The Potential Prognostic Value of Glutatione-S Transferase Izoenzymes in Non-small Cell Lung Cancer

Yıl 2025, Cilt: 14 Sayı: 1, 48 - 57, 26.03.2025

Aydın Keskin , Pınar Kaygın , Kayhan Başak , Fatma Çakmak Kazanci , Sezen Yılmaz Sarıaltın , Onur Dirican , Abbas Ali Husseini , Muharrem Atlı , Can Yılmaz , Serpil Oğuztüzün

https://doi.org/10.46810/tdfd.1585199

Öz

GST izozimlerinin prognostik değerini değerlendirmek için GST izozim düzeyleri ile tümör belirteçleri arasındaki korelasyonları araştırmak. Bu retrospektif çalışmada adenokarsinom ve skuamöz hücreli karsinomu olan 40 hastanın klinik verileri analiz edilmiştir. Tümör ve komşu sağlıklı doku örnekleri, GST enzimlerinin (Sigma, Omega, Pi, Mu) ve kaspaz-3, Bcl-2, p38, p53'ün profilini çıkarmak için immünohistokimyasal olarak boyandı. Protein ekspresyon düzeyleri ile hasta özellikleri arasındaki ilişkiler incelenmiş ve GST enzimleri ile Kaspaz-3, Bcl-2, p38, p53 arasındaki korelasyonlar analiz edilmiştir. Tüm belirteçler için tümörlü ve sağlıklı dokular arasında anlamlı immünohistokimyasal farklılıklar bulunmuştur. GST enzimleri (GSTS, GSTO, GSTP, GSTM) ağırlıklı olarak tümörlü dokularda eksprese edilmiş, GSTO ve GSTP yüksek ekspresyon seviyeleri göstermiştir. SCC dokularıyla karşılaştırıldığında, GSTP ekspresyonu AC dokularında yaklaşık %30 daha yüksektir. Buna karşılık, GSTO ekspresyonu ikinci evre tümörlerde, özellikle de AC dokularında yaklaşık %25 oranında artmaktadır. Korelasyon analizi, tümör dokularında Bcl-2 ile kaspaz-3, p38, GSTS arasında, kaspaz-3 ile GSTP arasında ve p38 ile GSTM arasında anlamlı pozitif ilişkiler olduğunu ortaya koymuştur. Çalışma, KHDAK'de GST izozimlerinin prognostik değerini desteklemektedir.

Anahtar Kelimeler

Lung cancer, Glutatione-S Transferase, Caspase-3, Bcl-2, p38, p53

Etik Beyan

There is no conflict of interest between the authors in our study. We also declare that all stages were carried out in accordance with all ethics.

