Correlation of pSTAT3 overexpression and prognosis in lung cancer patients: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

TONG Mengting , WANG Jing , JIANG Nanyu , PAN Hongming ,  LI Da

Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, P.R.China;

Corresponding author：

LI Da, Email: lidaxhb@aliyun.com

Keywords：

pSTAT3 overexpression; Lung cancer; Prognosis; Correlation; Meta-analysis

DOI：

10.7507/1672-2531.201702019

Video：

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ObjectiveTo systematically review the correlation of pSTAT3 overexpression and prognosis in lung cancer patients.MethodsWe searched from PubMed, EMbase, Web of Science, CNKI, VIP and WanFang Data databases to collect relevant studies about the correlation of pSTAT3 overexpression and prognosis in lung cancer patients from inception to November 2016. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then, meta-analysis was performed by using RevMan 5.2 software.Results A total of thirteen studies were enrolled. The results of the meta-analysis showed that the overall survival (HR=1.23, 95%CI 1.04 to 1.46, P=0.02) of pSTAT3 overexpression group was shorter than that of low expression group. In terms of clinical prognostic characteristics, pSTAT3 overexpression rate in stage Ⅲ to Ⅳ group was significantly higher than stage Ⅰ to Ⅱ (OR=1.92, 95%CI 1.13 to 3.27, P=0.02). pSTAT3 overexpression rate of lung cancer patients with lymphatic node metastasis was also significantly higher than lung cancer patients without lymphatic node metastasis (OR=1.81, 95%CI 1.20 to 2.72, P=0.004). However, there was no statistical difference of pSTAT3 overexpression between well-moderately differentiation and poorly differentiation group (OR=0.82, 95%CI 0.44 to 1.53, P=0.54).ConclusionpSTAT3 overexpression is associated with poorer overall survival of lung cancer patients, as well as with more and advanced TNM grade and lymph node metastasis. It may be an indicator poor biomarker in lung cancer patients. Due to limited quality and quantity of the included studies, more high quality studies are needed to verify above conclusion.

Citation： TONG Mengting, WANG Jing, JIANG Nanyu, PAN Hongming, LI Da. Correlation of pSTAT3 overexpression and prognosis in lung cancer patients: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2017, 17(9): 1021-1028. doi: 10.7507/1672-2531.201702019 Copy

