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Open Access 01-12-2021 | Kidney Cancer | Research

DNA methylation of tumor associated calcium signal transducer 2 (TACSTD2) loci shows association with clinically aggressive renal cell cancers

Authors: Olga Katzendorn, Inga Peters, Natalia Dubrowinskaja, Hossein Tezval, Pouriya Faraj Tabrizi, Christoph A. von Klot, Jörg Hennenlotter, Marcel Lafos, Markus A. Kuczyk, Jürgen Serth

Published in: BMC Cancer | Issue 1/2021

Abstract

Background

DNA methylation is frequently observed in the development and progression of many human tumors as well as renal cell cancer (RCC). Tumor Associated Calcium Signal Transducer 2 (TACSTD2) participates in cell cycle progression through MAPK signalling pathway activation. Moreover, tumor-specific hypermethylation and association with aggressive cancer characteristics has been found for lung adenocarcinoma, hepatocellular carcinoma and cholangiocarcinoma. Whether TACSTD2 is tumor specifically hypermethylated in RCC or shows association of methylation with adverse clinicopathological parameters and survival of patients has not been investigated at yet.

Methods

Quantitative methylation-specific PCR (qMSP) analysis of a locus in the intron 1 region of TACSTD2 gene was carried out in a cross-sectional study of 127 paired RCC and normal samples. In silico analysis of TACSTD2 methylation in the TCGA Kidney Renal Clear Cell Carcinoma (KIRC) dataset of 280 patients served as validation cohort. Statistical analyses were carried out using the two-sided paired t-test for matched tumor and normal sample comparisons, logistic regression for subgroup comparisons, Cox regression for analysis of recurrence free survival (RFS) and Pearson correlation analysis for correlation of TACSTD2 methylation and TACSTD2 mRNA in KIRC data.

Results

Higher methylation levels in RCC were significantly associated with advanced disease (p < 0.001), high tumor stage (p = 0.003), tumor differentiation (p = 0.033) and presence of lymph node (p = 0.021) or distant metastases (p = 0.008). TACSTD2 hypermethylation was associated with a shorter RFS of patients and demonstrate statistical independency from clinical parameters as state of metastasis, tumor stage, grade and state of advanced disease. In silico validation using TCGA KIRC data also demonstrated association of TACSTD2 loci with adverse clinicopathology and shortened RFS of patients. In addition, in silico analyses of TCGA KIRC data showed an inverse correlation between DNA methylation levels of TACSTD2 and mRNA expression.

Conclusions

Our results suggest an association between TACSTD2 methylation and disease progression and clinical course of RCC.

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Rossi SH, Klatte T, Usher-Smith J, Stewart GD. Epidemiology and screening for renal cancer. World J Urol. 2018;36(9):1341–53. https://doi.org/10.1007/s00345-018-2286-7.CrossRefPubMedPubMedCentral

Joosten SC, Deckers IA, Aarts MJ, Hoeben A, van Roermund JG, Smits KM, et al. Prognostic DNA methylation markers for renal cell carcinoma: a systematic review. Epigenomics. 2017;9(9):1243–57. https://doi.org/10.2217/epi-2017-0040.CrossRefPubMed

Ricketts CJ, De Cubas AA, Fan H, Smith CC, Lang M, Reznik E, et al. The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma. Cell Rep. 2018;23(1):313–326.e5.CrossRef

Audenet F, Yates DR, Cancel-Tassin G, Cussenot O, Rouprêt M. Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine. BJU Int. 2012;109(12):1864–70. https://doi.org/10.1111/j.1464-410X.2011.10661.x.CrossRefPubMed

Cheng L, Zhang S, MacLennan GT, Lopez-Beltran A, Montironi R. Molecular and cytogenetic insights into the pathogenesis, classification, differential diagnosis, and prognosis of renal epithelial neoplasms. Hum Pathol. 2009;40(1):10–29. https://doi.org/10.1016/j.humpath.2008.09.009.CrossRefPubMed

Morris MR, Ricketts C, Gentle D, Abdulrahman M, Clarke N, Brown M, et al. Identification of candidate tumour suppressor genes frequently methylated in renal cell carcinoma. Oncogene. 2010;29(14):2104–17. https://doi.org/10.1038/onc.2009.493.CrossRefPubMedPubMedCentral

Morris MR, Ricketts CJ, Gentle D, McRonald F, Carli N, Khalili H, et al. Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma. Oncogene. 2011;30(12):1390–401. https://doi.org/10.1038/onc.2010.525.CrossRefPubMed

Waki T, Tamura G, Sato M, Motoyama T. Age-related methylation of tumor suppressor and tumor-related genes: an analysis of autopsy samples. Oncogene. 2003;22(26):4128–33. https://doi.org/10.1038/sj.onc.1206651.CrossRefPubMed

Costa VL, Henrique R, Ribeiro FR, Pinto M, Oliveira J, Lobo F, et al. Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors. BMC Cancer. 2007;7(1):133. https://doi.org/10.1186/1471-2407-7-133.CrossRefPubMedPubMedCentral

10.

