THE CLINICAL SIGNIFICANCE OF SOX9 GENE IN DIFFERENT CANCER TYPES:AN IN-SILICO ANALYSIS

Yıl 2024, Cilt: 13 Sayı: 2, 63 - 73, 30.07.2024

Ethem Serhat Yavaş , Sedef Hande Aktaş , Göksel Efendioğlu , Dilara Fatma Akın

https://doi.org/10.18036/estubtdc.1312624

Öz

One of the common problems in the pathogenesis of human cancer is characterized as the dysregulation of transcription factors. SOX9 is important as it is one of the critical transcription factors involved in various diseases, including cancer. In addition, SOX9 also acts as a proto-oncogene or tumor suppressor gene, depending on the cancer type. In this study, we aimed to reveal the mutation and expression status of the SOX9 transcription factor and the effect of this gene on the survival of patients with different cancer groups. The data sets for expression analysis and overall survival analysis were performed by the GEPIA database. Analysis of the mutation profile was performed by the cBio database. As a result, SOX9 gene expressions were significantly elevated in BLCA, CESC, CHOL, COAD, ESCA, GBM, KIRP, LGG, LIHC, LUSC, OV, PAAD, READ, SKCM, STAD, TGCT, THYM, UCEC and UCS in cancer tissues compared to that in normal tissues (p<0.05). According to overall survival (OS) analysis; the SOX9 gene has a significant relationship with OS in ACC, CESC, KIRC, LGG, and THYM (ACC p:0.0079, CESC p:0.038, KIRC p:0.051, LGG p:0.00055, THYM p:0.031). A total of 170 mutations in SOX9 were determined according to mutation analysis. Seventy-six of them were detected as driver mutations. The analysis shows that SOX9 expression status has a different effect in each cancer type, and although there is no significant mutation in the SOX9 gene in ACC cancer type, high expression of this gene is important for survival. Therefore, it is of great importance to analyze the epigenetic changes in the SOX9 gene in ACC cancer type. The analysis also indicates that the SOX9 gene is discriminatory for the survival of adrenocortical carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, renal clear cell carcinoma, brain low-grade glioma and thymoma cancer types.

Anahtar Kelimeler

SOX9, Transcription factor, Tumorigenesis, Mutation, Gene expression

THE CLINICAL SIGNIFICANCE OF SOX9 GENE IN DIFFERENT CANCER TYPES:AN IN-SILICO ANALYSIS

Öz

İnsan kanserinin patogenezindeki yaygın sorunlardan biri, transkripsiyon faktörlerinin düzensizliği olarak karakterize edilir. SOX9, kanser de dahil olmak üzere çeşitli hastalıklarda rol oynayan kritik transkripsiyon faktörlerinden biri olduğu için önemlidir. Ayrıca SOX9, kanser türüne bağlı olarak bir proto-onkogen veya tümör baskılayıcı gen olarak da görev yapar. Bu çalışmada, SOX9 transkripsiyon faktörünün mutasyon ve ekspresyon durumunu ve bu genin farklı kanser türüne sahip hasta gruplarında sağ kalım üzerindeki etkisini ortaya koymayı amaçladık. Ekspresyon analizi ve genel sağ kalım analizi için veri setleri GEPIA veri tabanı üzerinden gerçekleştirilmiştir. Mutasyon profilinin analizi cBio veri tabanı üzerinden gerçekleştirilmiştir. Sonuç olarak, SOX9 gen ekspresyonları BLCA, CESC, CHOL, COAD, ESCA, GBM, KIRP, LGG, LIHC, LUSC, OV, PAAD, READ, SKCM, STAD, TGCT, THYM, UCEC ve UCS kanser dokularında normal dokulardakine kıyasla önemli ölçüde artmıştır (p<0.05). Genel sağ kalım (OS) analizine göre; SOX9 geni ACC, CESC, KIRC, LGG ve THYM'de OS ile anlamlı bir ilişkiye sahiptir (ACC p:0.0079, CESC p:0.038, KIRC p:0.051, LGG p:0.00055, THYM p:0.031). Mutasyon analizine göre SOX9'da toplam 170 mutasyon tespit edilmiştir. Bunlardan yetmiş altısı sürücü mutasyon olarak tespit edilmiştir. Gerçekleştirilen analizler SOX9 ekspresyon durumunun her kanser türünde farklı etkiye sahip olduğunu, ACC kanser türünde SOX9 geninde önemli bir mutasyon bulunmamasına rağmen bu genin yüksek ekspresyonunun sağkalım açısından önemli olduğunu göstermektedir. Bu nedenle, ACC kanser türünde SOX9 genindeki epigenetik değişikliklerin de analiz edilmesi büyük önem taşımaktadır. Analiz ayrıca SOX9 geninin adrenokortikal karsinom, servikal skuamöz hücreli karsinom ve endoservikal adenokarsinom, böbrek renal berrak hücreli karsinom, beyin düşük dereceli gliom ve timoma kanser türlerinin sağkalımı için ayırt edici olduğuna işaret etmektedir.

