STAT3 activation in thymic epithelial tumors: correlation with cyclin D1, JAK3, and clinical behavior.
Cyclin D1
JAK/STAT pathway
JAK3
STAT3
Thymic epithelial tumors
Journal
General thoracic and cardiovascular surgery
ISSN: 1863-6713
Titre abrégé: Gen Thorac Cardiovasc Surg
Pays: Japan
ID NLM: 101303952
Informations de publication
Date de publication:
Nov 2021
Nov 2021
Historique:
received:
16
02
2021
accepted:
19
05
2021
pubmed:
2
6
2021
medline:
9
10
2021
entrez:
1
6
2021
Statut:
ppublish
Résumé
Thymic epithelial tumors are the most common adult mediastinal tumors; however, their growth mechanism remains relatively unknown. Among the JAK/STAT pathway-related proteins, which control various intracellular events, STAT3 is deeply involved in cell proliferation. Constitutive activation of STAT3 and the resulting overexpression of cyclin D1 have been confirmed in various tumors, but have not been thoroughly investigated in thymic epithelial tumors. In this study, we immunohistochemically examined STAT3 activation, cyclin D1 expression, and JAK3 activation in thymic epithelial tumors and statistically analyzed their correlation with clinicopathological features. Formalin-fixed paraffin-embedded specimens of 94 thymic epithelial tumors surgically resected at Kyorin University Hospital between 2005 and 2018 were included in this study. pSTAT3, cyclin D1, and pJAK3 were immunohistochemically examined, and the correlation with histology, Masaoka stage, and survival time was statistically analyzed. Cyclin D1 was found to be significantly overexpressed in the STAT3-activated group. This phenomenon was associated with histology and Masaoka stage. JAK3 was also activated in thymic epithelial tumors; however, JAK3 and STAT3 activation were not always correlated. Using survival time analysis, the STAT3-activated group, cyclin D1-expressed group, and JAK3-activated group had significantly lower progression-free survival times than those for both the non-activated and non-expressed groups. STAT3 activation may promote cyclin D1 overexpression in thymic epithelial tumors, and intracellular signaling pathways other than JAK3 may be involved in STAT3 activation. STAT3 activation, cyclin D1 overexpression, and JAK3 activation are biomarker candidates that indicate clinically poor prognosis.
Identifiants
pubmed: 34061303
doi: 10.1007/s11748-021-01655-9
pii: 10.1007/s11748-021-01655-9
doi:
Substances chimiques
CCND1 protein, human
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Cyclin D1
136601-57-5
JAK3 protein, human
EC 2.7.10.2
Janus Kinase 3
EC 2.7.10.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1482-1491Subventions
Organisme : Japan Society for the Promotion of Science
ID : JP20K07451
Informations de copyright
© 2021. The Japanese Association for Thoracic Surgery.
Références
Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO classification of tumours of lung, pleura, thymus and heart. Lyon: International Agency for Research on Cancer; 2015. p. 183–233.
Okumura M, Fujii Y, Shiono H, Inoue M, Minami M, Utsumi T, et al. Immunological function of thymoma and pathogenesis of paraneoplastic myasthenia gravis. Gen Thorac Cardiovasc Surg. 2008;56:143–50.
doi: 10.1007/s11748-007-0185-8
Khanna P, Chua PJ, Bay BH, Baeg GH. The JAK/STAT signaling cascade in gastric carcinoma (review). Int J Oncol. 2015;47:1617–26.
doi: 10.3892/ijo.2015.3160
Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene. 2002;285:1–24.
doi: 10.1016/S0378-1119(02)00398-0
Bowman T, Garcia R, Turkson J, Jove R. STATs in oncogenesis. Oncogene. 2000;19:2474–88.
doi: 10.1038/sj.onc.1203527
Cornejo MG, Boggon TJ, Mercher T. JAK3: a two-faced player in hematological disorders. Int J Biochem Cell Biol. 2009;41:2376–9.
doi: 10.1016/j.biocel.2009.09.004
Lin Q, Lai R, Chirieac LR, Li C, Thomazy VA, Grammatikakis I, et al. Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. Am J Pathol. 2005;167:969–80.
doi: 10.1016/S0002-9440(10)61187-X
Mali SB. Review of STAT3 (signal transducers and activators of transcription) in head and neck cancer. Oral Oncol. 2015;51:565–9.
doi: 10.1016/j.oraloncology.2015.03.004
Ai T, Wang Z, Zhang M, Zhang L, Wang N, Li W, et al. Expression and prognostic relevance of STAT3 and cyclin D1 in non-small cell lung cancer. Int J Biol Markers. 2012;27:e132–8.
doi: 10.5301/JBM.2012.9146
Masuda M, Suzui M, Yasumatu R, Nakashima T, Kuratomi Y, Azuma K, et al. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res. 2002;62:3351–5.
pubmed: 12067972
Li H, Xiao W, Ma J, Zhang Y, Li R, Ye J, et al. Dual high expression of STAT3 and cyclinD1 is associated with poor prognosis after curative resection of esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2014;7:7989–98.
