Abstract
Oxygen molecule modulates tumour response to radiotherapy. Higher radiation doses are required under hypoxic conditions to induce cell death. Hypoxia may inhibit the non-homologous end-joining DNA repair through down regulating Ku70/80 expression. Hypoxia induces drug resistance in clinical tumours, although the mechanism is not clearly elucidated. Vaults are ribonucleoprotein particles with a hollow barrel-like structure composed of three proteins: major vault protein (MVP), vault poly(ADP-ribose) polymerase, and telomerase associated protein-1 and small untranslated RNA. Over-expression of MVP has been associated with chemotherapy resistance. Also, it has been related to poor outcome in patients treated with radiotherapy alone. The aim of the present study was to assess the relation of Major Vault Protein expression and tumor hypoxia in clinical cervical tumors. MVP, p53 and angiogenesis, together with tumor oxygenation, were determined in forty-three consecutive patients suffering from localized cervix carcinoma. High MVP expression was related to severe hypoxia compared to low MVP expressing tumors (p = 0.022). Tumors over-expressing MVP also showed increased angiogenesis (p = 0.003). Besides it, in this study we show for the first time that severe tumor hypoxia is associated with high MVP expression in clinical cervical tumors. Up-regulation of MVP by hypoxia is of critical relevance as chemotherapy is currently a standard treatment for those patients. From our results it could be suggested that hypoxia not only induces increased genetic instability, oncogenic properties and metastatization, but through the correlation observed with MVP expression, another pathway of chemo and radiation resistance could be developed.
Highlights
Growing cancers often acquire an increasing number of genetic alterations
High Major Vault Protein (MVP) expression was related to severe hypoxia as determined by higher hypoxic fractions HF (2.5) (45.82 ± 28.00%) compared to low MVP expressing tumors (27.26 ± 22.96%) (p = 0.022) (Figure 2a)
In this study we show for the first time that severe tumor hypoxia is related to high MVP expression in clinical cervical tumors
Summary
Growing cancers often acquire an increasing number of genetic alterations. Such genetic changes, including chromosomal translocation, gene amplification, intragenic mutation, and gene silencing, are responsible for the activation of oncogenes and the inactivation of tumour-sup-(page number not for citation purposes)Radiation Oncology 2009, 4:29 http://www.ro-journal.com/content/4/1/29 pressor genes [1]. Growing cancers often acquire an increasing number of genetic alterations. Such genetic changes, including chromosomal translocation, gene amplification, intragenic mutation, and gene silencing, are responsible for the activation of oncogenes and the inactivation of tumour-sup-. Exposure of cells to adverse conditions like hypoxia can lead to genome alterations, enhancing the progression potential of tumor cells and resistance to oncological treatments [1]. MVP over-expression has been associated with a suppression of NHEJ repair, and subsequent genomic instability [10]. These mechanisms would be responsible for tumor progression in cervical carcinoma. The aim of the present study was to assess the relation between the expression of the Major Vault Protein and tumor hypoxia in clinical cervical tumors
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