Prognostic Impact of HIF-1α Expression in Patients with Definitive Radiotherapy for Cervical Cancer

Dellas, Kathrin; Bache, Matthias; Pigorsch, Steffi; Täubert, Helge; Kappler, Matthias; Holzapfel, Daniel; Zorn, Ester; Holzhausen, H.-J.; Haensgen, G.

doi:10.1007/s00066-008-1764-z

Cited by 61 publications

(52 citation statements)

References 30 publications

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“…High expression of HIF-1A was also reported in cervical cancer tissue samples (21,(39)(40)(41)(42)(43)(44)(45)(46)(47), but only using the immunohistochemical method.…”

Section: Normal Tissue Cancerous Tissue -----------------------------mentioning

confidence: 84%

Increased expression of HIF-1A and its implication in the hypoxia pathway in primary advanced uterine cervical carcinoma

Łuczak

Roszak²,

Pawlik³

et al. 2011

Oncol Rep

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Abstract. The development of cervical cancer exhibits some unique differences compared to other solid tumors. Normal cervical stratified epithelia have characteristics of hypoxic tissue. Lack of oxygen (hypoxia) induces the HIF-1 (hypoxiainducible factor-1) transcription factor, which is a heterodimer composed of a constitutively expressed β subunit and a hypoxia-inducible α-subunit. HIF-1A targets the transcription of over 70 genes involved in many aspects of cancer biology. In well-oxygenated environments, the HIF-1A subunit is hydroxylated, recognized and marked for proteosomal destruction by an E3 ubiquitin ligase, the von Hippel-Lindau protein (pVHL) complex. Under hypoxic stress, proline hydroxylase (PHD) activity is diminished, and stabilized HIF-1A is involved in the activation of the tissue response to hypoxia. Here, we examined the HIF-1A and VHL transcript levels and HIF-1A protein levels in cancerous tissue (n=30) and non-cancerous, normal uterine cervical tissue (n=30). We also compared the methylation status of HIF-1A and of the VHL promoter regions in cancerous and normal tissue samples. Significantly higher levels of HIF-1A and VHL transcripts (p<0.0001 and p= 0.0042, respectively) and of HIF-1A protein (p= 0.0037) were detected in cancerous tissue compared to normal samples. We did not observe DNA methylation in the HIF-1A and VHL promoter region in either control or cancerous tissue samples. VHL has a functional hypoxia response element (HRE) in the promoter region, and the induction of this HRE acts within a negative feedback loop to limit the hypoxic HIF-1A response. Our findings may suggest that HIF-1A could promote its own degradation by the induction of VHL gene expression (Spearman correlation coefficient, 0.515; p=0.003). Our study shows for the first time that this increase in VHL expression could be HIF-1A-dependent and serves within a negative feedback pathway during hypoxia to regulate the cell-specific oxygen threshold for HIF-1A activation.

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“…High expression of HIF-1A was also reported in cervical cancer tissue samples (21,(39)(40)(41)(42)(43)(44)(45)(46)(47), but only using the immunohistochemical method.…”

Section: Normal Tissue Cancerous Tissue -----------------------------mentioning

confidence: 84%

Increased expression of HIF-1A and its implication in the hypoxia pathway in primary advanced uterine cervical carcinoma

Łuczak

Roszak²,

Pawlik³

et al. 2011

Oncol Rep

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“…Несмотря на противоречивость сведений о закономерностях изменения экспрессии HIF-1a в зависимости от клинико-патологических параметров РШМ, все они согласуются с общими представлениями о важной роли HIF-1a в прогрессии опухоли, однако, в литературе пока описаны лишь единичные результаты, подтверждающие значение HIF-1a в индукции ангиогенеза при естественном развитии РШМ [69,77]. Только в некоторых работах анализируется взаимосвязь HIF-1a и микроваскулярной плотности, колокализация или коэкспрессия HIF-1a с другими маркерами ангиогенеза.…”

Section: транскрипционные факторы: фактор индуцированный гипоксией-1unclassified

“…показана коэкспрессия VEGF и HIF-1a, которая, однако, не подтверждается работами No и соавт. и Fujimoto и соавт [69,71,77]. Авторы делают предположение о том, что in vivo, в ходе естественного развития РШМ, HIF-1a является далеко не единственным индуктором экспрессии VEGF [71].…”