Atschekzei F, Hennenlotter J, Jänisch S, Großhennig A, Tränkenschuh W, Waalkes S, et al. SFRP1 CpG island methylation locus is associated with renal cell cancer susceptibility and disease recurrence. Epigenetics. 2012;7(5):447–57. https://doi.org/10.4161/epi.19614.CrossRefPubMed

11.

Gebauer K, Peters I, Dubrowinskaja N, Hennenlotter J, Abbas M, Scherer R, et al. Hsa-mir-124-3 CpG island methylation is associated with advanced tumours and disease recurrence of patients with clear cell renal cell carcinoma. Br J Cancer. 2013;108(1):131–8. https://doi.org/10.1038/bjc.2012.537.CrossRefPubMedPubMedCentral

12.

Peters I, Gebauer K, Dubrowinskaja N, Atschekzei F, Kramer MW, Hennenlotter J, et al. GATA5 CpG island hypermethylation is an independent predictor for poor clinical outcome in renal cell carcinoma. Oncol Rep. 2014;31(4):1523–30. https://doi.org/10.3892/or.2014.3030.CrossRefPubMedPubMedCentral

13.

Tezval H, Dubrowinskaja N, Peters I, Reese C, Serth K, Atschekzei F, et al. Tumor specific epigenetic silencing of Corticotropin releasing hormone -binding protein in renal cell carcinoma: Association of Hypermethylation and Metastasis. PLoS One. 2016;11(10):e0163873. https://doi.org/10.1371/journal.pone.0163873.CrossRefPubMedPubMedCentral

14.

Peters I, Dubrowinskaja N, Hennenlotter J, Antonopoulos W, Von Klot C, Tezval H, et al. DNA methylation of neural EGFL like 1 (NELL1) is associated with advanced disease and the metastatic state of renal cell cancer patients. Oncol Rep. 2018;40(6):3861–8. https://doi.org/10.3892/or.2018.6732.CrossRefPubMed

15.

Serth J, Peters I, Dubrowinskaja N, Reese C, Albrecht K, Klintschar M, et al. Age-, tumor-, and metastatic tissue-associated DNA hypermethylation of a T-box brain 1 locus in human kidney tissue. Clin Epigenetics. 2020;12(1):33. https://doi.org/10.1186/s13148-020-0823-x.CrossRefPubMedPubMedCentral

16.

Dubrowinskaja N, Gebauer K, Peters I, Hennenlotter J, Abbas M, Scherer R, et al. Neurofilament heavy polypeptide CpG island methylation associates with prognosis of renal cell carcinoma and prediction of antivascular endothelial growth factor therapy response. Cancer Med. 2014;3(2):300–9. https://doi.org/10.1002/cam4.181.CrossRefPubMedPubMedCentral

17.

Peters I, Dubrowinskaja N, Abbas M, Seidel C, Kogosov M, Scherer R, et al. DNA methylation biomarkers predict progression-free and overall survival of metastatic renal cell Cancer (mRCC) treated with Antiangiogenic therapies. PLoS One. 2014;9(3):e91440. https://doi.org/10.1371/journal.pone.0091440.CrossRefPubMedPubMedCentral

18.

McDougall ARA, Tolcos M, Hooper SB, Cole TJ, Wallace MJ. Trop2: from development to disease. Dev Dyn. 2015 Feb;244(2):99–109. https://doi.org/10.1002/dvdy.24242.CrossRefPubMed

19.

Zhao W, Zhu H, Zhang S, Yong H, Wang W, Zhou Y, et al. Trop2 is overexpressed in gastric cancer and predicts poor prognosis. Oncotarget. 2016;7(5):6136–45. https://doi.org/10.18632/oncotarget.6733.CrossRefPubMed

20.

