Ribonucleotide Reductase Subunit M2 Predicts Survival in Subgroups of Patients with Non-Small Cell Lung Carcinoma: Effects of Gender and Smoking Status

Mah, Vei; Alavi, Mohammad; Márquez-Garbán, Diana C.; Maresh, Erin L.; Kim, Sara R.; Horvath, Steve; Bagryanova, Lora; Huerta-Yépez, Sara; Pietras, Richard J.; Goodglick, Lee

doi:10.1371/journal.pone.0127600

Cited by 30 publications

(26 citation statements)

References 45 publications

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“…Human RR is composed of three known subunits, RRM1 (large subunit), RRM2 (small subunit) and an encoded P53-controlled ribonucleotide reductase (P53R2) that are differentially regulated during the cell cycle2930. R1 protein concentrations are relatively constant throughout the cell cycle.…”

Section: Resultsmentioning

confidence: 99%

Profiling ribonucleotide and deoxyribonucleotide pools perturbed by gemcitabine in human non-small cell lung cancer cells

Guo

Chen

Lam

et al. 2016

Sci Rep

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In this study, we investigated the dosage effect of gemcitabine, an inhibitor of ribonucleotide reductase (RR), on cellular levels of ribonucleotides and deoxyribonucleotides using high performance liquid chromatography-electrospray ionization tandem mass spectrometric method. As anticipated, after 4-h incubation of non-small cell lung cancer (A549) cells with gemcitabine at 0.5 and 2 μM, there were consistent reductions in levels of deoxyribonucleoside diphosphates (dNDP) and their corresponding deoxyribonucleoside triphosphates (dNTP). However, after 24-h exposure to 0.5 μM gemcitabine, the amounts of dNTP were increased by about 3 fold, whereas cells after 24-h 2 μM gemcitabine treatment exhibited deoxycytidine diphosphate (dCDP), deoxyadenosine diphosphate (dADP) and deoxyguanosine diphosphate (dGDP) levels less than 50% of control values, with deoxycytidine triphosphate (dCTP) and deoxyguanosine triphosphate (dGTP) returning to the control level. Using cell cycle analysis, we found that 24-h incubation at 0.5 μM gemcitabine resulted in a significant increase in S phase arrest, while 2 μM treatment increased G0/G1 population. Our data demonstrated the correlation between the level of RR and the increased levels of dNTPs in the group of 0.5 μM treatment for 24-h with a markedly reduced level of dFdCTP. Accordingly, we proposed that the dosage of dFdC could determine the arrested phase of cell cycle, in turn affecting the recovery of dNTPs pools.

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Section: Resultsmentioning

confidence: 99%

Profiling ribonucleotide and deoxyribonucleotide pools perturbed by gemcitabine in human non-small cell lung cancer cells

Guo

Chen

Lam

et al. 2016

Sci Rep

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“…RRM2 is often overexpressed in many kinds of cancers, such as colorectal cancer, non-small cell lung cancer (NSCLC), breast cancer, bladder cancer, ovarian cancer, pancreatic cancer, head and neck cancer and lung cancer [12][13][14][15][16]. RRM2 also can be considered as a prognostic marker for cancers including NSCLC, cervical cancer, and pancreatic cancer [17][18][19]. Additionally, RRM2 is associated with chemo-resistance during cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

“…1A. It has been demonstrated that high RRM2 expression is an indicator of poor prognosis in many types of cancer [17][18][19][33][34][35]. Here, we analyzed the relationship between RRM2 expression and the survival of GBM patients.…”

Section: Rrm2 Expression Is Enhanced In Human Glioma Tissuesmentioning

confidence: 99%

“…For example, cervical cancer patients with positive RRM2 expression exhibited a higher recurrent rate and lower survival than those with negative RRM2 expression [17]. RRM2 also can be considered as a prognostic marker for NSCLC and pancreatic cancer [18,19]. Besides, it has been reported that RRM2 dysregulation is associated with chemoresistance during cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

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RRM2 is a potential prognostic biomarker with functional significance in glioma

Sun¹,

Yang²,

Zhang³

et al. 2019

Int. J. Biol. Sci.