pubmed: 25550842
pmcid: 4270557
Zhang XM, Zhou C, Gu H, Yan L, Zhang GY. Correlation of RKIP, STAT3 and cyclin D1 expression in pathogenesis of gastric cancer. Int J Clin Exp Pathol. 2014;7:5902–8.
pubmed: 25337233
pmcid: 4203204
Leslie K, Lang C, Devgan G, Azare J, Berishaj M, Gerald W, et al. Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Res. 2006;66:2544–52.
doi: 10.1158/0008-5472.CAN-05-2203
Chang KC, Wu MH, Jones D, Chen FF, Tseng YL. Activation of STAT3 in thymic epithelial tumours correlates with tumour type and clinical behaviour. J Pathol. 2006;210:224–33.
doi: 10.1002/path.2041
Li C, Wang Z, Liu Y, Wang P, Zhang R. STAT3 expression correlates with prognosis of thymic epithelial tumors. Cardiothorac Surg. 2013;8:92.
doi: 10.1186/1749-8090-8-92
Sano S, Takahama Y, Sugawara T, Kosaka H, Itami S, Yoshikawa K, et al. Stat3 in thymic epithelial cells is essential for postnatal maintenance of thymic architecture and thymocyte survival. Immunity. 2001;15:261–73.
doi: 10.1016/S1074-7613(01)00180-7
Satoh R, Kakugawa K, Yasuda T, Yoshida H, Sibilia M, Katsura Y, et al. Requirement of Stat3 signaling in the postnatal development of thymic medullary epithelial cells. PLoS Genet. 2016;12:e1005776.
doi: 10.1371/journal.pgen.1005776
Jin J, Desai BN, Navarro B, Donovan A, Andrews NC, Clapham DE. Deletion of trpm7 disrupts embryonic development and thymopoiesis without altering Mg
doi: 10.1126/science.1163493
Girard N. Thymic tumors: relevant molecular data in the clinic. J Thorac Oncol. 2010;5(10):S291–5 (Suppl 4).
doi: 10.1097/JTO.0b013e3181f209b9
Ruffini E, Detterbeck F, Van Raemdonck D, Rocco G, Thomas P, Weder W, et al. Tumours of the thymus: a cohort study of prognostic factors from the European society of thoracic surgeons database. Eur J Cardiothorac Surg. 2014;46:361–8.
doi: 10.1093/ejcts/ezt649
Ruffini E, Filosso PL, Mossetti C, Bruna MC, Novero D, Lista P, et al. Thymoma: inter-relationships among World Health Organization histology, Masaoka staging and myasthenia gravis and their independent prognostic significance: a single-centre experience. Eur J Cardiothorac Surg. 2011;40:146–53.
doi: 10.1016/j.ejcts.2010.09.042
Margaritora S, Cesario A, Cusumano G, Meacci E, D’Angelillo R, Bonassi S, et al. Thirty-five-year follow-up analysis of clinical and pathologic outcomes of thymoma surgery. Ann Thorac Surg. 2010;89:245–52.
doi: 10.1016/j.athoracsur.2009.08.074
Kim DJ, Yang WI, Choi SS, Kim KD, Chung KY. Prognostic and clinical relevance of the World Health Organization schema for the classification of thymic epithelial tumors: a clinicopathologic study of 108 patients and literature review. Chest. 2005;127:755–61.
doi: 10.1378/chest.127.3.755
Ströbel P, Bauer A, Puppe B, Kraushaar T, Krein A, Toyka K, et al. Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis. J Clin Oncol. 2004;22:1501–9.
doi: 10.1200/JCO.2004.10.113
Weis CA, Yao X, Deng Y, Detterbeck FC, Marino M, Nicholson AG, et al. The impact of thymoma histotype on prognosis in a worldwide database. J Thorac Oncol. 2015;10:367–72.
doi: 10.1097/JTO.0000000000000393
Nonaka D, Rosai J. Is there a spectrum of cytologic atypia in type a thymomas analogous to that seen in type B thymomas? A pilot study of 13 cases. Am J Surg Pathol. 2012;36:889–94.
doi: 10.1097/PAS.0b013e31824fff50
Vladislav IT, Gökmen-Polar Y, Kesler KA, Loehrer PJ, Badve S. The role of histology in predicting recurrence of type A thymomas: a clinicopathologic correlation of 23 cases. Mod Pathol. 2013;26:1059–64.
doi: 10.1038/modpathol.2013.49
Green AC, Marx A, Ströbel P, Mason M, Lim E, Jordan S, et al. Type A and AB thymomas: histological features associated with increased stage. Histopathology. 2015;66:884–91.
doi: 10.1111/his.12512
Marx A, Ströbel P, Badve SS, Chalabreysse L, Chan JK, Chen G, et al. ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting. J Thorac Oncol. 2014;9:596–611.
doi: 10.1097/JTO.0000000000000154