Cubas R, Zhang S, Li M, Chen C, Yao Q. Trop2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway. Mol Cancer. 2010;9(1):253. https://doi.org/10.1186/1476-4598-9-253.CrossRefPubMedPubMedCentral

21.

Salinas-Sánchez AS, Giménez-Bachs JM, Serrano-Oviedo L, Nam Cha S, Sánchez-Prieto R. Papel de las proteínas quinasas activadas por mitógenos (MAPK) en el carcinoma de células renales esporádico. Actas Urol Esp. 2012 Feb;36(2):99–103. https://doi.org/10.1016/j.acuro.2011.07.013.CrossRefPubMed

22.

Muhlmann G, Spizzo G, Gostner J, Zitt M, Maier H, Moser P, et al. TROP2 expression as prognostic marker for gastric carcinoma. J Clin Pathol. 2009;62(2):152–8. https://doi.org/10.1136/jcp.2008.060590.CrossRefPubMed

23.

Stepan LP, Trueblood ES, Hale K, Babcook J, Borges L, Sutherland CL. Expression of trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target. J Histochem Cytochem. 2011;59(7):701–10. https://doi.org/10.1369/0022155411410430.CrossRefPubMedPubMedCentral

24.

Trerotola M, Cantanelli P, Guerra E, Tripaldi R, Aloisi AL, Bonasera V, et al. Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene. 2013;32(2):222–33. https://doi.org/10.1038/onc.2012.36.CrossRefPubMed

25.

Avellini C, Licini C, Lazzarini R, Gesuita R, Guerra E, Tossetta G, et al. The trophoblast cell surface antigen 2 and miR-125b axis in urothelial bladder cancer. Oncotarget. 2017;8(35):58642–53. https://doi.org/10.18632/oncotarget.17407.CrossRefPubMedPubMedCentral

26.

Fang YJ, Lu ZH, Wang GQ, Pan ZZ, Zhou ZW, Yun JP, et al. Elevated expressions of MMP7, TROP2, and survivin are associated with survival, disease recurrence, and liver metastasis of colon cancer. Int J Color Dis. 2009;24(8):875–84. https://doi.org/10.1007/s00384-009-0725-z.CrossRef

27.

Bignotti E, Todeschini P, Calza S, Falchetti M, Ravanini M, Tassi RA, et al. Trop-2 overexpression as an independent marker for poor overall survival in ovarian carcinoma patients. Eur J Cancer. 2010;46(5):944–53. https://doi.org/10.1016/j.ejca.2009.12.019.CrossRefPubMed

28.

Liu T, Liu Y, Bao X, Tian J, Liu Y, Yang X. Overexpression of TROP2 predicts poor prognosis of patients with cervical Cancer and promotes the proliferation and invasion of cervical Cancer cells by regulating ERK signaling pathway. PLoS One. 2013;8(9):e75864. https://doi.org/10.1371/journal.pone.0075864.CrossRefPubMedPubMedCentral

29.

Zeng P, Chen M-B, Zhou L-N, Tang M, Liu C-Y, Lu P-H. Impact of TROP2 expression on prognosis in solid tumors: a systematic review and meta-analysis. Sci Rep. 2016;6(1):33658. https://doi.org/10.1038/srep33658.CrossRefPubMedPubMedCentral

30.

Shvartsur A, Bonavid B. Trop2 and its overexpression in cancers: regulation and clinical/ therapeutic implications. Genes Cancer. 2014;6(3-4):84–105. https://doi.org/10.18632/genesandcancer.40.CrossRef

31.

Chen G, Gharib TG, Huang C-C, Thomas DG, Shedden KA, Taylor JMG, et al. Proteomic analysis of lung adenocarcinoma. Clin Cancer Res. 2002 Jul 1;8(7):2298–305.PubMed

32.

Wang J, Zhang K, Grabowska D, Li A, Dong Y, Day R, et al. Loss of Trop2 promotes carcinogenesis and features of epithelial to Mesenchymal transition in squamous cell carcinoma. Mol Cancer Res. 2011;9(12):1686–95. https://doi.org/10.1158/1541-7786.MCR-11-0241.CrossRefPubMedPubMedCentral

33.

Sin STK, Li Y, Liu M, Yuan Y-F, Ma S, Guan X-Y. Down-regulation of TROP-2 predicts poor prognosis of hepatocellular carcinoma patients. Hepatol Commun. 2018;2(11):1408–14. https://doi.org/10.1002/hep4.1242.CrossRefPubMedPubMedCentral

34.

