Abstract
Objective:Apoptosis plays a critical role in carcinogenesis. Intracellular proteases known as caspase-9 directly or indirectly play
roles inactivating apoptosis. In this study, we aimed to investigate the effect of caspase-9 level in lung skuamous cancer tumor tissues on lymph
node metastasis, clinicopathologic parameters and prognosis. Material and Methods: The study included 50 patients diagnosed with squamous
cell lung cancer. The caspase-9 level in the tumor and metastatic lymph nodes was assessed using real time-polymerase chain reaction(
RT-PCR) methods. Results: The median age of the patients was 61 years (range, 54-68 years). All patients were men and smokers. The
average duration of follow-up was 50.26±39.21 months, and progression-free survival was 26.34±19.50 months. Among 50 patients, 22 (44%)
had lymph node metastasis. The caspase-9 level was studied in tumors with and without lymph node metastasis. Moreover, the caspase-9 levels
in tumors with lymph node metastasis were statistically and significantly lower than tumors without lymph node metastasis (p<0.001). The
caspase-9 level decreased as the stage increased (p<0.001). In the presence of angiolymphatic invasion and poorly differentiated tumor tissue,
a low level of caspase-9 was identified. Conclusion: The caspase-9 level decreased with increasing stage and the presence of lymph
node metastasis. No statistically significant association was detected between caspase-9 and survival. A literature review revealed that no
studies have evaluated the correlation between caspase-9 in the squamous cell subtype, clinicopathological parameters, and survival. Extensive
studies involving a significant number of patients are required to determine the prognostic and predictive significance of the caspase-9
level in our population.
Keywords:
Lung neoplasm, apoptosis, caspase 9
References
1Torre LA, Siegel RL, Jemal A. Lung cancer statistics. AdvExp Med Biol. 2016;893:1-19.
2Noone AM, Howlader N, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2015.
3Bratton SB, Salvesen GS. Regulation of the Apaf-1- caspase-9 apoptosome. Journal of Cell Science. 2010;123:3209-14.
4Adams JM, Cory S. Life or death decisions by the Bcl-2 family. Trends. BiochemSci. January 2001;26:61-6.
5Hu Q, Wu D, Chen W, Yan Z, Yan C, He T, Liang Q, Shi Y. Molecular determinants of caspase-9 activation by the Apaf-1 apoptosome. Proceedings of the National Academy of Sciences of the United States of America. November 2014;111:16254-61.
6Boatright KM, Salvesen GS. Mechanisms of caspase activation. Curr Opin Cell Biol. 2003;15(6):725-31.
7Li P, Zhou L, Zhao T, Liu X, Zhang P, Liu Y, X Zheng X, Q Li.Caspase-9: structure, mechanisms and clinical application.Oncotarget. 2017;8(14):23996-4008.
8Shultz JC, Goethe RW, Murudkar CS, Wijesinghe DS, Mayton EK, Massiello A, et al. srsf1 regulates the alternative splicing of caspase 9 via a novel ıntronic splicing enhancer. affecting the chemotherapeuticsensitivity of non-small cell lungcancercells. Mol Cancer Res. 2011;9(7):889-900.
9Straathof KC, Pulè MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, et al. An inducible caspase 9 safety switch for T-cell therapy. Blood. 2005;105(11):4247-54.
10Murray TV, McMahon JM, Howley BA, Stanley A, Ritter T, Mohr A, et al. A non-apoptotic role for caspase-9 in muscle differentiation. J Cell Sci. 2008;121(pt 22):3786-93.
11D'Sa-Eipper C, Leonard JR, Putcha G, Zheng TS, Flavell RA, Rakic P, et al. DNA damage-induced neural precursor cell apoptosis requires p53 and caspase 9 but neither Bax nor caspase 3. Development. 2001;128(1):137-46.
12Ercan S, Arinc S, Yilmaz SG, Altunok C, Yaman F, Isbir T. Investigation of caspase 9 gene polymorphism in patients with non-small cell lung cancer. Anticancer Res. 2019;39(5):2437-41.
13Yilmaz SG, Yencilek F, Yildirim A, Yencilek E, Isbir T.Effects of caspase 9 gene polymorphism in patients with prostate cancer. In Vivo. 2017;31(2):205-8.