Kaynakça

• Thandra KC, Barsouk A, Saginala K, Aluru JS, & Barsouk A. ( Epidemiology of lung cancer. Contemporary Oncology. 2021; 25(1): 45. https://doi.org/10.5114/WO.2021.103829
• Nicholson AG, Tsao MS, Beasley MB, Borczuk AC, Brambilla E, Cooper WA, et al. The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015. Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer. 2022; 17(3): 362–387. https://doi.org/10.1016/J.JTHO.2021.11.003
• Zappa C, & Mousa SA. Non-small cell lung cancer: current treatment and future advances. Translational Lung Cancer Research. 2016; 5(3): 288. https://doi.org/10.21037/TLCR.2016.06.07
• Siddiqui F, Vaqar S, Siddiqui AH . Lung Cancer. Cambridge Handbook of Psychology, Health and Medicine, Second Edition, 605–606, 2023. https://doi.org/10.1017/CBO9780511543579.138
• Greenberg AK, Basu S, Hu J, Yie TA, Kam MTW, Rom WN, Lee TC. Selective p38 activation in human non-small cell lung cancer. American Journal of Respiratory Cell and Molecular Biology. 2002;26(5): 558–564. https://doi.org/10.1165/AJRCMB.26.5.4689
• Kato S, Yokoyama S, Hayakawa Y, Li L, Iwakami Y, Sakurai H, Saiki I. P38 pathway as a key downstream signal of connective tissue growth factor to regulate metastatic potential in non-small-cell lung cancer. Cancer Science, 2016;107(10): 1416–1421. https://doi.org/10.1111/CAS.13009
• Huang J-S, Yang C-M, Wang J-S, Liou H-H, Hsieh I-C, Li G-C, et al. Caspase-3 expression in tumorigenesis and prognosis of buccal mucosa squamous cell carcinoma. Oncotarget. 2017; 8(48): 84237–84247. https://doi.org/10.18632/ONCOTARGET.20494
• Joseph B, Ekedahl J, Lewensohn R, Marchetti P, Formstecher P, Zhivotovsky B. Defective caspase-3 relocalization in non-small cell lung carcinoma. Oncogene. 2001;20(23): 2877–2888. https://doi.org/10.1038/SJ.ONC.1204402
• Takata T, Tanaka F, Yamada T, Yanagihara K, Otake Y, Kawano Y, et al. Clinical significance of caspase-3 expression in pathologic-stage I, nonsmall-cell lung cancer. International Journal of Cancer. 2001a; 96 Suppl(SUPPL.); 54–60. https://doi.org/10.1002/IJC.10347
• Anagnostou VK, Lowery FJ, Zolota V, Tzelepi V, Gopinath A, Liceaga C, Panagopoulos N, et al. High expression of BCL-2 predicts favorable outcome in non-small cell lung cancer patients with non squamous histology. BMC Cancer. 2010;10(1): 1–11. https://doi.org/10.1186/1471-2407-10-186/TABLES/2
• Sun PL, Sasano H, Gao H. Bcl-2 family in non-small cell lung cancer: its prognostic and therapeutic implications. Pathology International. 2017; 67(3): 121–130. https://doi.org/10.1111/PIN.12507
• Cakir E, Yilmaz A, Demirag F, Oguztuzun S, Sahin S, Yazici UE, Aydin M. Prognostic significance of micropapillary pattern in lung adenocarcinoma and expression of apoptosis-related markers: caspase-3, bcl-2, and p53. APMIS : Acta Pathologica, Microbiologica, et Immunologica Scandinavica. 2011; 119(9): 574–580. https://doi.org/10.1111/J.1600-0463.2011.02778.X
• Kim C H, Lee H S, Park JH, Choi JH, Jang SH, Park YB, et al. Prognostic role of p53 and Ki-67 immunohistochemical expression in patients with surgically resected lung adenocarcinoma: a retrospective study. Journal of Thoracic Disease. 2015; 7(5): 822. https://doi.org/10.3978/J.ISSN.2072-1439.2015.05.02
• Zhu CQ, Shih W, Ling CH, Tsao MS. Immunohistochemical markers of prognosis in non-small cell lung cancer: a review and proposal for a multiphase approach to marker evaluation. Journal of Clinical Pathology. 2006a; 59(8): 790–800. https://doi.org/10.1136/JCP.2005.031351
• Ma X, Le Teuff G, Lacas B, Tsao MS, Graziano S, Pignon JP, et al . Prognostic and Predictive Effect of TP53 Mutations in Patients with Non-Small Cell Lung Cancer from Adjuvant Cisplatin-Based Therapy Randomized Trials: A LACE-Bio Pooled Analysis. Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer.2016;11(6): 850–861. https://doi.org/10.1016/J.JTHO.2016.02.002
• Zhu CQ, Shih W, Ling CH, & Tsao MS. Immunohistochemical markers of prognosis in non‐small cell lung cancer: a review and proposal for a multiphase approach to marker evaluation. Journal of Clinical Pathology. 2006b; 59(8): 790. https://doi.org/10.1136/JCP.2005.031351
