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Tumor cell apoptosis mediated by cytoplasmic ING1 is associated with improved survival in oral squamous cell carcinoma patients.

ABSTRACT: The ING1 epigenetic regulator and tumor suppressor plays a central role in apoptosis. The Ing1 gene is functionally inactivated in many cancer types but is rarely mutated. Although most studies have implicated the major ING1 isoform, p33ING1b, in nuclear apoptotic signalling, we recently discovered a novel and potent apoptosis-inducing effect of p33ING1b translocation to the mitochondria in response to DNA damage. In the present study, we examined the impact of cytoplasmic/mitochondrial localization of p33ING1b in oral squamous cell carcinoma (OSCC) patient samples and explored the therapeutic potential of adenovirally-overexpressed p33ING1b in OSCC cell lines in combination with ionizing radiation (IR) treatment. In contrast with previous reports, we found that p33ING1b protein and mRNA levels are higher in OSCC compared to normal epithelial cells. In OSCC patient samples, higher levels of intra-tumoral cytoplasmic p33ING1b correlated with increased apoptotic markers and significantly better patient survival. This association was strongest in patients who received post-operative radiotherapy. IR treatment induced p33ING1b translocation to the mitochondria and adenoviral-p33ING1b synergized with IR to kill OSCC cells. Our results identify a novel functional relationship between cytoplasmic p33ING1b and patient survival and highlight the potential for the use of p33ING1b as a therapeutic agent in combination with adjuvant radiotherapy in OSCC.

SUBMITTER: Bose P

PROVIDER: S-EPMC4102804 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Tumor cell apoptosis mediated by cytoplasmic ING1 is associated with improved survival in oral squamous cell carcinoma patients.

Bose Pinaki P Thakur Satbir S SS Brockton Nigel T NT Klimowicz Alexander C AC Kornaga Elizabeth E Nakoneshny Steven C SC Riabowol Karl T KT Dort Joseph C JC

Oncotarget 20140501 10

The ING1 epigenetic regulator and tumor suppressor plays a central role in apoptosis. The Ing1 gene is functionally inactivated in many cancer types but is rarely mutated. Although most studies have implicated the major ING1 isoform, p33ING1b, in nuclear apoptotic signalling, we recently discovered a novel and potent apoptosis-inducing effect of p33ING1b translocation to the mitochondria in response to DNA damage. In the present study, we examined the impact of cytoplasmic/mitochondrial localiza ...[more]

PMID: 24912621

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Project description:ImportanceQuality metrics for patients with head and neck cancer are available, but it is unknown whether compliance with these metrics is associated with improved patient survival.ObjectiveTo identify whether compliance with various process-related quality metrics is associated with improved survival in patients with oral cavity squamous cell carcinoma who receive definitive surgery with or without adjuvant therapy.Design, setting, and participantsA retrospective cohort study was conducted at a tertiary academic medical center among 192 patients with previously untreated oral cavity squamous cell carcinoma who underwent definitive surgery with or without adjuvant therapy between January 1, 2003, and December 31, 2010. Data analysis was performed from January 26 to August 7, 2015.InterventionsSurgery with or without adjuvant therapy.Main outcomes and measuresCompliance with a collection of process-related quality metrics possessing face validity that covered pretreatment evaluation, treatment, and posttreatment surveillance was evaluated. Association between compliance with these quality metrics and overall survival, disease-specific survival, and disease-free survival was calculated using univariable and multivariable Cox proportional hazards analysis.ResultsAmong 192 patients, compliance with the individual quality metrics ranged from 19.7% to 93.6% (median, 82.8%). No pretreatment or surveillance metrics were associated with improved survival. Compliance with the following treatment-related quality metrics was associated with improved survival: elective neck dissection with lymph node yield of 18 or more, no unplanned surgery within 14 days of the index surgery, no unplanned 30-day readmissions, and referral for adjuvant radiotherapy for pathologic stage III or IV disease. Increased compliance with a "clinical care signature" composed of these 4 metrics was associated with improved overall survival, disease-specific survival, and disease-free survival on univariable analysis (log-rank test; P < .05 for each). On multivariable analysis controlling for pT stage, pN stage, extracapsular spread, margin status, and comorbidity, increased compliance with these 4 metrics was associated with improved overall survival (100% vs ≤50% compliance: adjusted hazard ratio [aHR], 4.2; 95% CI, 2.1-8.5; 100% vs 51%-99% compliance: aHR, 1.7; 95% CI, 1.0-3.1), improved disease-specific survival (100% vs ≤50% compliance: aHR, 3.9; 95% CI, 1.7-9.0; 100% vs 51%-99%: aHR, 1.3; 95% CI, 0.6-2.9), and improved disease-free survival (100% vs ≤50% compliance: aHR, 3.0; 95% CI, 1.5-5.8; 100% vs 51%-99% compliance: aHR, 1.6; 95% CI, 0.9-2.7).Conclusions and relevanceCompliance with a core set of process-related quality metrics was associated with improved survival for patients with surgically managed oral cavity squamous cell carcinoma. Multi-institutional validation of these metrics is warranted.

Dataset Information

Tumor cell apoptosis mediated by cytoplasmic ING1 is associated with improved survival in oral squamous cell carcinoma patients.

Publications

Tumor cell apoptosis mediated by cytoplasmic ING1 is associated with improved survival in oral squamous cell carcinoma patients.

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