The Expression of Caspase-3 and GRIM-19 in Non-mucinous Lung Adenocarcinoma and Their Clinicopathologic Significance

Year 2023, Volume: 25 Issue: 2, 158 - 166, 30.08.2023

Alev Ok Atılgan , Merih Tepeoğlu , Eda Yılmaz Akçay , Leyla Hasanaliyeva , Dalokay Kılıç , Handan Özdemir

https://doi.org/10.18678/dtfd.1294988

Cited By: 1

Abstract

Aim: The current study aimed to investigate apoptotic proteins such as caspase-3 and GRIM-19 protein expression in non-mucinous lung adenocarcinomas and their clinicopathologic significance.
Material and Methods: This study was performed on 81 patients diagnosed with non-mucinous lung adenocarcinoma between January 1, 2010, and June 1, 2020. Immunohistochemical analysis was performed to examine the expressions of caspase-3 and GRIM-19, and the association between these proteins and clinicopathological parameters was investigated.
Results: Caspase-3 nuclear positivity was more common in high-grade non-mucinous lung adenocarcinomas (p<0.001). Caspase-3 cytoplasmic expression was stronger in tumors with advanced-stage (p=0.021) and lymph node metastases (p=0.020). GRIM-19 expression was low in tumors with high-grade non-mucinous lung adenocarcinomas (p=0.002), and tumors with lymphovascular invasion (p=0.021). The median follow-up time was 31.7 (range, 1-145 months. The overall 5-year survival rate of patients with low and high GRIM-19 expression tumors was 48% and 92%, respectively. GRIM-19 expression significantly affected the 5-year overall survival rate (p=0.008), but not the 5-year disease-free survival rate (p=0.368).
Conclusion: We revealed a significant association between caspase-3 and GRIM-19 expressions and poor clinicopathologic features and prognosis. For the first time in the literature, we revealed an association between low GRIM-19 expression and worse clinical outcomes in patients with non-mucinous lung adenocarcinoma. Caspase-3 and GRIM-19 may become potential therapeutic targets and novel potential predictive biomarkers for non-mucinous lung adenocarcinoma patients.

Keywords

Apoptosis, Caspase-3, GRIM-19, Lung cancer

Supporting Institution

Baskent University

Project Number

Number: KA23/162; Date: 27.04.2023

Müsinöz Olmayan Akciğer Adenokarsinomlarında Caspase-3 ve GRIM-19 Ekspresyonu ile Bu Proteinlerin Klinikopatolojik Önemi

Abstract

Amaç: Bu çalışmada, müsinöz olmayan akciğer adenokarsinomlarında, apoptotik protein olarak bilinen caspase-3 ve GRIM-19 protein ekspresyonu ve bu proteinlerin klinikopatolojik öneminin araştırılması amaçlandı.
Gereç ve Yöntemler: Bu çalışma, 1 Ocak 2010 ile 1 Haziran 2020 tarihleri arasında müsinöz olmayan akciğer adenokarsinomu tanısı alan 81 hasta üzerinde gerçekleştirildi. Caspase-3 ve GRIM-19 ekspresyonlarını incelemek için immünohistokimyasal analiz yapıldı ve bu proteinler ile klinikopatolojik parametreler arasındaki ilişki araştırıldı.
Bulgular: Caspase-3 nükleer pozitifliği yüksek dereceli müsinöz olmayan akciğer adenokarsinomlarında daha yaygın bulundu (p<0,001). Caspase-3 sitoplazmik ekspresyonu ileri evre (p=0,021) ve lenf nodu metastazı (p=0,020) olan tümörlerde daha güçlü saptandı. GRIM-19 ekspresyonu, yüksek dereceli müsinöz olmayan akciğer adenokarsinomlu tümörlerde (p=0,002) ve lenfovasküler invazyonlu tümörlerde (p=0,021) düşük idi. Ortanca takip süresi 31,7 (aralık, 1-145) ay idi. Düşük ve yüksek GRIM-19 ekspresyonlu tümörlere sahip hastaların 5 yıllık genel sağkalım oranı sırasıyla %48 ve %92 idi. GRIM-19 ekspresyonu genel 5 yıllık sağkalım oranı üzerinde anlamlı bir etkisi olduğu (p=0,008), ancak 5 yıllık hastalıksız sağkalım oranı üzerinde anlamlı bir etkisi olmadığı (p=0,368) saptandı.
Sonuç: Caspase-3 ve GRIM-19 ekspresyonu ile kötü klinikoptolojik özellikler ve prognoz arasında anlamlı bir ilişki olduğunu gösterdik. Literatürde ilk kez, düşük GRIM-19 ekspresyonunun müsinöz olmayan akciğer adenokarsinomunda daha kötü bir klinik gidişle ilişkili olduğunu ortaya koyduk. Caspase-3 ve GRIM-19 müsinöz olmayan akciğer adenokarsinomu hastaları için yeni potansiyel prognostik biyobelirteçlerin yanı sıra potansiyel terapötik hedefler haline gelebilir.

