overexpressed in human HCC and induced by hypoxia. NDUFA4L2 overexpression was closely associated with tumor microsatellite formation, absence of tumor encapsulation, and poor overall survival in HCC patients. We confirmed that NDUFA4L2 was HIF1-regulated in HCC cells. Inactivation of HIF1/NDUFA4L2 increased mitochondrial activity and oxygen consumption, resulting in ROS accumulation and apoptosis. Knockdown of NDUFA4L2 markedly suppressed HCC growth and metastasis in vivo HIF inhibitor, digoxin, significantly suppressed growth of tumors that expressed high level of NDUFA4L2. CONCLUSIONS: Our study has provided the first clinical relevance of NDUFA4L2 in human cancer and suggested that HCC patients with NDUFA4L2 overexpression may be suitable candidates for HIF inhibitor treatment. Clin Cancer Res; 22(12); 3105-17. (c)2016 AACR.
Persistent Identifierhttp://hdl.handle.net/10722/232165
ISSN
2023 Impact Factor: 10.0
2023 SCImago Journal Rankings: 4.623
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLai, KH-
dc.contributor.authorXu, M-
dc.contributor.authorChiu, KC-
dc.contributor.authorTse, PW-
dc.contributor.authorWei, L-
dc.contributor.authorLaw, CT-
dc.contributor.authorLee, D-
dc.contributor.authorWong, CM-
dc.contributor.authorWong, MP-
dc.contributor.authorNg, IOL-
dc.contributor.authorWong, CCL-
dc.date.accessioned2016-09-20T05:28:10Z-
dc.date.available2016-09-20T05:28:10Z-
dc.date.issued2016-
dc.identifier.citationClinical Cancer Research, 2016, v. 22 n. 12, p. 3105-3117-
dc.identifier.issn1078-0432-
dc.identifier.urihttp://hdl.handle.net/10722/232165-
dc.description.abstractPURPOSE: Hepatocellular carcinoma (HCC) lacks effective curative therapy. Hypoxia is commonly found in HCC. Hypoxia elicits a series of protumorigenic responses through hypoxia-inducible factor-1 (HIF1). Better understanding of the metabolic adaptations of HCC cells during hypoxia is essential to the design of new therapeutic regimen. EXPERIMENTAL DESIGN: Expressions of genes involved in the electron transport chain (ETC) in HCC cell lines (20% and 1% O2) and human HCC samples were analyzed by transcriptome sequencing. Expression of NDUFA4L2, a less active subunit in complex I of the ETC, in 100 pairs of HCC and nontumorous liver tissues were analyzed by qRT-PCR. Student t test and Kaplan-Meier analyses were used for clinicopathologic correlation and survival studies. Orthotopic HCC implantation model was used to evaluate the efficiency of HIF inhibitor. RESULTS: NDUFA4L2 was drastically overexpressed in human HCC and induced by hypoxia. NDUFA4L2 overexpression was closely associated with tumor microsatellite formation, absence of tumor encapsulation, and poor overall survival in HCC patients. We confirmed that NDUFA4L2 was HIF1-regulated in HCC cells. Inactivation of HIF1/NDUFA4L2 increased mitochondrial activity and oxygen consumption, resulting in ROS accumulation and apoptosis. Knockdown of NDUFA4L2 markedly suppressed HCC growth and metastasis in vivo HIF inhibitor, digoxin, significantly suppressed growth of tumors that expressed high level of NDUFA4L2. CONCLUSIONS: Our study has provided the first clinical relevance of NDUFA4L2 in human cancer and suggested that HCC patients with NDUFA4L2 overexpression may be suitable candidates for HIF inhibitor treatment. Clin Cancer Res; 22(12); 3105-17. (c)2016 AACR.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://clincancerres.aacrjournals.org/-
dc.relation.ispartofClinical Cancer Research-
dc.titleNDUFA4L2 Fine-tunes Oxidative Stress in Hepatocellular Carcinoma-
dc.typeArticle-
dc.identifier.emailTse, PW: akipwtse@hku.hk-
dc.identifier.emailWei, L: larrywei@hku.hk-
dc.identifier.emailWong, CM: jcmwong@hku.hk-
dc.identifier.emailWong, MP: mwpik@hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.emailWong, CCL: carmencl@pathology.hku.hk-
dc.identifier.authorityWong, CM=rp00231-
dc.identifier.authorityWong, MP=rp00348-
dc.identifier.authorityNg, IOL=rp00335-
dc.identifier.authorityWong, CCL=rp01602-
dc.identifier.doi10.1158/1078-0432.CCR-15-1987-
dc.identifier.scopuseid_2-s2.0-84975055719-
dc.identifier.hkuros264758-
dc.identifier.volume22-
dc.identifier.issue12-
dc.identifier.spage3105-
dc.identifier.epage3117-
dc.identifier.isiWOS:000377958800030-
dc.publisher.placeUnited States-
dc.identifier.issnl1078-0432-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats