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Cytoplasmic expression of Twist1, an EMT-related transcription factor, is associated with higher grades renal cell carcinomas and worse progression-free survival in clear cell renal cell carcinoma

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Abstract

Twist1 is a key transcription factor, which confers tumor cells with cancer stem cell (CSC)-like characteristics and enhances epithelial–mesenchymal transition in pathological conditions including tumor malignancy and metastasis. This study aimed to evaluate the expression patterns and clinical significance of Twist1 in renal cell carcinoma (RCC). The cytoplasmic and nuclear expression of Twist1 were examined in 252 well-defined renal tumor tissues, including 173 (68.7%) clear cell renal cell carcinomas (ccRCC), 45 (17.9%) papillary renal cell carcinomas (pRCC) and 34 (13.5%) chromophobe renal cell carcinoma, by immunohistochemistry on a tissue microarray. The association between expression of this marker and clinicopathologic parameters and survival outcomes were then analyzed. Twist1 was mainly localized to the cytoplasm of tumor cells (98.8%). Increased cytoplasmic expression of Twist1 was associated with higher grade tumors (P = 0.045), renal vein invasion (P = 0.031) and microvascular invasion (P = 0.044) in RCC. It was positively correlated with higher grade tumors (P = 0.026), shorter progression-free survival time (P = 0.027) in patients with ccRCC, and also with higher stage in pRCC patients (P = 0.036). Significantly higher cytoplasmic expression levels of Twist1 were found in ccRCC and pRCC subtypes, due to their more aggressive tumor behavior. Increased cytoplasmic expression of Twist1 had a critical role in worse prognosis in ccRCC. These findings suggest that cytoplasmic, rather than nuclear expression of Twist1 can be considered as a prognostic and therapeutic marker for targeted therapy of RCC, especially for ccRCC patients.

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References

  1. Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev. 2008;34(3):193–205.

    Article  PubMed  Google Scholar 

  2. Arai E, Kanai Y. Genetic and epigenetic alterations during renal carcinogenesis. Int J Clin Exp Pathol. 2010;4(1):58–73.

    PubMed  PubMed Central  Google Scholar 

  3. Rini BI, Rathmell WK, Godley P. Renal cell carcinoma. Curr Opin Oncol. 2008;20(3):300–6.

    Article  PubMed  Google Scholar 

  4. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 1996;335(12):865–75.

    Article  CAS  PubMed  Google Scholar 

  5. Slaby O, Redova M, Poprach A, Nekvindova J, Iliev R, Radova L, et al. Identification of MicroRNAs associated with early relapse after nephrectomy in renal cell carcinoma patients. Genes Chromosom Cancer. 2012;51(7):707–16.

    Article  CAS  PubMed  Google Scholar 

  6. Kapur P, Peña-Llopis S, Christie A, Zhrebker L, Pavía-Jiménez A, Rathmell WK, et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol. 2013;14(2):159–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265–73.

    Article  CAS  PubMed  Google Scholar 

  8. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.

    Article  CAS  PubMed  Google Scholar 

  9. Guarino M. Epithelial–mesenchymal transition and tumour invasion. Int J Biochem Cell Biol. 2007;39(12):2153–60.

    Article  CAS  PubMed  Google Scholar 

  10. Mikami S, Oya M, Mizuno R, Kosaka T, Katsube K-I, Okada Y. Invasion and metastasis of renal cell carcinoma. Med Mol Morphol. 2014;47(2):63–7.

    Article  CAS  PubMed  Google Scholar 

  11. Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S, et al. Epithelial–mesenchymal transition in cancer development and its clinical significance. Cancer Sci. 2010;101(2):293–9.

    Article  CAS  PubMed  Google Scholar 

  12. Roussos ET, Keckesova Z, Haley JD, Epstein DM, Weinberg RA, Condeelis JS. AACR special conference on epithelial-mesenchymal transition and cancer progression and treatment. AACR; 2010.

  13. Hoek K, Rimm DL, Williams KR, Zhao H, Ariyan S, Lin A, et al. Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas. Cancer Res. 2004;64(15):5270–82.

    Article  CAS  PubMed  Google Scholar 

  14. Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, et al. Twist is a potential oncogene that inhibits apoptosis. Genes Dev. 1999;13(17):2207–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kwok WK, Ling M-T, Lee T-W, Lau TC, Zhou C, Zhang X, et al. Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Res. 2005;65(12):5153–62.

    Article  CAS  PubMed  Google Scholar 

  16. Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, et al. Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol. 2002;161(5):1881–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. van Doorn RDR, Vermeer MH, Out-Luiting JJ, van der Raaij-Helmer EM, Willemze R, Tensen CP. Aberrant expression of the tyrosine kinase receptor EphA4 and the transcription factor twist in Sezary syndrome identified by gene expression analysis. Cancer Res. 2004;64:5578–86.