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Glioma is one of the most common brain tumors, suggesting the importance of investigating the molecular mechanism of gliomas. We studied the roles of Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) in glioma. Expressions of RRM2 are higher in glioma tissues evidenced by TCGA data, western blot and immunohistochemistry. RRM2 is negatively correlated with glioma patient's survival. RNA-seq showed that genes involved in apoptosis, proliferation, cell adhesion and negative regulation of signaling were up-regulated upon RNAi-mediated knock-down of RRM2. Cell phenotypes specific for stably knocking down RRM2 were determined using stable transfection in vitro. In an in vivo model, knock-down of RRM2 inhibited tumor growth and caused suppression of AKT and ERK1/2 signalings. Interfering RRM2 also down-regulated the expression of cyclin A, cyclin B1, cyclin D1, Vimentin, and N-cadherin, and elevated E-cadherin expression. Moreover, overexpression of RRM2 failed to increase the expression of cyclin B1, cyclin D1, and N-cadherin when phosphorylation of AKT and ERK1/2 was suppressed by LY294002 or PD98059. These findings indicated that RRM2 is a positive regulator of glioma progression which contributes to the migration and proliferation of glioma cells through ERK1/2 and AKT signalings and might be a novel prognostic indicator for glioma patients.

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“…Further analyses would be needed to clarify this issue. RRM2 is a ribonucleotide reductase which participates in DNA repair, invasion and proliferation and has been related to poor lung cancer prognosis 46. SLC2A1 is a glucose receptor (also named GLUT1) involved in the uptake of glucose by mammalian cells 47.…”

Section: Discussionmentioning

confidence: 99%

5 protein-based signature for resectable lung squamous cell carcinoma improves the prognostic performance of the TNM staging

Martínez-Terroba

Behrens

Agorreta³

et al. 2018

Thorax

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IntroductionPrognostic biomarkers have been very elusive in the lung squamous cell carcinoma (SCC) and none is currently being used in the clinical setting. We aimed to identify and validate the clinical utility of a protein-based prognostic signature to stratify patients with early lung SCC according to their risk of recurrence or death.MethodsPatients were staged following the new International Association for the Study of Lung Cancer (IASLC) staging criteria (eighth edition, 2018). Three independent retrospective cohorts of 117, 96 and 105 patients with lung SCC were analysed to develop and validate a prognostic signature based on immunohistochemistry for five proteins.ResultsWe identified a five protein-based signature whose prognostic index (PI) was an independent and significant predictor of disease-free survival (DFS) (p<0.001; HR=4.06, 95% CI 2.18 to 7.56) and overall survival (OS) (p=0.004; HR=2.38, 95% CI 1.32 to 4.31). The prognostic capability of PI was confirmed in an external multi-institutional cohort for DFS (p=0.042; HR=2.01, 95% CI 1.03 to 3.94) and for OS (p=0.031; HR=2.29, 95% CI 1.08 to 4.86). Moreover, PI added complementary information to the newly established IASLC TNM 8th edition staging system. A combined prognostic model including both molecular and anatomical (TNM) criteria improved the risk stratification in both cohorts (p<0.05).ConclusionWe have identified and validated a clinically feasible protein-based prognostic model that complements the updated TNM system allowing more accurate risk stratification. This signature may be used as an advantageous tool to improve the clinical management of the patients, allowing the reduction of lung SCC mortality through a more accurate knowledge of the patient’s potential outcome.

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Ribonucleotide Reductase Subunit M2 Predicts Survival in Subgroups of Patients with Non-Small Cell Lung Carcinoma: Effects of Gender and Smoking Status

Cited by 30 publications

References 45 publications

Profiling ribonucleotide and deoxyribonucleotide pools perturbed by gemcitabine in human non-small cell lung cancer cells

Profiling ribonucleotide and deoxyribonucleotide pools perturbed by gemcitabine in human non-small cell lung cancer cells

RRM2 is a potential prognostic biomarker with functional significance in glioma

5 protein-based signature for resectable lung squamous cell carcinoma improves the prognostic performance of the TNM staging

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