Abstract
Amaç: Küçük hücre dışı akciğer kanseri (KHDAK), kansere bağlı ölümlerin önde gelen nedenlerinden biridir ve genellikle ileri evrede teşhis edilir. DHRS2, lipid metabolizması, hormon regülasyonu ve oksidatif stresle ilişkili olup, p53 stabiliza syonu ve MDM2 inhibisyonu yoluyla kanser progresyonunu etkileyen önemli bir tümör baskılayıcıdır. TP53 ve BRCA1, DNA hasar yanıtı ve tümör baskılama süreç lerinde kritik roller oynarken, BRCA1 aynı zamanda KHDAK’de prognostik bir belirteç olarak öne çıkmaktadır. Bu çalışma, KHDAK hücrelerinde DHRS2 ekspresyon düzey leri ile BRCA1 arasındaki etkileşimleri inceleyerek, moleküler mekanizmalarını daha iyi anlamayı ve yeni terapötik hedefler ile tedavi stratejileri geliştirmeyi amaçla maktadır.
Gereç ve Yöntemler: Bu çalışmada ekspresyon vektörü kullanılarak akciğer kanser hücre hatları (A549, H1299) ve normal bronş epitel hücre hattında (BEAS-2B), DHRS2 aşırı ekspresyonu sağlanmış ve quantitative PCR (qPCR) ile doğrulanmıştır. Ardından, DHRS2 aşırı ekspresyonunun BRCA1 ekspresyon seviyeleri üzerindeki etkisi incelenmiştir. Ayrıca KHDAK'nin alt tiplerinde BRCA1 ekspresyon düzeyleri GEPIA2, BRCA1 ve DHRS2 genlerindeki genomik değişiklikler ise cBioPortal-TCGA ile incelenmiştir.
Bulgular: DHRS2’nin aşırı ekspresyonu, A549 hücrelerinde (p53 wild type) BRCA1 ekspresyonunu azaltırken, H1299 hücrelerinde (p53 null) herhangi bir değişikliğe neden olmamaktadır. BEAS-2B hücre hattında ise DHRS2’nin aşırı ekspresyonu BRCA1 ekspresyonunu baskılamaktadır. GEPIA2 verileri, BRCA1'in tümör dokularında normal dokulara kıyasla belirgin şekilde arttığını göstermektedir. Genomik değişik lik analizi, BRCA1'deki amplifikasyonlar ve delesyonlar, genomik instabiliteyi işaret ederken, DHRS2'nin daha az mutasyon sergilemesi, düzenleyici rolünü ortaya koy maktadır.
Sonuç: Elde ettiğimiz bulgular DHRS2'nin BRCA1 ekspresyonunu modüle edebile ceğini ve p53’ün bu süreçte kritik rol oynayabileceğini göstermektedir. BRCA1 ve DHRS2'deki genetik değişiklikler, KHDAK tümörigenezinde etkili olduğunu düşündürmektedir, gelecekteki çalışmalarla DHRS2 ve p53 aracılı mekanizmaları daha ayrıntılı incelemelidir.
Supporting Institution
Bu çalışma, İstanbul Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi tarafından desteklenmiştir.
Project Number
41514
References
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70(1):7-30. google scholar
- Liang Z, Zhong Y, Meng L, Chen Y, Liu Y, Wu A, et al. HAX1 enhances the survival and metastasis of non-small cell lung cancer through the AKT/mTOR and MDM2/p53 signaling pathway. Thorac Cancer 2020;11(11):3155-67. google scholar
- Gabrielli F, Tofanelli S. Molecular and functional evolution of human DHRS2 and DHRS4 duplicated genes. Gene 2012;511(2):461-9. google scholar
- Pellegrini S, Censini S, Guidotti S, Iacopetti P, Rocchi M, Bianchi M, et al. A human short-chain dehydrogenase/reductase gene: structure, chromosomal localization, tissue expression and subcellular localization of its product. Biochim Biophys Acta 2002;1574(3):215-22. google scholar
- Li Z, Liu H, Bode A, Luo X. Emerging roles of dehydrogenase/reductase member 2 (DHRS2) in the pathology of disease. Eur J Pharmacol 2021;898:173972. google scholar
- Steffens Reinhardt L, Groen K, Newton C, Avery-Kiejda KA. The role of truncated p53 isoforms in the DNA damage response. Biochim Biophys Acta Rev Cancer 2023;1878(3):188882. google scholar
- Rosen EM, Fan S, Isaacs C. BRCA1 in hormonal carcinogenesis: basic and clinical research. Endocr Relat Cancer 2005;12(3):533-48. google scholar
- Gachechiladze M, Skarda J. The role of BRCA1 in non-small cell lung cancer. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2012;156(3):200-3. google scholar
- Zhou Y, Wang L, Ban X, Zeng T, Zhu Y, Li M, et al. DHRS2 inhibits cell growth and motility in esophageal squamous cell carcinoma. Oncogene 2018;37(8):1086-94. google scholar
- Yamada H, Arakawa Y, Saito S, Agawa M, Kano Y, Horiguchi-Yamada J. Depsipeptide-resistant KU812 cells show reversible P-glycoprotein expression, hyper-acetylated histones, and modulated gene expression profile. Leuk Res 2006;30(6):723-34. google scholar
- An Z, Bo W, Qin J, Jiang L, Jiang J. Auxiliary Diagnosis and Prognostic Value of Dehydrogenase/Reductase 2 (DHRS2) in Various Tumors. Iran J Public Health 2023;52(6):1150-60. google scholar
- Han Y, Song C, Wang J, Tang H, Peng Z, Lu S. HOXA13 contributes to gastric carcinogenesis through DHRS2 interacting with MDM2 and confers 5-FU resistance by a p53-dependent pathway. Mol Carcinog 2018;57(6):722-34. google scholar
- Jiang J, Yang ES, Jiang G, Nowsheen S, Wang H, Wang T, et al. p53-dependent BRCA1 nuclear export controls cellular susceptibility to DNA damage. Cancer Res 2011;71(16):5546-57. google scholar
Abstract
Objective: Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality and is often diagnosed late. DHRS2 regulates lipid metabolism, hormones, and oxidative stress, acting as a tumour suppressor by stabilising p53 and inhibiting MDM2. Tp53 and BRCA1 are crucial for DNA repair and tumour suppression, with BRCA1 as a prognostic marker in NSCLC. However, the interaction between DHRS2 and BRCA1 in NSCLC remains unclear. This study aimed to examine how DHRS2 expression influences BRCA1 levels in NSCLC cells, providing insight into potential therapeutic targets.