    Article  PubMed  Google Scholar 

  18. Lei P, Ding D, Xie J, Wang L, Liao Q, Hu Y. Expression profile of Twist, vascular endothelial growth factor and CD34 in patients with different phases of osteosarcoma. Oncol Lett. 2015;10(1):417–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hosono S, Kajiyama H, Terauchi M, Shibata K, Ino K, Nawa A, et al. Expression of Twist increases the risk for recurrence and for poor survival in epithelial ovarian carcinoma patients. Br J Cancer. 2007;96(2):314–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117(7):927–39.

    Article  CAS  PubMed  Google Scholar 

  21. Ohba K, Miyata Y, Matsuo T, Asai A, Mitsunari K, Shida Y, et al. High expression of Twist is associated with tumor aggressiveness and poor prognosis in patients with renal cell carcinoma. Int J Clin Exp Pathol. 2014;7(6):3158–65.

    PubMed  PubMed Central  Google Scholar 

  22. Harada KI, Miyake H, Kusuda Y, Fujisawa M. Expression of epithelial–mesenchymal transition markers in renal cell carcinoma: impact on prognostic outcomes in patients undergoing radical nephrectomy. BJU Int. 2012;110(11c):E1131–7.

    Article  CAS  PubMed  Google Scholar 

  23. Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D et al. (2013) The International Society of Urological Pathology (ISUP) vancouver classification of renal neoplasia. Amer J Surg Pathol 37(10):1469–1489

    Article  Google Scholar 

  24. Rasti A, Abolhasani M, Zanjani LS, Asgari M, Mehrazma M, Madjd Z. Reduced expression of CXCR4, a novel renal cancer stem cell marker, is associated with high-grade renal cell carcinoma. J Cancer Res Clin Oncol. 2017;143(1):95–104.

    Article  CAS  PubMed  Google Scholar 

  25. Roudi R, Korourian A, Shariftabrizi A, Madjd Z. Differential expression of cancer stem cell markers ALDH1 and CD133 in various lung cancer subtypes. Cancer Invest. 2015;33(7):294–302.

    Article  PubMed  Google Scholar 

  26. Erfani E, Roudi R, Rakhshan A, Sabet M, Shariftabrizi A, Madjd Z. Comparative expression analysis of putative cancer stem cell markers CD44 and ALDH1A1 in various skin cancer subtypes. Int J Biol Mark. 2015;31(1):e53–61.

    Article  Google Scholar 

  27. Madjd Z, Ramezani B, Molanae S, Asadi-Lari M. High expression of stem cell marker ALDH1 is associated with reduced BRCA1 in invasive breast carcinomas. Asian Pac J Cancer Prev. 2012;13(6):2973–8.

    Article  PubMed  Google Scholar 

  28. Mohsenzadegan M, Madjd Z, Asgari M, Abolhasani M, Shekarabi M, Taeb J, et al. Reduced expression of NGEP is associated with high-grade prostate cancers: a tissue microarray analysis. Cancer Immunol Immunother. 2013;62(10):1609–18.

    Article  CAS  PubMed  Google Scholar 

  29. McCarty K Jr, Miller L, Cox E, Konrath J, McCarty K Sr. Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med. 1985;109(8):716–21.

    PubMed  Google Scholar 

  30. Turun S, Banghua L, Zheng S, Wei Q (2012) Is tumor size a reliable predictor of histopathological characteristics of renal cell carcinoma? Urol Annals 4(1):24

    Article  Google Scholar 

  31. Sountoulides P, Metaxa L, Cindolo L. Atypical presentations and rare metastatic sites of renal cell carcinoma: a review of case reports. J Med Case Rep. 2011;5(1):429.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–24.

    Article  CAS  PubMed  Google Scholar 

  33. Davis FM, Stewart TA, Thompson EW, Monteith GR. Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol Sci. 2014;35(9):479–88.

    Article  CAS  PubMed  Google Scholar 

  34. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29(34):4741–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ansieau S, Bastid J, Doreau A, Morel A-P, Bouchet BP, Thomas C, et al. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell. 2008;14(1):79–89.

    Article  CAS  PubMed  Google Scholar 

  36. Wushou A, Hou J, Zhao Y-J, Shao Z-M. Twist-1 up-regulation in carcinoma correlates to poor survival. Int J Mol Sci. 2014;15(12):21621–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Singh S, Mak IW, Handa D, Ghert M. The role of TWIST in angiogenesis and cell migration in giant cell tumor of bone. Ad Biol. 2014;2014.

  38. Pardis S, Zare R, Jaafari-Ashkavandi Z, Javad Ashraf M, Khademi B. Twist expression in pleomorphic adenoma, adenoid cystic carcinoma and mucoepidermoid carcinoma of salivary glands. Turk J Pathol. 2016;32(1):15–21.

    CAS  Google Scholar 

  39. Yuen HF, Chua CW, Chan YP, Wong YC, Wang X, Chan KW. Significance of TWIST and E-cadherin expression in the metastatic progression of prostatic cancer. Histopathology. 2007;50(5):648–58.

    Article  PubMed  Google Scholar 

  40. Harb O, Hegazy A, Ali M, Haggag R. Prognostic implication of MYb-like, swirm and Mpn domain-containing protein-1 and Twist-1 in renal cell carcinoma. J Interdiscip Histopathol. 2016;4(1):1–8.

