A Systematic Review of Phospho-p70 Ribosomal Protein S6 Kinase Expression and Its Clinical Signi cance in Lung Cancer_West China Medical Journal

Authors：

 SUNRong-fei ¹ , PANLin ¹ , ZHANGLi ² , PUDan ¹ ,  LIWei-min ¹

1. Department of Respiratory;West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Pathology;West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LIWei-min, Email: weimin003@163.com

Keywords：

Phospho-p70 ribosomal protein S6 kinase; Lung cancer; Lymph node metastasis; Cell differentiation; Systematic review

DOI：

10.7507/1002-0179.20140374

Video：

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Objective To systematically evaluate the expression and clinical features of phospho-p70 ribosomal protein S6 kinase (p-p70S6K) in lung cancer. Methods We systematically searched the published researches about p-p70S6K expression and clinical features of lung cancer in Medline, EMbase, Chinese BioMedical Literature, China National Knowledge Infrastructure and WeiPu databases from their establishment to February 4th, 2014. According to the inclusion and exclusion criteria, the data were extracted and the Cochrane Review Manager 5 and Stata 12.0 were used for data analysis. Results Eight studies including 953 patients were included in this systematic review. Analysis with random effects model showed that the positive expression rate of p-p70S6K in non-small cell lung cancer (NSCLC) tissues spread from 41% to 70%. In small cell lung cancer tissues, the positive expression rate of p-p70S6K ranged from 17% to 91%. The positive expression rate of p-p70S6K in NSCLC was significantly higher than adjacent normal tissues[OR=5.08, 95%CI (2.96, 8.71), P<0.00001]. Divided by status of cell differentiation, the positive expression rate of p-p70S6K between low differentiation and moderate-high differentiation groups had no statistically significant difference[OR=1.40, 95%CI (0.50, 3.92), P=0.53]. In addition, the positive expression rate of p-p70S6K was not related to lymph node metastasis[OR=1.11, 95%CI (0.56, 2.23), P=0.76]. Conclusion Compared with adjacent normal tissues, positive expression rate of p-p70S6K in NSCLC is significantly higher, indicating that p-p70S6K may be associated with the development of lung cancer. The positive expression rate of p-p70S6K in different kinds of lung cancer is still unclear, which needs further studies to explore.

Citation： SUNRong-fei, PANLin, ZHANGLi, PUDan, LIWei-min. A Systematic Review of Phospho-p70 Ribosomal Protein S6 Kinase Expression and Its Clinical Signi cance in Lung Cancer. West China Medical Journal, 2014, 29(7): 1213-1219. doi: 10.7507/1002-0179.20140374 Copy

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3.	D'Addario G, Felip E, ESMO Guidelines Working Group. Nonsmall-cell lung cancer:ESMO clinical recommendations for diagnosis, treatment and follow up[J]. Ann Oncology, 2008, 19(Suppl 2):ii39-ii40.
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17.	Du W, Gerald D, Perruzzi CA, et al. Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin[J]. Lab Invest, 2013, 93(10):1115-1127.
18.	Sahin F, Kannangai R, Adegbola O, et al. mTOR and P70 S6 kinase expression in primary liver neoplasms[J]. Clin Cancer Res, 2004, 10(24):8421-8425.
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20.	侯桂琴, 刘明月, 薛乐勋, 等. 雷帕霉素对食管鳞癌细胞系EC9706的mTOR/p70S6K信号通路的影响[J]. 肿瘤, 2007, 27(3):172-175.
21.	庄桂山, 张哲, 孔垂泽, 等. P70s6k和4EBP1在膀胱癌中的表达及临床意义[J]. 现代肿瘤医学, 2012, 20(12):2563-2565.
22.	Ip CK, Wong AS. Exploiting p70 S6 kinase as a target for ovarian cancer[J]. Expert Opin Ther Targets, 2012, 16(6):619-630.
23.	Baba HA, Wohlschlaeger J, Cicinnati VR, et al. Phosphorylation of p70S6 kinase predicts overall survival in patients with clear marginresected hepatocellular carcinoma[J]. Liver Int, 2009, 29(3):399-405.
24.	Bian CX, Shi Z, Meng Q, et al. P70S6K 1 regulation of angiogenesis through VEGF and HIF-1alpha expression[J]. Biochem Biophys Res Commun, 2010, 398(3):395-399.
25.	Kim EK, Kim JH, Kim HA, et al. Phosphorylated S6 kinase-1:a breast cancer marker predicting resistance to neoadjuvant chemotherapy[J]. Anticancer Res, 2013, 33(9):4073-4079.
26.	Dhar R, Persaud SD, Mireles JR, et al. Proteolytic cleavage of p70 ribosomal S6 kinase by caspase-3 during DNA damage-induced apoptosis[J]. Biochemistry, 2009, 48(7):1474-1480.
27.	Pearce LR, Alton GR, Richter DT, et al. Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1)[J]. Biochem J, 2010, 431(2):245-255.
28.	Bussenius J, Anand NK, Blazey CM, et al. Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors[J]. Bioorg Med Chem Lett, 2012, 22(6):2283-2286.

