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Open Access 01-12-2017 | Research article

Overexpression of p53R2 is associated with poor prognosis in lung sarcomatoid carcinoma

Authors: Jiewei Chen, Yongbo Xiao, Xiaoyan Cai, Jun Liu, Keming Chen, Xinke Zhang

Published in: BMC Cancer | Issue 1/2017

Abstract

Background

This study aimmed to evaluate the expression of p53-inducible RR small subunit 2 homologue (p53R2) in Lung sarcomatoid carcinoma (LSC) and its association with clinicopathological parameters and prognosis.

Methods

In this study, clinicopathological factors and prognostic significance of the expression of p53R2 was investigated by immunohistochemistry (IHC) in 100 cases of LSC.

Results

The results showed that the expression of p53R2 was significantly correlated with clinical stage (P<0.05). But there was no statistically correlation with gender, age, smoking, tumor size, pT stage, pN stage, pM stage, therapy and relapse. Kaplan-Meier analysis revealed that the expression of p53R2, clinical stage, pT stage, pN stage, pM stage and tumor size were closely related to patients’ survival, and the analysis also revealed that patients with low expression of p53R2 had a longer overall survival than that with high expression (Mean overall survival: 84.8 months vs. 34.7 months, P<0.05). Further multivariate analysis indicated that the expression of p53R2 was identified as an independent prognostic factor in the prediction of the overall survival for patients with LSC (HR = 3.217, P<0.05).

Conclusions

The expression of p53R2 was inversely associated with the proliferation and progression of LSC, and the results indicated that the high expression of p53R2 was an independent factor for unfavorable prognosis of patients with LSC.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.CrossRefPubMed

Yendamuri S, Caty L, Pine M, Adem S, Bogner P, Miller A, Demmy TL, Groman A, Reid M. Outcomes of sarcomatoid carcinoma of the lung: a surveillance, epidemiology, and end results database analysis. Surgery. 2012;152(3):397–402.CrossRefPubMed

Park JS, Lee Y, Han J, Kim HK, Choi YS, Kim J, Shim YM, Kim K. Clinicopathologic outcomes of curative resection for sarcomatoid carcinoma of the lung. Oncology. 2011;81(3–4):206–13.CrossRefPubMed

Chaft JE, Sima CS, Ginsberg MS, Huang J, Kris MG, Travis WD, Azzoli CG. Clinical outcomes with perioperative chemotherapy in sarcomatoid carcinomas of the lung. J Thorac Oncol. 2012;7(9):1400–5.CrossRefPubMedPubMedCentral

Jiang X, Liu Y, Chen C, Zhan Z, Yan Q, Guo Y, Wang Q, Li K. The value of biomarkers in patients with sarcomatoid carcinoma of the lung: molecular analysis of 33 cases. Clin Lung Cancer. 2012;13(4):288–96.CrossRefPubMed

Thomas VT, Hinson S, Konduri K. Epithelial-mesenchymal transition in pulmonary carcinosarcoma: case report and literature review. Ther Adv Med Oncol. 2012;4(1):31–7.CrossRefPubMedPubMedCentral

Pelosi G, Sonzogni A, De Pas T, Galetta D, Veronesi G, Spaggiari L, Manzotti M, Fumagalli C, Bresaola E, Nappi O, et al. Review article: pulmonary sarcomatoid carcinomas: a practical overview. Int J Surg Pathol. 2010;18(2):103–20.CrossRefPubMed

Kashlan OB, Cooperman BS. Comprehensive model for allosteric regulation of mammalian ribonucleotide reductase: refinements and consequences. Biochemistry. 2003;42(6):1696–706.CrossRefPubMed

Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda S, Matsui K, Takei Y, Nakamura Y. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature. 2000;404(6773):42–9.CrossRefPubMed

10.