Lin J-C, Wu Y-Y, Wu J-Y, Lin T-C, Wu C-T, Chang Y-L, et al. TROP2 is epigenetically inactivated and modulates IGF-1R signalling in lung adenocarcinoma: epigenetic inactivation of TROP2 promotes lung tumours. EMBO Mol Med. 2012;4(6):472–85. https://doi.org/10.1002/emmm.201200222.CrossRefPubMedPubMedCentral

35.

Sawanyawisuth K, Tantapotinan N, Wongkham C, Riggins GJ, Kraiklang R, Wongkham S, et al. Suppression of trophoblast cell surface antigen 2 enhances proliferation and migration in liver fluke-associated cholangiocarcinoma. Ann Hepatol. 2016;15(1):71–81. https://doi.org/10.5604/16652681.1184223.CrossRefPubMed

36.

Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 2006;125(2):301–13. https://doi.org/10.1016/j.cell.2006.02.043.CrossRefPubMedPubMedCentral

37.

Waalkes S, Atschekzei F, Kramer MW, Hennenlotter J, Vetter G, Becker JU, et al. Fibronectin 1 mRNA expression correlates with advanced disease in renal cancer. BMC Cancer. 2010;10(1):503. https://doi.org/10.1186/1471-2407-10-503.CrossRefPubMedPubMedCentral

38.

Weisenberger DJ. Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res. 2005;33(21):6823–36. https://doi.org/10.1093/nar/gki987.CrossRefPubMedPubMedCentral

39.

Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499(7456):43–9. https://doi.org/10.1038/nature12222.CrossRef

40.

Team RDC. R: a language and environment for statistical computing. 2011.

41.

Lausen B, Schumacher M. Maximally selected rank statistics. Biometrics. 1992;48(1):73–85. https://doi.org/10.2307/2532740.CrossRef

42.

The Human Protein Atlas. https://www.proteinatlas.org/ENSG00000184292-TACSTD2/pathology/renal+cancer. Accessed 13.05.2020.

43.

Kim T-Y, Zhong S, Fields CR, Kim JH, Robertson KD. Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant Glioma. Cancer Res. 2006;66(15):7490–501. https://doi.org/10.1158/0008-5472.CAN-05-4552.CrossRefPubMed

44.

Lv C, Bai Z, Liu Z, Luo P, Zhang J. MicroRNA-495 suppresses human renal cell carcinoma malignancy by targeting SATB. Am J Transl Res. 2015;7(10):1992–9.PubMedPubMedCentral

45.

Chen Y, Luo D, Tian W, Li Z, Zhang X. Demethylation of miR-495 inhibits cell proliferation, migration and promotes apoptosis by targeting STAT-3 in breast cancer. Oncol Rep. 2017;37(6):3581–9. https://doi.org/10.3892/or.2017.5621.CrossRefPubMed

46.

Nakanishi H, Taccioli C, Palatini J, Fernandez-Cymering C, Cui R, Kim T, et al. Loss of miR-125b-1 contributes to head and neck cancer development by dysregulating TACSTD2 and MAPK pathway. Oncogene. 2014;33(6):702–12. https://doi.org/10.1038/onc.2013.13.CrossRefPubMed

47.

Jin L, Zhang Z, Li Y, He T, Hu J, Liu J, et al. miR-125b is associated with renal cell carcinoma cell migration, invasion and apoptosis. Oncol Lett. 2017;13(6):4512–20. https://doi.org/10.3892/ol.2017.5985.CrossRefPubMedPubMedCentral

48.

Tracz AF, Szczylik C, Porta C, Czarnecka AM. Insulin-like growth factor-1 signaling in renal cell carcinoma. BMC Cancer. 2016;16(1):453. https://doi.org/10.1186/s12885-016-2437-4.CrossRefPubMedPubMedCentral

Title: DNA methylation of tumor associated calcium signal transducer 2 (TACSTD2) loci shows association with clinically aggressive renal cell cancers
Authors: Olga Katzendorn
Inga Peters
Natalia Dubrowinskaja
Hossein Tezval
Pouriya Faraj Tabrizi
Christoph A. von Klot
Jörg Hennenlotter
Marcel Lafos
Markus A. Kuczyk
Jürgen Serth
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Kidney Cancer
Metastasis
Kidney Cancer
Kidney Cancer
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08172-1

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Abstract

Background

Methods

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Conclusions

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