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2.	Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015, 65(2): 87-108.
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4.	Lam WK, White NW, Chan-Yeung MM. Lung cancer epidemiology and risk factors in Asia and Africa. Int J Tuberc Lung Dis, 2004, 8(9): 1045-1057.
5.	Thun MJ, Hannan LM, Adams-Campbell LL, et al. Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies. PLoS Med, 2008, 5(9): e185.
6.	Gao YT, Blot WJ, Zheng W, et al. Lung cancer among Chinese women. Int J Cancer, 1987, 40(5): 604-609.
7.	Chen W, Zheng R, Baade P, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 2(66): 115-132.
8.	Zheng Y, Bueno R. Commercially available prognostic molecular models in early stage lung cancer a review of the pervenio lung rs and myriad myplan lung cancer tests. Expert Rev Mol Diagn, 2015, 15(5): 589-596.
9.	Darnell JJ. Stats and gene regulation. Science, 1997, 277(5332): 1630-1635.
10.	Bowman T, Garcia R, Turkson J, et al. Stats in oncogenesis. Oncogene, 2000, 19(21): 2474-2488.
11.	Bromberg J, Darnell JJ. The role of stats in transcriptional control and their impact on cellular function. Oncogene, 2000, 19(21): 2468-2473.
12.	Novak U, Ji H, Kanagasundaram V, et al. Stat3 forms stable homodimers in the presence of divalent cations prior to activation. Biochem Biophys Res Commun, 1998, 247(3): 558-563.
13.	Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med, 2004, 10(8): 789-799.
14.	Kanda N, Seno H, Konda Y, et al. Stat3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene, 2004, 23(28): 4921-4929.
15.	Haura EB, Zheng Z, Song L, et al. Activated epidermal growth factor receptor-stat-3 signaling promotes tumor survival in vivo in non-small cell lung cancer. Clin Cancer Res, 2005, 11(23): 8288-8294.
16.	Król M, Pawłowski KM, Dolka I, et al. Density of gr1-positive myeloid precursor cells, p-stat3 expression and gene expression pattern in canine mammary cancer metastasis. Vet Res Commun, 2011, 35(7): 409-423.
17.	Duan ZF, Foster R, Bell DA, et al. Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin Cancer Res, 2006, 12(17): 5055-5063.
18.	Yakata Y, Nakayama T, Yoshizaki A, et al. Expression of p-stat3 in human gastric carcinoma: Significant correlation in tumour invasion and prognosis. Int J Oncol, 2007, 30(2): 437-442.
19.	Kusaba T, Nakayama T, Yamazumi K, et al. Activation of stat3 is a marker of poor prognosis in human colorectal cancer. Oncol Rep, 2006, 15(6): 1445-1451.
20.	Wormann SM, Song L, Ai J, et al. Loss of p53 function activates JAK2-STAT3 signaling to promote pancreatic tumor growth, stroma modification, and gemcitabine resistance in mice and is associated with patient survival. Gastroenterology, 2016, 151(1): 180-193..
21.	Xu YH, Lu S. A meta-analysis of STAT3 and phospho-stat3 expression and survival of patients with non-small-cell lung cancer. Eur J Surg Oncol, 2014, 40(3): 311-317.
22.	Zhao X, Sun X, Li XL. Expression and clinical significance of stat3, p-stat3, and VEGF-C in small cell lung cancer. Asian Pac J Cancer Prev, 2012, 13(6): 2873-2877.
23.	Zhang W, Pal SK, Liu X, et al. Myeloid clusters are associated with a pro-metastatic environment and poor prognosis in smoking-related early stage non-small cell lung cancer. PLoS One, 2013, 8(5): e65121.
24.	Jiang R, Wang X, Jin Z, et al. Association of nuclear pim1 expression with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma and squamous cell carcinoma. J Cancer, 2016, 7(3): 324-334.
25.	Stang A. Critical evaluation of the newcastle-ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 2010, 25(9): 603-605.
26.	Yu Y, Zhao Q, Wang Z, et al. Activated stat3 correlates with prognosis of non-small cell lung cancer and indicates new anticancer strategies. Cancer Chemother Pharmacol, 2015, 75(5): 917-922.