Material and Methods: DHRS2 overexpression was induced in NSCLC cells (A549, H1299) and normal bronchial epithelial cells (BEAS-2B) using an expression vector and confirmed by quantitative PCR (qPCR). The effect of DHRS2 overexpression on BRCA1 expression levels was examined. In addition, BRCA1 expression levels in NSCLC subtypes were analysed using GEPIA2, while genomic alterations in BRCA1 and DHRS2 were investigated via cBioPortal-TCGA.
Results: DHRS2 overexpression led to a decrease in BRCA1 expression in A549 cells (p53 wild-type) but had no effect in H1299 cells (p53-null). In BEAS-2B cells, DHRS2 overexpression also resulted in BRCA1 suppression. GEPIA2 analysis showed significantly higher BRCA1 expression in tumour tissues. Genomic analysis revealed frequent BRCA1 alterations, indicating instability, whereas DHRS2 had fewer muta tions, implying a regulatory role.
Conclusion: This study demonstrates that DHRS2 modulates BRCA1 expression through a p53-dependent mechanism. Genetic alterations in BRCA1 and DHRS2 indicate their potential involvement in NSCLC tumorigenesis. Future studies should further investigate the mechanisms mediated by DHRS2 and p53 to elucidate their roles in cancer progression.
Project Number
41514
References
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70(1):7-30. google scholar
- Liang Z, Zhong Y, Meng L, Chen Y, Liu Y, Wu A, et al. HAX1 enhances the survival and metastasis of non-small cell lung cancer through the AKT/mTOR and MDM2/p53 signaling pathway. Thorac Cancer 2020;11(11):3155-67. google scholar
- Gabrielli F, Tofanelli S. Molecular and functional evolution of human DHRS2 and DHRS4 duplicated genes. Gene 2012;511(2):461-9. google scholar
- Pellegrini S, Censini S, Guidotti S, Iacopetti P, Rocchi M, Bianchi M, et al. A human short-chain dehydrogenase/reductase gene: structure, chromosomal localization, tissue expression and subcellular localization of its product. Biochim Biophys Acta 2002;1574(3):215-22. google scholar
- Li Z, Liu H, Bode A, Luo X. Emerging roles of dehydrogenase/reductase member 2 (DHRS2) in the pathology of disease. Eur J Pharmacol 2021;898:173972. google scholar
- Steffens Reinhardt L, Groen K, Newton C, Avery-Kiejda KA. The role of truncated p53 isoforms in the DNA damage response. Biochim Biophys Acta Rev Cancer 2023;1878(3):188882. google scholar
- Rosen EM, Fan S, Isaacs C. BRCA1 in hormonal carcinogenesis: basic and clinical research. Endocr Relat Cancer 2005;12(3):533-48. google scholar
- Gachechiladze M, Skarda J. The role of BRCA1 in non-small cell lung cancer. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2012;156(3):200-3. google scholar
- Zhou Y, Wang L, Ban X, Zeng T, Zhu Y, Li M, et al. DHRS2 inhibits cell growth and motility in esophageal squamous cell carcinoma. Oncogene 2018;37(8):1086-94. google scholar
- Yamada H, Arakawa Y, Saito S, Agawa M, Kano Y, Horiguchi-Yamada J. Depsipeptide-resistant KU812 cells show reversible P-glycoprotein expression, hyper-acetylated histones, and modulated gene expression profile. Leuk Res 2006;30(6):723-34. google scholar
- An Z, Bo W, Qin J, Jiang L, Jiang J. Auxiliary Diagnosis and Prognostic Value of Dehydrogenase/Reductase 2 (DHRS2) in Various Tumors. Iran J Public Health 2023;52(6):1150-60. google scholar
- Han Y, Song C, Wang J, Tang H, Peng Z, Lu S. HOXA13 contributes to gastric carcinogenesis through DHRS2 interacting with MDM2 and confers 5-FU resistance by a p53-dependent pathway. Mol Carcinog 2018;57(6):722-34. google scholar
- Jiang J, Yang ES, Jiang G, Nowsheen S, Wang H, Wang T, et al. p53-dependent BRCA1 nuclear export controls cellular susceptibility to DNA damage. Cancer Res 2011;71(16):5546-57. google scholar
Details
| Primary Language | English |
|---|---|
| Subjects | Clinical Sciences (Other) |
| Journal Section | Research Article |
| Authors | |
| Project Number | 41514 |
| Publication Date | June 30, 2025 |
| Submission Date | February 18, 2025 |
| Acceptance Date | March 26, 2025 |
| Published in Issue | Year 2025 |