Xue L, Zhou B, Liu X, Heung Y, Chau J, Chu E, Li S, Jiang C, Un F, Yen Y. Ribonucleotide reductase small subunit p53R2 facilitates p21 induction of G1 arrest under UV irradiation. Cancer Res. 2007;67(1):16–21.CrossRefPubMed

11.

Qiu W, Zhou B, Darwish D, Shao J, Yen Y. Characterization of enzymatic properties of human ribonucleotide reductase holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits. Biochem Biophys Res Commun. 2006;340(2):428–34.CrossRefPubMed

12.

Kunos CA, Chiu SM, Pink J, Kinsella TJ. Modulating radiation resistance by inhibiting ribonucleotide reductase in cancers with virally or mutationally silenced p53 protein. Radiat Res. 2009;172(6):666–76.CrossRefPubMedPubMedCentral

13.

Zhang K, Wu J, Wu X, Wang X, Wang Y, Zhou N, Kuo ML, Liu X, Zhou B, Chang L, et al. p53R2 inhibits the proliferation of human cancer cells in association with cell-cycle arrest. Mol Cancer Ther. 2011;10(2):269–78.CrossRefPubMedPubMedCentral

14.

Liu X, Lai L, Wang X, Xue L, Leora S, Wu J, Hu S, Zhang K, Kuo ML, Zhou L, et al. Ribonucleotide reductase small subunit M2B prognoses better survival in colorectal cancer. Cancer Res. 2011;71(9):3202–13.CrossRefPubMedPubMedCentral

15.

Okumura H, Natsugoe S, Yokomakura N, Kita Y, Matsumoto M, Uchikado Y, Setoyama T, Owaki T, Ishigami S, Aikou T. Expression of p53R2 is related to prognosis in patients with esophageal squamous cell carcinoma. Clin Cancer Res. 2006;12(12):3740–5.CrossRefPubMed

16.

Greiner M, Pfeiffer D, Smith RD. Principles and practical application of the receiver-operating characteristic analysis for diagnostic tests. Preventive veterinary medicine. 2000;45(1–2):23–41.CrossRefPubMed

17.

Cho EC, Yen Y. Novel regulators and molecular mechanisms of p53R2 and its disease relevance. Biochimie. 2016;123:81–4.CrossRefPubMed

18.

Wang X, Zhenchuk A, Wiman KG, Albertioni F. Regulation of p53R2 and its role as potential target for cancer therapy. Cancer Lett. 2009;276(1):1–7.CrossRefPubMed

19.

Liu X, Zhou B, Xue L, Shih J, Tye K, Qi C, Yen Y. The ribonucleotide reductase subunit M2B subcellular localization and functional importance for DNA replication in physiological growth of KB cells. Biochem Pharmacol. 2005;70(9):1288–97.CrossRefPubMed

20.

Guittet O, Hakansson P, Voevodskaya N, Fridd S, Graslund A, Arakawa H, Nakamura Y, Thelander L. Mammalian p53R2 protein forms an active ribonucleotide reductase in vitro with the R1 protein, which is expressed both in resting cells in response to DNA damage and in proliferating cells. J Biol Chem. 2001;276(44):40647–51.CrossRefPubMed

21.

Xue L, Zhou B, Liu X, Qiu W, Jin Z, Yen Y. Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits. Cancer Res. 2003;63(5):980–6.PubMed

22.

Hsu NY, JY W, Liu X, Yen Y, Chen CY, Chou MC, Lee H, Cheng YW. p53R2 expression as a prognostic biomarker in early stage non-small cell lung cancer. Oncol Lett. 2010;1(4):609–13.PubMedPubMedCentral

23.

Yanamoto S, Kawasaki G, Yoshitomi I, Mizuno A. Expression of p53R2, newly p53 target in oral normal epithelium, epithelial dysplasia and squamous cell carcinoma. Cancer Lett. 2003;190(2):233–43.CrossRefPubMed

24.