Section: транскрипционные факторы: фактор индуцированный гипоксией-1unclassified

Remodeling of angiogenesis and lymphangiogenesis in cervical cancer development

et al. 2015

BIOMED KHIM

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Ability to stimulate angiogenesis/lymphangiogenesis is recognized as an inherent feature of cancer cells providing necessary conditions for their growth and dissemination. “Angiogenic switch” is one of the earliest consequences of malignant transformation that encompasses a great number of genes and triggers a complex set of signaling cascades in endothelial cells. The processes of tumor microvasculature development are closely connected to the steps of carcinogenesis (from benign lesions to invasive forms) and occur through multiple deviations from the norm. Analysis of expression of proangiogenic factors at successive steps of cervical cancer development (intraepithelial neoplasia, cancer in situ, microinvasive, and invasive cancer) enables to reconstruct the regulatory mechanisms of (lymph-)angiogenesis and to discriminate the most important components. This review presents detailed analysis of literature data on expression of the key regulators of angiogenesis in cervical intraepithelial neoplasia and cervical cancer. Their possible involvement in molecular mechanisms of neoplastic transformation of epithelial cells, as well as invasion and tumor metastasis is discussed. Correlation between expression of proangiogenic molecular factors and various clinicopathological parameters is considered, the potential of their use in molecular diagnostics and targeted therapy of cervical cancer is reviewed. Particular attention is paid to relatively poorly studied regulators of lymphangiogenesis and “non-VEGF dependent”, or alternative, angiogenic pathways that constitute the prospect of future research in the field.

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“…Ένας από τους επικρατέστερους μηχανισμούς δημιουργίας υποξικών συνθηκών στον καρκίνο προτάθηκε για από τους Thomlinson και Gray (Brown and Giaccia 1998 (ROS) οι οποίες μπορούν αφενός να σταθεροποιούν το HIF-1α και αφετέρου να επάγουν τη μεταγραφική ενεργότητα του (Park et al 2003 (Semenza 2010). Στα περισσότερα είδη καρκίνου έχει αναφερθεί υπερέκφραση της ρυθμιστικής υπομονάδας του HIF-1, HIF-1α, καθιστώντας πλέον τον HIF-1α σημαντικό βιολογικό μάρτυρα για την πρόγνωση του καρκίνου (Lu et al 2006;Theodoropoulos et al 2006;Dellas et al 2008;Rasheed et al 2009). …”

Section: αυξητικοί παράγοντες/κινάσεςunclassified

“…Άμεση συσχέτιση επιπέδων HIF-1α και χημειοθεραπείας, όσον αφορά τον καρκίνο του ορθού, έχει αναφερθεί γενικότερα σε αρκετές περιπτώσεις Korkeila et al 2010;Toiyama et al 2010). Ο ανασταλτικός ρόλος του HIF-1α στη χημειοθεραπεία υπογραμμίζεται επίσης σε περιστατικά καρκίνου του τραχήλου της μήτρας (Dellas et al 2008), του οισοφάγου (Koukourakis et al 2001) του πνεύμονα (Ou et al 2009;Zhang et al 2009), του πλακώδους επιθηλίου του φάρυγγα αλλά και σε ασθενείς με ολιγοδενδρογλοίωμα (Aebersold et al 2001). …”

Section: αυξητικοί παράγοντες/κινάσεςunclassified

Εφαρμογή Της Μοριακής Αποτύπωσης Στη Στοχευμένη Απομόνωση Βιοδραστικών Φυσικών Ενώσεων Για Τη Ρύθμιση Της Απόκρισης Των Κυττάρων Στην Υποξία

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Prognostic Impact of HIF-1α Expression in Patients with Definitive Radiotherapy for Cervical Cancer

Abstract: The study indicates, that endogenous tumor markers such as HIF-1alpha may serve as prognostic markers of clinical outcome concerning cervical cancer after primary radiotherapy.

Cited by 61 publications

References 30 publications

Increased expression of HIF-1A and its implication in the hypoxia pathway in primary advanced uterine cervical carcinoma

Increased expression of HIF-1A and its implication in the hypoxia pathway in primary advanced uterine cervical carcinoma

Remodeling of angiogenesis and lymphangiogenesis in cervical cancer development

Εφαρμογή Της Μοριακής Αποτύπωσης Στη Στοχευμένη Απομόνωση Βιοδραστικών Φυσικών Ενώσεων Για Τη Ρύθμιση Της Απόκρισης Των Κυττάρων Στην Υποξία

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