Keywords

Apoptosis, Caspase-3, GRIM-19, Akciğer kanseri

Project Number

Number: KA23/162; Date: 27.04.2023

References

• WHO Classification of Tumours Editorial Board. Thoracic Tumours. 5th ed. Lyon, France: International Agency for Research on Cancer; 2021.
• Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33.
• Haura EB, Cress WD, Chellappan S, Zheng Z, Bepler G. Antiapoptotic signaling pathways in non-small-cell lung cancer: biology and therapeutic strategies. Clin Lung Cancer. 2004;6(2):113-22.
• Eskandari E, Eaves CJ. Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis. J Cell Biol. 2022;221(6):e202201159.
• Boice A, Bouchier-Hayes L. Targeting apoptotic caspases in cancer. Biochim Biophys Acta Mol Cell Res. 2020;1867(6):118688.
• Liu X, Li F, Huang Q, Zhang Z, Zhou L, Deng Y, et al. Self-inflicted DNA double-strand breaks sustain tumorigenicity and stemness of cancer cells. Cell Res. 2017;27(6):764-83.
• Boudreau MW, Peh J, Hergenrother PJ. Procaspase-3 overexpression in cancer: a paradoxical observation with therapeutic potential. ACS Chem Biol. 2019;14(11):2335-48.
• Kalvakolanu DV, Nallar SC, Kalakonda S. Cytokine-induced tumor suppressors: a GRIM story. Cytokine. 2010;52(1-2):128-42.
• Sun P, Nallar SC, Raha A, Kalakonda S, Velalar CN, Reddy SP, et al. GRIM-19 and p16(INK4a) synergistically regulate cell cycle progression and E2F1-responsive gene expression. J Biol Chem. 2010;285(36):27545-52.
• Nallar SC, Kalvakolanu DV. GRIM-19: A master regulator of cytokine induced tumor suppression, metastasis and energy metabolism. Cytokine Growth Factor Rev. 2017;33:1-18.
• Lufei C, Ma J, Huang G, Zhang T, Novotny-Diermayr V, Ong CT, et al. GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional interaction. EMBO J. 2003;22(6):1325-35.
• Moreira S, Correia M, Soares P, Máximo V. GRIM-19 function in cancer development. Mitochondrion. 2011;11(5):693-9.
• Angell JE, Lindner DJ, Shapiro PS, Hofmann ER, Kalvakolanu DV. Identification of GRIM-19, a novel cell death-regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach. J Biol Chem. 2000;275(43):33416-26.
• Huang Y, Yang M, Yang H, Zeng Z. Upregulation of the GRIM-19 gene suppresses invasion and metastasis of human gastric cancer SGC-7901 cell line. Exp Cell Res. 2010;316(13):2061-70.
• Wang T, Yan XB, Zhao JJ, Ye J, Jiang ZF, Wu DR, et al. Gene associated with retinoid-interferon-induced mortality-19 suppresses growth of lung adenocarcinoma tumor in vitro and in vivo. Lung Cancer. 2011;72(3):287-93.
• Hu Q, Peng J, Liu W, He X, Cui L, Chen X, et al. Elevated cleaved caspase-3 is associated with shortened overall survival in several cancer types. Int J Clin Exp Pathol. 2014;7(8):5057-70.
• 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. Int J Cancer. 2001;96(Suppl):54-60.
