For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
61
views
35
references
 Top references
cited by
26
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    16
    shares
      186
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Prognostic assessment of hypoxia and metabolic markers in cervical cancer using automated digital image analysis of immunohistochemistry

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Hypoxia inducible factor-1 alpha (HIF-1α), induced by tumor hypoxia, regulates tumor cell metabolism and metastasis by up-regulation of c-Met, carbonic anhydrase 9 (CA9) and glucose transporter 1 (GLUT1). The prognostic significance of hypoxia and metabolic markers is not clearly defined in cervical cancer. Here, we have examined the primary players in the hypoxia signaling pathway, by immunohistochemistry, but confirming their interactions, as well as defining which proteins are associated with outcome.

          Methods

          The study subjects were comprised of cervical intraepithelial neoplasia (CIN, n = 209), carcinoma in situ (CIS, n = 74), cervical cancer ( n = 179), and matched nonadjacent normal tissues ( n = 357). Immunohistochemistry (IHC) was performed to identify HIF-1α, c-Met, CA9, and GLUT1. IHC scoring was performed using automated digital image analysis and the association of hypoxic markers with prognostic outcome was evaluated.

          Results

          HIF-1α, c-Met, CA9 and GLUT1 expression were higher in cervical cancer than in CIN and normal cervix (all P < 0.001). Among these markers, expression of HIF-1α and c-Met were significantly different in FIGO stage ( P < 0.001 and P = 0.019, respectively) and patients with lymph node metastasis ( P < 0.001 and P = 0.010, respectively). HIF-1α expression was correlated with c-Met expression in cervical cancer ( P < 0.001). High expression of HIF-1α and c-Met showed worse 5-year overall survival rate ( P = 0.047 and P = 0.005, respectively) than low expression group, but CA9 and GLUT1 did not show significant survival difference. After adjusting the prognostic covariates, c-Met was found to be an independent risk factor (HR=3.27; 95% CI, 1.05-10.23, P = 0.041) for overall survival in cervical cancer.

          Conclusions

          We demonstrate that c-Met correlates with HIF-1α and is a poor prognostic factor in survival in cervical cancer.

          Related collections

          Most cited references35

          • Record: found
          • Abstract: found
          • Article: not found

          Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking.

          Heather L Wieman, Jessica Wofford, Jeffrey Rathmell (2007)
          Cells require growth factors to support glucose metabolism for survival and growth. It is unclear, however, how noninsulin growth factors may regulate glucose uptake and glucose transporters. We show that the hematopoietic growth factor interleukin (IL)3, maintained the glucose transporter Glut1 on the cell surface and promoted Rab11a-dependent recycling of intracellular Glut1. IL3 required phosphatidylinositol-3 kinase activity to regulate Glut1 trafficking, and activated Akt was sufficient to maintain glucose uptake and surface Glut1 in the absence of IL3. To determine how Akt may regulate Glut1, we analyzed the role of Akt activation of mammalian target of rapamycin (mTOR)/regulatory associated protein of mTOR (RAPTOR) and inhibition of glycogen synthase kinase (GSK)3. Although Akt did not require mTOR/RAPTOR to maintain surface Glut1 levels, inhibition of mTOR/RAPTOR by rapamycin greatly diminished glucose uptake, suggesting Akt-stimulated mTOR/RAPTOR may promote Glut1 transporter activity. In contrast, inhibition of GSK3 did not affect Glut1 internalization but nevertheless maintained surface Glut1 levels in IL3-deprived cells, possibly via enhanced recycling of internalized Glut1. In addition, Akt attenuated Glut1 internalization through a GSK3-independent mechanism. These data demonstrate that intracellular trafficking of Glut1 is a regulated component of growth factor-stimulated glucose uptake and that Akt can promote Glut1 activity and recycling as well as prevent Glut1 internalization.
          Article 0 comments Cited 194 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha.

            R. Ravi, B Mookerjee, Z Bhujwalla … (2000)
            The switch to an angiogenic phenotype is a fundamental determinant of neoplastic growth and tumor progression. We demonstrate that homozygous deletion of the p53 tumor suppressor gene via homologous recombination in a human cancer cell line promotes the neovascularization and growth of tumor xenografts in nude mice. We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation. Loss of p53 in tumor cells enhances HIF-1alpha levels and augments HIF-1-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene in response to hypoxia. Forced expression of HIF-1alpha in p53-expressing tumor cells increases hypoxia-induced VEGF expression and augments neovascularization and growth of tumor xenografts. These results indicate that amplification of normal HIF-1-dependent responses to hypoxia via loss of p53 function contributes to the angiogenic switch during tumorigenesis.
            Article 0 comments Cited 171 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Oxygen, a source of life and stress.

              M Brahimi-Horn, Jacques Pouysségur (2007)
              Oxygen is an essential element in the survival of complex organisms, however the level of oxygen, low or high, can be a source of stress depending on the biological context. Low levels of oxygen in tissues (hypoxia) can be the consequence of a number of pathophysiological conditions including ischemic disorders and cancer while relative, higher levels (hyperoxia) can lead to retinopathy of prematurity. The local oxygen environment and oxygen consumption dictate vascular homeostasis, vaso-proliferation and vaso-cessation, which is deregulated in these diseases through oxygen-dependent growth factors. In this review, we will introduce aspects of the physiology and biology of oxygen partial pressure and the molecular mechanisms implicated in oxygen sensing. We will outline the regulation and function of the key operator in cellular signalling of hypoxia, the transcription factor, hypoxia-inducible factor. In addition, we will focus on cancer cell hypoxia and on its role in driving cell metabolism, pH regulation and survival.
              Article 0 comments Cited 96 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Bo Wook Kim
                Hanbyoul Cho
                Joon-Yong Chung
                Catherine Conway
                Kris Ylaya
                Jae-Hoon Kim
                Stephen M Hewitt
                Journal
                Journal ID (nlm-ta): J Transl Med
                Journal ID (iso-abbrev): J Transl Med
                Title: Journal of Translational Medicine
                Publisher: BioMed Central
                ISSN (Electronic): 1479-5876
                Publication date Collection: 2013
                Publication date (Electronic): 8 August 2013
                Volume: 11
                Page: 185
                Affiliations
                [1 ]Tissue Array Research Program & Applied Molecular Pathology Lab, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
                [2 ]Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, 146-92 Dogok-Dong, Gangnam-Gu, Seoul 135-720, Korea
                [3 ]Department of Obstetrics and Gynecology, Korea Cancer Center Hospital, Seoul 139-706, Korea
                Article
                Publisher ID: 1479-5876-11-185
                DOI: 10.1186/1479-5876-11-185
                PMC ID: 3750663
                PubMed ID: 23927384
                SO-VID: 36b3fa14-12cb-48b4-961c-21d1b4f14e14
                Copyright © Copyright © 2013 Kim et al.; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 29 March 2013
                Date accepted : 6 August 2013
                Categories
                Subject: Research

                ScienceOpen disciplines: Medicine
                Keywords: hif-1α,c-met,cervical cancer,prognosis,automated digital image analysis
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: hif-1α, c-met, cervical cancer, prognosis, automated digital image analysis

                Comments

                Comment on this article

                scite_

                Similar content186

                See all similar

                Cited by26

                See all cited by

                Most referenced authors475

                See all reference authors