Cyclin D1 overexpression associates with radiosensitivity in oral squamous cell carcinoma

Shintani, Satoru; Mihara, Mariko; Ueyama, Yoshiya; Matsumura, Tomohiro; Wong, David T.

doi:10.1002/ijc.1014

Cited by 35 publications

(25 citation statements)

References 15 publications

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“…There are conflicting studies on how cyclin D1 expression affects response to ionizing radiation in HNSCCs. Whereas some groups reported a negative correlation between high cyclin D1 expression and radiosensitivity (30), other groups observed that high cyclin D1 expression is associated with increased radiosensitivity in oral squamous cell cancer and early-stage of laryngeal cancer (45,46). It is possible that the contradictory observations in these reports are due to the lack of p16INK4a and HPV detection.…”

Section: Discussionmentioning

confidence: 94%

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

et al. 2014

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The p16INK4a protein is a principal cyclin-dependent kinase inhibitor that decelerates the cell cycle. Abnormally high levels of p16INK4a are commonly observed in human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCC). We and others found that p16INK4a overexpression is associated with improved therapy response and survival of patients with HNSCC treated with radiotherapy. However, the functional role of p16INK4a in HNSCC remains unexplored. Our results implicate p16INK4a in regulation of homologous recombination-mediated DNA damage response independently from its role in control of the cell cycle. We found that expression of p16INK4a dramatically affects radiation sensitivity of HNSCC cells. p16INK4a overexpression impairs the recruitment of RAD51 to the site of DNA damage in HPV-positive cells by downregulating of cyclin D1 protein expression. Consistent with the in vitro findings, immunostaining of HNSCC patient samples revealed that high levels p16INK4a expression significantly correlated with decreased cyclin D1 expression. In summary, these findings reveal an unexpected function of p16INK4a in homologous recombination-mediated DNA repair response and imply p16INK4a status as an independent marker to predict response of patients with HNSCC to radiotherapy. Cancer Res; 74(6);

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Section: Discussionmentioning

confidence: 94%

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

et al. 2014

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“…31,32 In oral cancer, very few reports associate cyclin D1 with radiotherapy. 33 The results of the above referred study showed that the expression of cyclin D1 correlated with radiosensitivity of the tumors. 33 One of the reasons for this observation is that they dichotomized the samples with 10% of positive cells as cut-off point and they have correlated cyclin D1 expression with the pathologic response.…”

Section: Adenoviral P16mentioning

confidence: 93%

p53, p16 and cyclin D1: Molecular determinants of radiotherapy treatment response in oral carcinoma

Jayasurya

Francis

Kannan

et al. 2004

Intl Journal of Cancer

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Management of oral cancer by radiotherapy has witnessed promising advances in the past few years, with patient-tailored radio fractionation regimens. Different fractionation schedules, conventional and altered regimes, have been used in curative radiotherapy. Although contribution of biological markers on radio response has been evaluated, its unique influence on various radio fractionation schemes has not been accounted so far. Our study analyses a set of proteins that previously demonstrated radio response influence for their possible prognostic value in decision-making process between the respective fractionation schemes. Expression patterns of regulatory proteins such as p53, cyclin D1, p16, Cdk4, p21, Rb, bcl-2 and PCNA were determined by immunohistochemistry utilizing monoclonal antibodies in 125 patients who received curative radiotherapy dose. Among these 125 patients, 90 (72%) received altered fractionation, whereas 35 (28%) received conventional fractionation. p53 over-expression correlated with local treatment failure among the patients treated with conventional fractionation whereas cyclin D1 over-expression and p16 underexpression were associated with local treatment failure as well as overall survival in altered fractionation treated cases. Our findings suggest that wild-type p53 status may be an important parameter for achieving high local control in those patients undergoing conventional fractionation, where as intact p16 and cyclin D1 status may be beneficial for effective local control in patients who are treated with altered fractionation. Furthermore, it can be assumed that conventional fractionation employs p53-mediated apoptosis, whereas altered fractionation activates the functional G1 cell-cycle checkpoint for tumor growth suppression.

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“…In contrast, cyclin D1 overexpression enhances sensitivity to ionizing radiation in vitro, although this interaction has received scant attention in clinical strategies to treat tumors overexpressing cyclin D1 (17). Clinically, low levels of cyclin D1 have indeed been shown to correlate with radiation treatment failures (18,19). This effect has been attributed to cyclin D1's release of p21 CIP1 from interactions with Cdk4 after cyclin D1 binding, leading to consequent inhibition of Cdk2 (17,20).…”

Section: Introductionmentioning

confidence: 99%

Heat Shock Protein B8, a Cyclin-Dependent Kinase–Independent Cyclin D1 Target Gene, Contributes to Its Effects on Radiation Sensitivity

Trent

Yang

et al. 2007

Cancer Research

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Overexpression of cyclin D1 is associated with many cancers, and its overexpression is especially associated with a poor prognosis in breast cancer. Paradoxically, cyclin D1 is known to enhance radiation sensitivity, a finding that has not yet been therapeutically exploited. Proposed cyclin D1 functions that could be involved in this effect include cyclin-dependent kinase (CDK)-dependent phosphorylation of retinoblastoma gene product (pRb), titration of p21/p27 complexes, and less well-characterized effects on gene expression. In this report, we sought to clarify the functions of cyclin D1 that might contribute to enhanced radiation sensitivity. Breast cancer cells stably overexpressing a cyclin D1 mutant (KE) that cannot interact with its CDK partners to phosphorylate pRb were as radiation sensitive as those expressing wild-type D1. Although cyclin D1 has been proposed to affect radiation sensitivity through interactions with p21, a cyclin D1 mutant defective for p21 interactions also increased radiation sensitivity. Cyclin D1 overexpression is generally confined to hormone receptor-positive breast cancers, wherein standard therapies include both radiation and hormonal therapies. Among several proposed CDK-independent cyclin D1 targets, we have identified heat shock protein B8 (HSPB8) as a target particularly associated with cyclin D1 and ER-positive tumors. We therefore evaluated its potential contribution to radiation sensitivity. Overexpression of HSPB8 markedly increased radiation sensitivity, and HSPB8 small interfering RNA blocked cyclin D1's enhancement of radiation sensitivity. Taken together, our results show that some of cyclin D1's effects on radiation sensitivity are CDK and p21 independent and identify HSPB8 as a candidate CDK-independent cyclin D1 target that can mediate its effects. [Cancer Res 2007;67(22): 10774-81]

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Cyclin D1 overexpression associates with radiosensitivity in oral squamous cell carcinoma

Cited by 35 publications

References 15 publications

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

p53, p16 and cyclin D1: Molecular determinants of radiotherapy treatment response in oral carcinoma

Heat Shock Protein B8, a Cyclin-Dependent Kinase–Independent Cyclin D1 Target Gene, Contributes to Its Effects on Radiation Sensitivity

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