27.	Wang M, Chen GY, Song HT, et al. Significance of cxcr4, phosphorylated stat3 and vegf-a expression in resected non-small cell lung cancer. Exp Ther Med, 2011, 2(3): 517-522.
28.	van Cruijsen H, Ruiz MG, van der Valk P, et al. Tissue micro array analysis of ganglioside n-glycolyl gm3 expression and signal transducer and activator of transcription (stat)-3 activation in relation to dendritic cell infiltration and microvessel density in non-small cell lung cancer. BMC Cancer, 2009, 9: 180.
29.	Cortas T, Eisenberg R, Fu P, et al. Activation state egfr and stat-3 as prognostic markers in resected non-small cell lung cancer. Lung Cancer, 2007, 55(3): 349-355.
30.	Zhao M, Gao FH, Wang JY, et al. Jak2/stat3 signaling pathway activation mediates tumor angiogenesis by upregulation of vegf and bfgf in non-small-cell lung cancer. Lung Cancer, 2011, 73(3): 366-374.
31.	Kim HS, Park YH, Lee J, et al. Clinical impact of phosphorylated signal transducer and activator of transcription 3, epidermal growth factor receptor, p53, and vascular endothelial growth factor receptor 1 expression in resected adenocarcinoma of lung by using tissue microarray. Cancer, 2010, 116(3): 676-685.
32.	Achcar RO, Cagle PT, Jagirdar J. Expression of activated and latent signal transducer and activator of transcription 3 in 303 non-small cell lung carcinomas and 44 malignant mesotheliomas: Possible role for chemotherapeutic intervention. Arch Pathol Lab Med, 2007, 131(9): 1350-1360.
33.	王瑞娟, 张建中, 王萍. 磷酸化 STAT3 在非小细胞肺癌组织中的表达及其临床意义. 细胞与分子免疫学杂志, 2012, 28(3): 288-290.
34.	Mukohara T, Kudoh S, Yamauchi S, et al. Expression of epidermal growth factor receptor (egfr) and downstream-activated peptides in surgically excised non-small-cell lung cancer (nsclc). Lung Cancer, 2003, 41(2): 123-130.
35.	Yang Q, Shen SS, Zhou S, et al. Stat3 activation and aberrant ligand-dependent sonic hedgehog signaling in human pulmonary adenocarcinoma. Exp Mol Pathol, 2012, 93(2): 227-236.
36.	Mountain CF. A new international staging system for lung cancer. Chest, 1986, 89(4 Suppl): 225-233.
37.	Koh J, Jang JY, Keam B, et al. Eml4-alk enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (hif)-1alpha and stat3. Oncoimmunology, 2016, 5(3): e1108514.
38.	Wang Y, Li J, Chen H, et al. Down-regulation of mir-133a as a poor prognosticator in non-small cell lung cancer. Gene, 2016, 591(2): 333-337.
39.	Wu P, Wu D, Zhao L, et al. Prognostic role of stat3 in solid tumors: a systematic review and meta-analysis. Oncotarget, 2016, 7(15): 19863-19883.
40.	Li MX, Bi XY, Huang Z, et al. Prognostic role of phospho-stat3 in patients with cancers of the digestive system: a systematic review and meta-analysis. PLoS One, 2015, 10(5): e0127356.
41.	He S, Liao G, Liu Y, et al. Overexpression of stat3/pSTAT3 was associated with poor prognosis in gastric cancer: A meta-analysis. Int J Clin Exp Med, 2015, 8(11): 20014-20023.
42.	Ji K, Zhang M, Chu Q, et al. The role of p-stat3 as a prognostic and clinicopathological marker in colorectal cancer: A systematic review and meta-analysis. PLoS One, 2016, 11(8): e0160125.
43.	Kong H, Zhang Q, Zeng Y, et al. Prognostic significance of stat3/phosphorylated-stat3 in tumor: A meta-analysis of literatures. Int J Clin Exp Med, 2015, 8(6): 8525-8539.
44.	Gollob JA, Schnipper CP, Murphy EA, et al. The functional synergy between il-12 and il-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of stat serine phosphorylation. J Immunol, 1999, 162(8): 4472-4481.
45.	Yue P, Turkson J. Targeting stat3 in cancer: How successful are we?. Expert Opin Investig Drugs, 2009, 18(1): 45-56.
46.	Huang W, Dong Z, Chen Y, et al. Small-molecule inhibitors targeting the DNA-binding domain of stat3 suppress tumor growth, metastasis and stat3 target gene expression in vivo. Oncogene, 2016, 35(6): 783-792.
47.	Shou J, You L, Yao J, et al. Cyclosporine a sensitizes human non-small cell lung cancer cells to gefitinib through inhibition of stat3. Cancer Lett, 2016, 379(1): 124-133.

