This study was carried out to explore the clinical association between MVP expression and prognosis on a series of OCSCC patients treated by surgery and radiotherapy. MVP was overexpressed in 67 (51.1%) of our oral cavity carcinoma patients. Only one study has reported data of MVP expression in head and neck cancer
. Silva et al. detected positive expression of MVP in 49 out of 78 (62.8%) patients suffering from carcinoma in the posterior third of tongue and the tonsil.
Tumour stage was the most important prognostic factor for survival in our series. The rates of local recurrence for clinical stages III or IV tumours may be as high as 40%. In our whole series, MVP was not a predictive factor for survival. Nonetheless, when patients were segregated according to low (I-II) or high (III-IV) tumour stage, MVP expression was predictive for DMFS, DFS, and CSS. The fact that patients with advanced stages of the disease suffer more amount of adverse events related to the tumour, together with the radioresistance role of MVP previously reported in tongue and cervical carcinoma, helps to explain the predictive role of this oncoprotein only in patients suffering OCSCC in stage III-IV, all treated with surgery and RT. MVP may have a role in favouring increased genetic instability by reducing DNA damage repair by means of non-homologous end joining (NHEJ) and downregulating Ku70/80 expression
. The most important radiation-induced DNA damage is the double-strand breaks (DSB), mainly repaired by NHEJ. Ku70/80 are key genes in the NHEJ repair pathway for radiation-induced DNA DSB. If vaults are overexpressed, NHEJ repair may be suppressed by several mechanisms; thus, genomic instability could arise because either repair of DSB damage by homologous repair is prevented or NHEJ repair is defective. The PARP-1, part of Vault complex, promotes homologous repair over NHEJ, suppressing Ku70/80 function. These events are associated with the decision of damaged cells to survive and proliferate, favouring tumour progression and reducing tumour response to oncologic treatment through the development of resistant cell phenotypes. Our results are in agreement with the published study of Silva et al.
 where MVP has strongly predicted the clinical outcome in 78 oropharyngeal cancer patients who received primary radiotherapy with a curative intent. Because OCSCC in advanced stages (III-IV) were all referred to postoperative radiotherapy, the role of MVP was only observed in this subset of patients and not in the whole series.
We reported here the first clinical evidence of a direct relation between IGF-1R and MVP expression in OCSCC. The association between both oncoproteins has been previously reported in cervical carcinoma patients
. It seems that both proteins must be overexpressed to confer radioresistance and subsequent poor clinical outcome in cervical cancer. It would be suggested that both MVP and IGF-1R increase proliferation by activation of Src, PTEN, ERK and inhibit apoptosis through the ATM COP1/P53 axis, resulting in tumour resistance to DNA damage agents. It has been reported an association between MVP expression and cell proliferation, as well as other molecules involved in apoptosis
. Thus, resistance to radiotherapy in the clinical setting as a result of MVP
[8, 14] may be causes by the enhanced of proliferation and inhibition of apoptosis, as well as by the regulation of DSB repair by suppressing NHEJ repair through the inhibition of Ku70/80
. The IGF-1R cooperates with MVP in preventing apoptosis by upregulating BCL-2 and, to a lesser extent, downregulating BAX
, and it may also affect NHEJ repair through the AKT/p38MAPK pathways, mainly by modifying Ku expression
. Activation of IGF-1R triggers a cascade of reactions involving signal transduction pathways: Ras, Raf, mitogen-activated protein kinase and phosphoinositol-3-kinase (PI3K)/AKT/BAD (Bcl-xL/Bcl2-associated death promoter). IGF-1R overexpression has been linked to disease progression, increased resistance to radiotherapy, and poor prognosis
[9, 12, 18]. IGF-1R gene seems to be a novel downstream target in an Ataxia Telangiectasia Mutated (ATM)-mediated DNA damage response pathway. The potential role of the IGF-1R gene as a target ing an ATM-dependent pathway, involved in regulating the radiation response, was recently inferred
. Thus, deregulated expression of the IGF-1R gene after ionizing radiation may be linked to genomic instability and enhanced transforming capacity
The expression of MVP has a complex regulation not fully understood, influenced by the expression of other oncoproteins and other important clinical factors as hypoxia. In that sense, high MVP expression is related to severe hypoxia in clinical cervical tumours
. Interestingly, hypoxia inhibits the NHEJ DNA repair through down-regulating Ku70/80 expression, combined with increased angiogenesis and altered p53
, and an inverse association between MVP and KU70/80 exists
. Although the prognosis role of MVP is still contradictory, at a clinical level, vaults have been proposed as a useful predictive marker associated with radiotherapy resistance
, and the interaction between IGF-1R and MVP can help to explain the predictive role of these oncoproteins in response to radiotherapy