Matsushita S, Ikeda R, Fukushige T, Tajitsu Y, Gunshin K, Okumura H, Ushiyama M, Akiyama S, Kawai K, Takeda Y, et al. p53R2 is a prognostic factor of melanoma and regulates proliferation and chemosensitivity of melanoma cells. J Dermatol Sci. 2012;68(1):19–24.CrossRefPubMed

25.

Yanamoto S, Kawasaki G, Yamada S, Yoshitomi I, Yoshida H, Mizuno A. Ribonucleotide reductase small subunit p53R2 promotes oral cancer invasion via the E-cadherin/beta-catenin pathway. Oral Oncol. 2009;45(6):521–5.CrossRefPubMed

26.

Link PA, Baer MR, James SR, Jones DA, Karpf AR. p53-inducible ribonucleotide reductase (p53R2/RRM2B) is a DNA hypomethylation-independent decitabine gene target that correlates with clinical response in myelodysplastic syndrome/acute myelogenous leukemia. Cancer Res. 2008;68(22):9358–66.CrossRefPubMedPubMedCentral

27.

Xu X, Page JL, Surtees JA, Liu H, Lagedrost S, Lu Y, Bronson R, Alani E, Nikitin AY, Weiss RS. Broad overexpression of ribonucleotide reductase genes in mice specifically induces lung neoplasms. Cancer Res. 2008;68(8):2652–60.CrossRefPubMedPubMedCentral

28.

Abid MR, Li Y, Anthony C, De Benedetti A. Translational regulation of ribonucleotide reductase by eukaryotic initiation factor 4E links protein synthesis to the control of DNA replication. J Biol Chem. 1999;274(50):35991–8.CrossRefPubMed

29.

Yamaguchi T, Matsuda K, Sagiya Y, Iwadate M, Fujino MA, Nakamura Y, Arakawa H. p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle checkpoint. Cancer Res. 2001;61(22):8256–62.PubMed

30.

Lewis RC, Bostick RM, Xie D, Deng Z, Wargovich MJ, Fina MF, Roufail WM, Geisinger KR. Polymorphism of the cyclin D1 gene, CCND1, and risk for incident sporadic colorectal adenomas. Cancer Res. 2003;63(23):8549–53.PubMed

31.

Deng ZL, Xie DW, Bostick RM, Miao XJ, Gong YL, Zhang JH, Wargovich MJ. Novel genetic variations of the p53R2 gene in patients with colorectal adenoma and controls. World J Gastroenterol. 2005;11(33):5169–73.PubMedPubMedCentral

32.

Yousefi B, Rahmati M, Ahmadi Y. The roles of p53R2 in cancer progression based on the new function of mutant p53 and cytoplasmic p21. Life Sci. 2014;99(1–2):14–7.CrossRefPubMed

33.

Yokomakura N, Natsugoe S, Okumura H, Ikeda R, Uchikado Y, Mataki Y, Takatori H, Matsumoto M, Owaki T, Ishigami S, et al. Improvement in radiosensitivity using small interfering RNA targeting p53R2 in esophageal squamous cell carcinoma. Oncol Rep. 2007;18(3):561–7.PubMed

34.

Yanamoto S, Iwamoto T, Kawasaki G, Yoshitomi I, Baba N, Mizuno A. Silencing of the p53R2 gene by RNA interference inhibits growth and enhances 5-fluorouracil sensitivity of oral cancer cells. Cancer Lett. 2005;223(1):67–76.CrossRefPubMed

35.

Guittet O, Tebbi A, Cottet MH, Vesin F, Lepoivre M. Upregulation of the p53R2 ribonucleotide reductase subunit by nitric oxide. Nitric oxide. Biology and Chemistry. 2008;19(2):84–94.

Title: Overexpression of p53R2 is associated with poor prognosis in lung sarcomatoid carcinoma
Authors: Jiewei Chen
Yongbo Xiao
Xiaoyan Cai
Jun Liu
Keming Chen
Xinke Zhang
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-017-3811-6

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Abstract

Background

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