Anahtar Kelimeler

SOX9, Transkripsiyon faktörü, gen ifadesi, mutasyon, sağkalım

Kaynakça

• [1] Kumar P, Mistri TK. Transcription factors in SOX family: Potent regulators for cancer initiation and development in the human body. Semin Cancer Biol 2020; 67: 105–113.
• [2] Lambert M, Jambon S, Depauw S, David-Cordonnier MH. Targeting Transcription Factors for Cancer Treatment. Molecules 2018; 23: 1479.
• [3] Hawkins LJ, Al-attar R, Storey KB. Transcriptional regulation of metabolism in disease: From transcription factors to epigenetics. PeerJ 2018; 6: e5062.
• [4] Bushweller JH. Targeting transcription factors in cancer—From undruggable to reality. Nat Rev Cancer 2019; 19: 611–624.
• [5] Grimm D, Bauer J, Wise P, Krüger M, Simonsen U, Wehland M, Infanger M, Corydon TJ. The role of SOX family members in solid tumours and metastasis. Semin Cancer Biol 2020; 67:122-153. Academic Press.
• [6] Grimm D, Bauer J, Wise P, Krüger M, Simonsen U, Wehland M, Infanger M, Corydon, TJ. The role of SOX family members in solid tumours and metastasis. Semin. Cancer Biol 2020; 67: 122–153.
• [7] McDowall S, Argentaro A, Ranganathan S, Weller P, Mertin S, Mansour S, Tolmie J, Harley V. Functional and Structural Studies of Wild Type SOX9 and Mutations Causing Campomelic Dysplasia. J. Biol. Chem 1999; 274: 24023–24030.
• [8] Cheng PF, Shakhova O, Widmer DS, Eichhoff OM, Zingg D, Frommel SC, Belloni B, Raaijmakers MI, Goldinger SM, Santoro R. et al. Methylation-dependent SOX9 expression mediates invasion in human melanoma cells and is a negative prognostic factor in advanced melanoma. Genome Biol 2015; 16: 42.
• [9] Richtig G, Aigelsreiter A, Schwarzenbacher D, Ress AL, Adiprasito JB, Stiegelbauer V, Hoefler G, Schauer S, Kiesslich T, Kornprat P, Winder T, Eisner F, Gerger A, Stoeger H, Stauber R, Lackner C, Pichler M. SOX9 is a proliferation and stem cell factor in hepatocellular carcinoma and possess widespread prognostic significance in different cancer types. PloS one 2017; 12: e0187814.
• [10] Yang X, Liang R, Liu C, Liu JA, Cheung MPL, Liu X, Man OY, Guan XY, Lung HL, Cheung M. SOX9 is a dose-dependent metastatic fate determinant in melanoma. J. Exp. Clin. Cancer Res 2019; 38: 17.
• [11] Sumita Y, Yamazaki M, Maruyama S, Abé T, Cheng J, Takagi R, Tanuma J. Cytoplasmic expression of SOX9 as a poor prognostic factor for oral squamous cell carcinoma. Oncol. Rep 2018; 40: 2487-2496.
• [12] Liu C, Liu L, Chen X, Cheng J, Zhang H, Shen J, Shan J, Xu Y, Yang Z, Lai M, Qian C. Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma: Hepatobiliary Malignancies. Hepatology 2016; 64: 117–129.