• Ilelis F, do Amaral NS, Alves MR, da Costa AABA, Calsavara VF, Lordello L, et al. Prognostic value of GRIM-19, NF-κB and IKK2 in patients with high-grade serous ovarian cancer. Pathol Res Pract. 2018;214(2):187-94.
• Liu X, Jiang S, Tian X, Jiang Y. Expression of cleaved caspase-3 predicts good chemotherapy response but poor survival for patients with advanced primary triple-negative breast cancer. Int J Clin Exp Pathol. 2018;11(9):4363-73.
• Huang KH, Fang WL, Li AF, Liang PH, Wu CW, Shyr YM, et al. Caspase-3, a key apoptotic protein, as a prognostic marker in gastric cancer after curative surgery. Int J Surg. 2018;52:258-63.
• Noble P, Vyas M, Al-Attar A, Durrant S, Scholefield J, Durrant L. High levels of cleaved caspase-3 in colorectal tumour stroma predict good survival. Br J Cancer. 2013;108(10):2097-105.
• Nassar A, Lawson D, Cotsonis G, Cohen C. Survivin and caspase-3 expression in breast cancer: correlation with prognostic parameters, proliferation, angiogenesis, and outcome. Appl Immunohistochem Mol Morphol. 2008;16(2):113-20.
• Vranic A. Caspase-3 and survivin expression in primary atypical and malignant meningiomas. ISRN Neurosci. 2013;2013:626290.
• Huang YL, Zhang GH, Zhu Q, Wu X, Wu LG. Expression levels of caspase-3 and gasdermin E and their involvement in the occurrence and prognosis of lung cancer. Cancer Rep (Hoboken). 2022;5(9):e1561.
• Yoo Jy, 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 Res Treat. 2004;36(5):303-7.
• Koomägi R, Volm M. Relationship between the expression of caspase-3 and the clinical outcome of patients with non-small cell lung cancer. Anticancer Res. 2000;20(1B):493-6.
• Fan XY, Jiang ZF, Cai L, Liu RY. Expression and clinical significance of GRIM-19 in lung cancer. Med Oncol. 2012;29(5):3183-9.
• Wang Y, Yan Y, Yang M, Yang Z. Expressions and clinical significances of STAT3 and Grim19 in epithelial ovarian cancer. 3 Biotech. 2020;10(6):246.
• Hao M, Shu Z, Sun H, Sun R, Wang Y, Liu T, et al. GRIM-19 expression is a potent prognostic marker in colorectal cancer. Hum Pathol. 2015;46(12):1815-20.
• Yan N, Feng X, Jiang S, Sun W, Sun MZ, Liu S. GRIM-19 deficiency promotes clear cell renal cell carcinoma progression and is associated with high TNM stage and Fuhrman grade. Oncol Lett. 2020;19(6):4115-21.
• Zhou T, Chao L, Rong G, Wang C, Ma R, Wang X. Down-regulation of GRIM-19 is associated with STAT3 overexpression in breast carcinomas. Hum Pathol. 2013;44(9):1773-9.
• Zhou AM, Zhao JJ, Ye J, Xiao WH, Kalvakolanu DV, Liu RY. Expression and clinical significance of GRIM-19 in non-small cell lung cancer. Ai Zheng. 2009;28(4):431-5. Chinese.
• Wu HM, Jiang ZF, Fan XY, Wang T, Ke-Xu, Yan XB, et al. Reversed expression of GRIM-1 and GRP78 in human non-small cell lung cancer. Hum Pathol. 2014;45(9):1936-43.