14Shen XG, Wang C, Li Y, Wang L, Zhou B, Xu B, Jiang X, et al. Downregulation of caspase-9 is a frequent event in patients with stage II colorectal cancer and correlates with poor clinical outcome. ColorectalDis. 2010;12(12):1213-8.
15Park JY, Park JM, Jang JS, Choi JE, Kim KM, Cha SI, Kim CHet al. Caspase 9 promoter polymorphisms and risk of primary lung cancer.Hum Mol Genet. 2006;15(12):1963-71.
16Xu W, Jiang S, Xu Y, Chen B, Li Y, Zong F, Zhao W, Wu J. A meta-analysis of caspase 9 polymorphisms in promoter and exon sequence on cancer susceptibility. PLoS One. 2012;7(5):e37443.
17Asadi M, Shanehbandi D, Asvadi Kermani T, Sanaat Z, Zafari V, Hashemzadeh S. Expression level of caspase genes in colorectal cancer. Asian Pac J Cancer Prev. 2018;19(5):1277-80.
18Theodoropoulos GE, Michalopoulos NV, Pantou MP, Kontogianni P, Gazouli M, Karantanos T, et al. Caspase 9 promoter polymorphisms confer increased susceptibility to breast cancer. Cancer Genet. 2012;205(10):508-12.
19Zhang L, Zhang X, Wang X, He M, Qiao S. MicroRNA-224 Promotes tumorigenesis through downregulation of caspase-9 in triple-negative breast cancer. Dis Markers. February 2019;2019:7378967.
20Ozdogan S, Kafadar A, Yilmaz SG, Timirci-Kahraman O, Gormus U, Isbir T. Role of caspase-9 Gene Ex5+32 G>A [rs1052576] variant in susceptibility to primary brain tumors. Anticancer Res. 2017;37(9):4997-5000.
21Marques I, Teixeira AL, Ferreira M, Assis J, Lobo F, Maurício J, et al. Influence of survivin [BIRC5] and caspase-9 [CASP9] functional polymorphisms in renal cell carcinoma development: a study in a southern European population. Mol Biol Rep. 2013;40(8):4819-26.
22Sharifi S, Barar J, Hejazi MS, Samadi N. Roles of the Bcl-2/Bax ratio, caspase-8 and 9 in resistance of breast cancer cells to paclitaxel. Asian Pac J Cancer Prev. 2014;15(20):8617-22.
23Kuwahara D, Tsutsumi K, Kobayashi T, Hyoudou M, Koizuka I. Inhibition of caspase-9 activity in cisplatin-resistant head and neck squamous cell carcinoma. Nihon Jibiinkoka Gakkai Kaiho. 2002;105(2):152-7.
24Kemper K, Rodermond H, Colak S, Grandela C, Medema JP.Targeting colorectal cancer stem cells with inducible caspase-9. Apoptosis. 2012;17(5):528-37.
25Iwai N, Yasui K, Tomie A, Gen Y, Terasaki K, Kitaichi T, et al. Oncogenic miR-96-5p inhibits apoptosis by targeting the caspase-9 gene in hepatocellular carcinoma. Int J Oncol. 2018;53(1):237-45.
26Sträter J, Herter I, Merkel G, Hinz U, Weitz J, Möller P. Expression and prognosticsignificance of APAF-1, caspase-8 and caspase-9 in stage II/III colon carcinoma: caspase-8 and caspase-9 is associated with poorprognosis. Int J Cancer. 2010;127(4):873-80.
27Terlizzi M, Colarusso C, De Rosa I, De Rosa N, Somma P, Curcio C, et al. Circulating and tumor-associated caspase-4: a novel diagnostic and prognostic biomarker for non-small cell lung cancer. Oncotarget. 2018;9(27):19356-67.
28Liu D, Xu W, Ding X, Yang Y, Lu Y, Fei K, et al. Caspase 8 polymorphisms contribute to the prognosis of advanced lung adenocarcinoma patients after platinum-based chemotherapy. Cancer Biol Ther. 2017;18(12):948-57.
29Theodoropoulos GE, Gazouli M, Vaiopoulou A, Leandrou M, Nikouli S, Vassou E, et al. Polymorphisms of caspase 8 and caspase 9 gene and colorectal cancer susceptibility and prognosis. Int J Colorectal Dis. 2011;26(9):1113-8.