• Singh RR, Reindl KM. Glutathione S-Transferases in Cancer. Antioxidants (Basel, Switzerland). 2021;10(5): 701. https://doi.org/10.3390/ANTIOX10050701
• Zeng B, Ge C, Li R, Zhang Z, Fu Q, Li Z, Lin Z, Liu L, Xue Y, Xu Y, He J, Guo H, Li C, Huang W, Song X, & Huang Y. Knockdown of microsomal glutathione S-transferase 1 inhibits lung adenocarcinoma cell proliferation and induces apoptosis. Biomedicine & Pharmacotherapy. 2020; 121: 109562. https://doi.org/10.1016/J.BIOPHA.2019.109562
• Albarakati N, Khayyat D, Dallol A, Al-Maghrabi J, & Nedjadi T.The prognostic impact of GSTM1/GSTP1 genetic variants in bladder Cancer. BMC Cancer. 2019; 19(1): 1–11. https://doi.org/10.1186/S12885-019-6244-6/TABLES/5
• Chen Y, Li B, Wang J, Liu J, Wang Z, Mao Y, Liu S, Liao X, Chen J. Identification and verification of the prognostic value of the glutathione S-transferase Mu genes in gastric cancer. Oncology Letters. 2020; 20(4): https://doi.org/10.3892/OL.2020.11961
• Hsu CH, Chen CL, Hong RL, Chen KL, Lin JF, Cheng AL.Prognostic value of multidrug resistance 1, glutathione-S-transferase-pi and p53 in advanced nasopharyngeal carcinoma treated with systemic chemotherapy. Oncology. 2002;62(4):305–312. https://doi.org/10.1159/000065061
• Huang J, Tan PH, Thiyagarajan J, Bay BH. Prognostic Significance of Glutathione S-Transferase-Pi in Invasive Breast Cancer. Modern Pathology.2003; 16(6): 558–565. https://doi.org/10.1097/01.mp.0000071842.83169.5a
• Voso M T, D’Alo F, Putzulu R, Mele L, Scardocci A, Chiusolo P, et al. (2002). Negative prognostic value of glutathione S-transferase (GSTM1 and GSTT1) deletions in adult acute myeloid leukemia. Blood. 2002; 100(8): 2703–2707. https://doi.org/10.1182/BLOOD.V100.8.2703
• Wang Y, Spitz MR, Schabath MB, Ali-Osman F, Mata H, & Wu X. Association between glutathione S-transferase p1 polymorphisms and lung cancer risk in Caucasians: a case-control study. Lung Cancer. 2003; 40(1): 25–32. https://doi.org/10.1016/S0169-5002(02)00537-8
• Pan C, Zhu G, Yan Z, Zhou Y, Liu Z. Glutathione S-Transferase T1 and M1 Polymorphisms Are Associated with Lung Cancer Risk in a Gender-Specific Manner. Oncology Research and Treatment. 2014;37(4): 164–169. https://doi.org/10.1159/000361083
• Wang SQ, Chen JJ, Jiang Y, Lei ZN, Ruan YC, Pan Y, et al. Targeting GSTP1 as Therapeutic Strategy against Lung Adenocarcinoma Stemness and Resistance to Tyrosine Kinase Inhibitors. Advanced Science (Weinheim, Baden-Wurttemberg, Germany). 2023; 10(7): https://doi.org/10.1002/ADVS.202205262
• Inoue T, Ishida T, Sugio K, Maehara Y, Sugimachi K. Glutathione S Transferase Pi Is a Powerful Indicator in Chemotherapy of Human Lung Squamous-Cell Carcinoma. Respiration. 1995;62(4): 223–227. https://doi.org/10.1159/000196451
• Rybárová S, Hodorová I, Mihalik J, Mirossay L. MRP1 and GSTp1 expression in non-small cell lung cancer does not correlate with clinicopathological parameters: A Slovakian population study. Acta Histochemica. 2014;116(8): 1390–1398. https://doi.org/10.1016/J.ACTHIS.2014.09.002
• Jankova L, Robertson G, Chan C, Tan KL, Kohonen-Corish M, Fung CLS, et al . Glutathione S-transferase Pi expression predicts response to adjuvant chemotherapy for stage C colon cancer: A matched historical control study. BMC Cancer. 2012;12(1): 1–9. https://doi.org/10.1186/1471-2407-12-196/TABLES/3
• Wang K, Zhang FL, Jia W. Glutathione S-transferase ω 1 promotes the proliferation, migration and invasion, and inhibits the apoptosis of non-small cell lung cancer cells, via the JAK/STAT3 signaling pathway. Molecular Medicine Reports, 2021; 23(1): 1–7. https://doi.org/10.3892/MMR.2020.11709
• Mora Vidal R, Regufe da Mota S, Hayden A, Markham H, Douglas J, Packham G, Crabb SJ. Epidermal Growth Factor Receptor Family Inhibition Identifies P38 Mitogen-activated Protein Kinase as a Potential Therapeutic Target in Bladder Cancer. Urology. 2018; 112: 225.e1-225.e7. https://doi.org/10.1016/J.UROLOGY.2017.10.041
• Zarczynska I, Gorska-Arcisz M, Cortez A J, Kujawa KA, Wilk A M, Skladanowski A C, Stanczak A, Skupinska M, Wieczorek M, Lisowska K M, Sadej R, & Kitowska K. P38 mediates resistance to fgfr inhibition in non-small cell lung cancer. Cells. 2021;