1. Bray F, Ren JS, Masuyer E, et al. Estimates of global cancer prevalence for 27 sites in the adult population in 2008[J]. Int J Cancer, 2013, 132(5):1133-1145.
2. Nana-Sinkam SP, Powell CA. Molecular biology of lung cancer, diagnosis and management of lung cancer, 3rd ed:American College of Chest Physicians evidence-based clinical practice guidelines[J]. Chest, 2013, 143(Suppl 5):e30S-e39S.
3. D'Addario G, Felip E, ESMO Guidelines Working Group. Nonsmall-cell lung cancer:ESMO clinical recommendations for diagnosis, treatment and follow up[J]. Ann Oncology, 2008, 19(Suppl 2):ii39-ii40.
4. Sørensen M, Pijls-Johannesma M, Felip E, et al. Small-cell lung cancer:ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2010, 21(Suppl 5):v120-v125.
5. Fenton TR, Gout IT. Functions and regulation of the 70kDa ribosomal S6 kinases[J]. Int J Biochem Cell Biol, 2011, 43(1):47-59.
6. Wullschleger S, Loewith R, Hall MN. mTOR signaling in growth and metabolism[J]. Cell, 2006, 124(3):471-484.
7. Wells GA, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in metaanalyses[EB/OL]. (2012-06-15)[2014-02-01]. http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm.
8. 庄莹, 曾波航. P-S6K1在肺癌的表达及其意义[J]. 广东医学, 2009, 30(4):517-519.
9. Dobashi Y, Suzuki S, Kimura M, et al. Paradigm of kinase-driven pa thway downstream of epidermal growth factor receptor/Akt in human lung carcinomas[J]. Hum Pathol, 2011, 42(2):214-226.
10. Dobashi Y, Suzuki S, Matsubara H, et al. Critical and diverse involvement of Akt/mammalian target of rapamycin signaling in human lung carcinomas[J]. Cancer, 2009, 115(1):107-118.
11. Kaira K, Ohde Y, Endo M, et al. Expression of 4F_2hc (CD98) in pulmonary neuroendocrine tumors[J]. Oncology, 2011, 26(4):931-937.
12. Kaira K, Oriuchi N, Takahashi T, et al. LAT1 expression is closely associated with hypoxic markers and mTOR in resected non-small cell lung cancer[J]. Am J Transl Res, 2011, 3(5):468-478.
13. Liu D, Huang Y, Chen B, et al. Activation of mammalian target of rapamycin pathway confers adverse outcome in nonsmall cell lung carcinoma[J]. Cancer, 2011, 117(16):3763-3773.
14. Schmid K, Bago-Horvath Z, Berger W, et al. Dual inhibition of EGFR and mTOR pathways in small cell lung cancer[J]. Br J Cancer, 2010, 103(5):622-628.
15. Zhang Y, Ni HJ, Cheng DY. Prognostic value of phosphorylated mTOR/RPS6KB1 in non-small cell lung cancer[J]. Asian Pac J Cancer Prev, 2013, 14(6):3725-3728.
16. Filonenko VV, Tytarenko R, Azatjan SK, et al. Immunohistochemical analysis of S6K1 and S6K2 localization in human breast tumors[J]. Exp Oncol, 2004, 26(4):294-299.
17. Du W, Gerald D, Perruzzi CA, et al. Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin[J]. Lab Invest, 2013, 93(10):1115-1127.
18. Sahin F, Kannangai R, Adegbola O, et al. mTOR and P70 S6 kinase expression in primary liver neoplasms[J]. Clin Cancer Res, 2004, 10(24):8421-8425.
19. Li PD, Zhang WJ, Zhang MY, et al. Overexpression of RPS6KB1 predicts worse prognosis in primary HCC patients[J]. Med Oncol, 2012, 29(5):3070-3076.
20. 侯桂琴, 刘明月, 薛乐勋, 等. 雷帕霉素对食管鳞癌细胞系EC9706的mTOR/p70S6K信号通路的影响[J]. 肿瘤, 2007, 27(3):172-175.
21. 庄桂山, 张哲, 孔垂泽, 等. P70s6k和4EBP1在膀胱癌中的表达及临床意义[J]. 现代肿瘤医学, 2012, 20(12):2563-2565.
22. Ip CK, Wong AS. Exploiting p70 S6 kinase as a target for ovarian cancer[J]. Expert Opin Ther Targets, 2012, 16(6):619-630.
23. Baba HA, Wohlschlaeger J, Cicinnati VR, et al. Phosphorylation of p70S6 kinase predicts overall survival in patients with clear marginresected hepatocellular carcinoma[J]. Liver Int, 2009, 29(3):399-405.
24. Bian CX, Shi Z, Meng Q, et al. P70S6K 1 regulation of angiogenesis through VEGF and HIF-1alpha expression[J]. Biochem Biophys Res Commun, 2010, 398(3):395-399.
25. Kim EK, Kim JH, Kim HA, et al. Phosphorylated S6 kinase-1:a breast cancer marker predicting resistance to neoadjuvant chemotherapy[J]. Anticancer Res, 2013, 33(9):4073-4079.
26. Dhar R, Persaud SD, Mireles JR, et al. Proteolytic cleavage of p70 ribosomal S6 kinase by caspase-3 during DNA damage-induced apoptosis[J]. Biochemistry, 2009, 48(7):1474-1480.
27. Pearce LR, Alton GR, Richter DT, et al. Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1)[J]. Biochem J, 2010, 431(2):245-255.
28. Bussenius J, Anand NK, Blazey CM, et al. Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors[J]. Bioorg Med Chem Lett, 2012, 22(6):2283-2286.

West China Medical Journal

A Systematic Review of Phospho-p70 Ribosomal Protein S6 Kinase Expression and Its Clinical Signi cance in Lung Cancer

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