• [13] Panda M, Tripathi SK, Biswal BK. SOX9: An emerging driving factor from cancer progression to drug resistance. Biochim Biophys Acta Rev Cancer 2021; 1875: 188517.
• [14] Zhang S, Che D, Yang F, Chi C, Meng H, Shen J, Qi L, Liu F, Lv L, Li Y et al. Tumor-associated macrophages promote tumor metastasis via the TGF-β/SOX9 axis in non-small cell lung cancer. Oncotarget 2017; 8: 99801–99815.
• [15] Huang JQ, Wei FK, Xu XL, Ye SX, Song JW, Ding PK, Zhu J, Li HF, Luo XP, Gong H, SOX9 drives the epithelial–mesenchymal transition in non-small-cell lung cancer through the Wnt/β-catenin pathway. J. Transl. Med 2019; 17: 143.
• [19] Xiao S, Li Y, Pan Q, Ye M, He S, Tian Q & Xue M. MiR‐34c/SOX9 axis regulates the chemoresistance of ovarian cancer cell to cisplatin‐based chemotherapy. J. Cell. Biochem 2019; 120: 2940–2953.
• [16] Xiao S, Li Y, Pan Q, Ye M, He S, Tian Q & Xue M. MiR‐34c/SOX9 axis regulates the chemoresistance of ovarian cancer cell to cisplatin‐based chemotherapy. J. Cell. Biochem 2019; 120: 2940–2953.
• [17] Higashihara T, Yoshitomi H, Nakata Y, Kagawa S, Takano S, Shimizu H, Kato A, Furukawa K, Ohtsuka M, Miyazaki M. Sex Determining Region Y Box 9 Induces Chemoresistance in Pancreatic Cancer Cells by Induction of Putative Cancer Stem Cell Characteristics and Its High Expression Predicts Poor Prognosis. Pancreas 2017; 46: 1296–1304.
• [18] Zhu H, Tang J, Tang M, Cai H. Upregulation of SOX9 in osteosarcoma and its association with tumor progression and patients’ prognosis. Diagn. Pathol 2013; 8: 183.
• [19] Wu JH, Liang XA, Wu YM, Li FS, Dai YM. Identification of DNA methylation of SOX9 in cervical cancer using methylated-CpG island recovery assay. Oncol rep 2013; 29:125-32.
• [20] Zhao J, Li H, Yuan M. EGR1 promotes stemness and predicts a poor outcome of uterine cervical cancer by inducing SOX9 expression. Genes Genom 2021; 43:459-70.
• [21] Wang HY, Lian P, Zheng PS. SOX9, a potential tumor suppressor in cervical cancer, transactivates p21WAF1/CIP1 and suppresses cervical tumor growth. Oncotarget 2015; 6:20711.
• [22] Ettaieb M, Kerkhofs T, van Engeland M, Haak H. Past, present and future of epigenetics in adrenocortical carcinoma. Cancers 2020; 12: 1218.
• [23] Chen H, He Y, Wen X, Shao S, Liu Y & Wang J. SOX9: Advances in Gynecological Malignancies. Front. Oncol 2021; 11: 768264.
• [24] Belo J, Krishnamurthy M, Oakie A & Wang R. The Role of SOX9 Transcription Factor in Pancreatic and Duodenal Development. Stem Cells Dev 2013; 22: 2935–2943.