1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin, 2011, 61(2): 69-90.
2. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015, 65(2): 87-108.
3. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2014, National Cancer Institute. Available at: https://seer.cancer.gov/csr/1975_2014/.
4. Lam WK, White NW, Chan-Yeung MM. Lung cancer epidemiology and risk factors in Asia and Africa. Int J Tuberc Lung Dis, 2004, 8(9): 1045-1057.
5. Thun MJ, Hannan LM, Adams-Campbell LL, et al. Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies. PLoS Med, 2008, 5(9): e185.
6. Gao YT, Blot WJ, Zheng W, et al. Lung cancer among Chinese women. Int J Cancer, 1987, 40(5): 604-609.
7. Chen W, Zheng R, Baade P, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 2(66): 115-132.
8. Zheng Y, Bueno R. Commercially available prognostic molecular models in early stage lung cancer a review of the pervenio lung rs and myriad myplan lung cancer tests. Expert Rev Mol Diagn, 2015, 15(5): 589-596.
9. Darnell JJ. Stats and gene regulation. Science, 1997, 277(5332): 1630-1635.
10. Bowman T, Garcia R, Turkson J, et al. Stats in oncogenesis. Oncogene, 2000, 19(21): 2474-2488.
11. Bromberg J, Darnell JJ. The role of stats in transcriptional control and their impact on cellular function. Oncogene, 2000, 19(21): 2468-2473.
12. Novak U, Ji H, Kanagasundaram V, et al. Stat3 forms stable homodimers in the presence of divalent cations prior to activation. Biochem Biophys Res Commun, 1998, 247(3): 558-563.
13. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med, 2004, 10(8): 789-799.
14. Kanda N, Seno H, Konda Y, et al. Stat3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene, 2004, 23(28): 4921-4929.
15. Haura EB, Zheng Z, Song L, et al. Activated epidermal growth factor receptor-stat-3 signaling promotes tumor survival in vivo in non-small cell lung cancer. Clin Cancer Res, 2005, 11(23): 8288-8294.
16. Król M, Pawłowski KM, Dolka I, et al. Density of gr1-positive myeloid precursor cells, p-stat3 expression and gene expression pattern in canine mammary cancer metastasis. Vet Res Commun, 2011, 35(7): 409-423.
17. Duan ZF, Foster R, Bell DA, et al. Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin Cancer Res, 2006, 12(17): 5055-5063.
18. Yakata Y, Nakayama T, Yoshizaki A, et al. Expression of p-stat3 in human gastric carcinoma: Significant correlation in tumour invasion and prognosis. Int J Oncol, 2007, 30(2): 437-442.
19. Kusaba T, Nakayama T, Yamazumi K, et al. Activation of stat3 is a marker of poor prognosis in human colorectal cancer. Oncol Rep, 2006, 15(6): 1445-1451.
20. Wormann SM, Song L, Ai J, et al. Loss of p53 function activates JAK2-STAT3 signaling to promote pancreatic tumor growth, stroma modification, and gemcitabine resistance in mice and is associated with patient survival. Gastroenterology, 2016, 151(1): 180-193..
21. Xu YH, Lu S. A meta-analysis of STAT3 and phospho-stat3 expression and survival of patients with non-small-cell lung cancer. Eur J Surg Oncol, 2014, 40(3): 311-317.
22. Zhao X, Sun X, Li XL. Expression and clinical significance of stat3, p-stat3, and VEGF-C in small cell lung cancer. Asian Pac J Cancer Prev, 2012, 13(6): 2873-2877.
23. Zhang W, Pal SK, Liu X, et al. Myeloid clusters are associated with a pro-metastatic environment and poor prognosis in smoking-related early stage non-small cell lung cancer. PLoS One, 2013, 8(5): e65121.
24. Jiang R, Wang X, Jin Z, et al. Association of nuclear pim1 expression with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma and squamous cell carcinoma. J Cancer, 2016, 7(3): 324-334.
25. Stang A. Critical evaluation of the newcastle-ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 2010, 25(9): 603-605.
26. Yu Y, Zhao Q, Wang Z, et al. Activated stat3 correlates with prognosis of non-small cell lung cancer and indicates new anticancer strategies. Cancer Chemother Pharmacol, 2015, 75(5): 917-922.
27. Wang M, Chen GY, Song HT, et al. Significance of cxcr4, phosphorylated stat3 and vegf-a expression in resected non-small cell lung cancer. Exp Ther Med, 2011, 2(3): 517-522.