• 10(12): 3363. https://doi.org/10.3390/CELLS10123363/S1
• Fang Y, Wang J, Wang G, Zhou C, Wang P, Zhao S, et al. Inactivation of p38 MAPK contributes to stem cell-like properties of non-small cell lung cancer. Oncotarget. 2017; 8(16): 26702. https://doi.org/10.18632/ONCOTARGET.15804
• Sunaga N, Miura Y, Tsukagoshi Y, Kasahara N, Masuda T, et al. Dual inhibition of MEK and p38 impairs tumor growth in KRAS-mutated non-small cell lung cancer. Oncology Letters. 2019; 17(3): https://doi.org/10.3892/OL.2019.10009
• Feng C, Wu J, Yang F, Qiu M, Hu S, Guo S, Wu J, Ying X, Wang J. Expression of Bcl-2 is a favorable prognostic biomarker in lung squamous cell carcinoma. Oncology Letters. 2018; 15(5): 6925. https://doi.org/10.3892/OL.2018.8198
• Zhang J, Wang S, Wang L, Wang R, Chen S, Pan B, Sun Y, Chen H. Prognostic value of Bcl-2 expression in patients with non-small-cell lung cancer: a meta-analysis and systemic review. OncoTargets and Therapy. 2015; 8: 3361. https://doi.org/10.2147/OTT.S89275
• Takata T, Tanaka F, Yamada T, Yanagihara K, Otake Y, Kawano Y, et al. Clinical significance of caspase-3 expression in pathologic-stage I, nonsmall-cell lung cancer. International Journal of Cancer. 2001b; 96 Suppl(SUPPL.), 54–60. https://doi.org/10.1002/IJC.10347
• Yoo J, Kim CH, Song SH, Shim BY, Jeong YJ, Ahn MI, et al. Expression of Caspase-3 and c-myc in Non-Small Cell Lung Cancer. Cancer Research and Treatment : Official Journal of Korean Cancer Association. 2004;36(5): 303. https://doi.org/10.4143/CRT.2004.36.5.303
• Sahu V, Mohan A, Dey S. p38 MAP kinases: plausible diagnostic and prognostic serum protein marker of non small cell lung cancer. Experimental and Molecular Pathology. 2019;107:118–123. https://doi.org/10.1016/J.YEXMP.2019.01.009
• Liu H, Tong X, Zhao H, Li Y, Zhang L. P2-080: Prognostic value of Smad4 and p38 proteins in Non-Small Cell Lung Cancer. Journal of Thoracic Oncology. 2007;2(8): S522. https://doi.org/10.1097/01.jto.0000283544.26342.98
• Ahrendt SA, Hu Y, Buta M, McDermot MP, Benoit N, Yang SC, et al. p53 mutations and survival in stage I non-small-cell lung cancer: results of a prospective study. Journal of the National Cancer Institute. 2003;95(13):961–970. https://doi.org/10.1093/JNCI/95.13.961
• Mogi A, Kuwano H. TP53 mutations in nonsmall cell lung cancer. Journal of Biomedicine and Biotechnology. 2011;Jan18,2011:583929 https://doi.org/10.1155/2011/583929
• Bhattacharya P, Madden JA, Sen N, Hoyer PB, Keating AF. Glutathione S-transferase class μ regulation of apoptosis signal-regulating kinase 1 protein during VCD-induced ovotoxicity in neonatal rat ovaries. Toxicology and Applied Pharmacology. 2013;267(1): 49–56. https://doi.org/10.1016/J.TAAP.2012.12.013
• Dorion S, Lambert H, Landry J. Activation of the p38 signaling pathway by heat shock involves the dissociation of glutathione S-transferase Mu from Ask1. The Journal of Biological Chemistry.2002;277(34): 30792–30797. https://doi.org/10.1074/JBC.M203642200
• Luo HY, Tang WL, Xiang L, Peng LL, Wu D, Zhu ZY, Gu, HT, et al . Comprehensive analysis of the correlation between GSTM1 and tumor immunity in colon cancer. Journal of Gastrointestinal Oncology, 2022;13(6): 3025–3037. https://doi.org/10.21037/JGO-22-1060/COIF
• Jakubowska K, Guzińska-Ustymowicz K, Famulski W, Cepowicz D, Jagodzińska D, Pryczynicz A. Reduced expression of caspase-8 and cleaved caspase-3 in pancreatic ductal adenocarcinoma cells. Oncology Letters. 2016;11(3): 1879. https://doi.org/10.3892/OL.2016.4125
• Oguztüzun S, Aydin M, Demirag F, Yazici Ü, Özhavzali M, Kiliç M, Işcan M. The expression of GST isoenzymes and p53 in non-small cell lung cancer. Folia Histochemica et Cytobiologica. 2010;48(1): 122–127. https://doi.org/10.2478/V10042-008-0084-6
• Cancer Today. (n.d.). Retrieved February 19, from https://gco.iarc.fr/today/en, 2024.
• Scott A, Salgia R. Biomarkers in lung cancer: from early detection to novel therapeutics and decision making. Biomarkers in Medicine.2008;2(6): 577. https://doi.org/10.2217/17520363.2.6.577