28. van Cruijsen H, Ruiz MG, van der Valk P, et al. Tissue micro array analysis of ganglioside n-glycolyl gm3 expression and signal transducer and activator of transcription (stat)-3 activation in relation to dendritic cell infiltration and microvessel density in non-small cell lung cancer. BMC Cancer, 2009, 9: 180.
29. Cortas T, Eisenberg R, Fu P, et al. Activation state egfr and stat-3 as prognostic markers in resected non-small cell lung cancer. Lung Cancer, 2007, 55(3): 349-355.
30. Zhao M, Gao FH, Wang JY, et al. Jak2/stat3 signaling pathway activation mediates tumor angiogenesis by upregulation of vegf and bfgf in non-small-cell lung cancer. Lung Cancer, 2011, 73(3): 366-374.
31. Kim HS, Park YH, Lee J, et al. Clinical impact of phosphorylated signal transducer and activator of transcription 3, epidermal growth factor receptor, p53, and vascular endothelial growth factor receptor 1 expression in resected adenocarcinoma of lung by using tissue microarray. Cancer, 2010, 116(3): 676-685.
32. Achcar RO, Cagle PT, Jagirdar J. Expression of activated and latent signal transducer and activator of transcription 3 in 303 non-small cell lung carcinomas and 44 malignant mesotheliomas: Possible role for chemotherapeutic intervention. Arch Pathol Lab Med, 2007, 131(9): 1350-1360.
33. 王瑞娟, 张建中, 王萍. 磷酸化 STAT3 在非小细胞肺癌组织中的表达及其临床意义. 细胞与分子免疫学杂志, 2012, 28(3): 288-290.
34. Mukohara T, Kudoh S, Yamauchi S, et al. Expression of epidermal growth factor receptor (egfr) and downstream-activated peptides in surgically excised non-small-cell lung cancer (nsclc). Lung Cancer, 2003, 41(2): 123-130.
35. Yang Q, Shen SS, Zhou S, et al. Stat3 activation and aberrant ligand-dependent sonic hedgehog signaling in human pulmonary adenocarcinoma. Exp Mol Pathol, 2012, 93(2): 227-236.
36. Mountain CF. A new international staging system for lung cancer. Chest, 1986, 89(4 Suppl): 225-233.
37. Koh J, Jang JY, Keam B, et al. Eml4-alk enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (hif)-1alpha and stat3. Oncoimmunology, 2016, 5(3): e1108514.
38. Wang Y, Li J, Chen H, et al. Down-regulation of mir-133a as a poor prognosticator in non-small cell lung cancer. Gene, 2016, 591(2): 333-337.
39. Wu P, Wu D, Zhao L, et al. Prognostic role of stat3 in solid tumors: a systematic review and meta-analysis. Oncotarget, 2016, 7(15): 19863-19883.
40. Li MX, Bi XY, Huang Z, et al. Prognostic role of phospho-stat3 in patients with cancers of the digestive system: a systematic review and meta-analysis. PLoS One, 2015, 10(5): e0127356.
41. He S, Liao G, Liu Y, et al. Overexpression of stat3/pSTAT3 was associated with poor prognosis in gastric cancer: A meta-analysis. Int J Clin Exp Med, 2015, 8(11): 20014-20023.
42. Ji K, Zhang M, Chu Q, et al. The role of p-stat3 as a prognostic and clinicopathological marker in colorectal cancer: A systematic review and meta-analysis. PLoS One, 2016, 11(8): e0160125.
43. Kong H, Zhang Q, Zeng Y, et al. Prognostic significance of stat3/phosphorylated-stat3 in tumor: A meta-analysis of literatures. Int J Clin Exp Med, 2015, 8(6): 8525-8539.
44. Gollob JA, Schnipper CP, Murphy EA, et al. The functional synergy between il-12 and il-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of stat serine phosphorylation. J Immunol, 1999, 162(8): 4472-4481.
45. Yue P, Turkson J. Targeting stat3 in cancer: How successful are we?. Expert Opin Investig Drugs, 2009, 18(1): 45-56.
46. Huang W, Dong Z, Chen Y, et al. Small-molecule inhibitors targeting the DNA-binding domain of stat3 suppress tumor growth, metastasis and stat3 target gene expression in vivo. Oncogene, 2016, 35(6): 783-792.
47. Shou J, You L, Yao J, et al. Cyclosporine a sensitizes human non-small cell lung cancer cells to gefitinib through inhibition of stat3. Cancer Lett, 2016, 379(1): 124-133.

Chinese Journal of Evidence-Based Medicine

Correlation of pSTAT3 overexpression and prognosis in lung cancer patients: a meta-analysis

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