    Article  Google Scholar 

  41. Lang H, Lindner V, Saussine C, Havel D, et al. Microscopic venous invasion: a prognostic factor in renal cell carcinoma. Eur Urol. 2000;38(5):600–5.

    Article  CAS  PubMed  Google Scholar 

  42. Ball MW, Gorin MA, Harris KT, Curtiss KM, Netto GJ, Pavlovich CP et al. Extent of renal vein invasion influences prognosis in patients with renal cell carcinoma. BJU Int 2015.

  43. Mai KT, Landry DC, Robertson SJ, Commons AS, Burns BF, Thijssen A, et al. A comparative study of metastatic renal cell carcinoma with correlation to subtype and primary tumor. Pathol Res Pract. 2001;197(10):671–5.

    Article  CAS  PubMed  Google Scholar 

  44. Galván Hernández JA, Helbling M, Kölzer V, Tschan M, Berger MD, Hädrich M, et al. TWIST1 and TWIST2 promoter methylation and protein expression in tumor stroma influence the epithelial-mesenchymal transition-like tumor budding phenotype in colorectal cancer. Oncotarget. 2015;6(2):874–85.

    Google Scholar 

  45. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Q-w Zhang, Liu L, C-y Gong, H-s Shi, Y-h Zeng, X-z Wang, et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS ONE. 2012;7(12):e50946.

    Article  Google Scholar 

  47. Hemmerlein B, Markus A, Wehner M, Kugler A, Zschunke F, Radzun H-J. Expression of acute and late-stage inflammatory antigens, c-fms, CSF-1, and human monocytic serine esterase 1, in tumor-associated macrophages of renal cell carcinomas. Cancer Immunol Immunother. 2000;49(9):485–92.

    Article  CAS  PubMed  Google Scholar 

  48. Santoni M, Massari F, Amantini C, Nabissi M, Maines F, Burattini L, et al. Emerging role of tumor-associated macrophages as therapeutic targets in patients with metastatic renal cell carcinoma. Cancer Immunol Immunother. 2013;62(12):1757–68.

    Article  CAS  PubMed  Google Scholar 

  49. Bajetto A, Barbieri F, Dorcaratto A, Barbero S, Daga A, Porcile C, et al. Expression of CXC chemokine receptors 1–5 and their ligands in human glioma tissues: role of CXCR4 and SDF1 in glioma cell proliferation and migration. Neurochem Int. 2006;49(5):423–32.

    Article  CAS  PubMed  Google Scholar 

  50. Zhang B, Yu W, Feng X, Zhao Z, Fan Y, Meng Y, et al. Prognostic significance of PD–L1 expression on tumor cells and tumor-infiltrating mononuclear cells in upper tract urothelial carcinoma. Med Oncol. 2017;34(5):94.

    Article  PubMed  Google Scholar 

  51. Massari F, Santoni M, Ciccarese C, Santini D, Alfieri S, Martignoni G, et al. PD-1 blockade therapy in renal cell carcinoma: current studies and future promises. Cancer Treat Rev. 2015;41(2):114–21.

    Article  CAS  PubMed  Google Scholar 

  52. Wang Y, Wang H, Zhao Q, Xia Y, Hu X, Guo J. PD-L1 induces epithelial-to-mesenchymal transition via activating SREBP-1c in renal cell carcinoma. Med Oncol. 2015;32(8):1–7.

    Article  Google Scholar 

  53. Noman MZ, Janji B, Abdou A, Hasmim M, Terry S, Tan TZ, et al. The immune checkpoint ligand PD–L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200. Oncoimmunology. 2017;6(1):e1263412.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Xin H, Kong Y, Jiang X, Wang K, Qin X, Miao Z-H, et al. Multi-drug–resistant cells enriched from chronic myeloid leukemia cells by doxorubicin possess tumor-initiating–cell properties. J Pharmacol Sci. 2013;122(4):299–304.

    Article  CAS  PubMed  Google Scholar 

  55. Li J, Zhou BP. Activation of β-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer. 2011;11(1):1.

    Article  Google Scholar 

  56. Vesuna F, Lisok A, Kimble B, Raman V. Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression. Neoplasia. 2009;11(12):1318–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lichner Z, Saleh C, Subramaniam V, Seivwright A, Prud’homme GJ, Yousef GM. miR-17 inhibition enhances the formation of kidney cancer spheres with stem cell/tumor initiating cell properties. Oncotarget. 2015;6(8):5567.

    Article  PubMed  Google Scholar 

  58. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8(10):755–68.

    Article  CAS  PubMed  Google Scholar 

  59. White NM, Yousef GM. Translating molecular signatures of renal cell carcinoma into clinical practice. Amsterdam: Elsevier; 2011.

    Google Scholar 

  60. Matak D, Szymanski L, Szczylik C, Sledziewski R, Lian F, Bartnik E, et al. Biology of renal tumour cancer stem cells applied in medicine. Contemp Oncol. 2015;19(1A):A44.

    Google Scholar 

  61. Bussolati B, Bruno S, Grange C, Ferrando U, Camussi G. Identification of a tumor-initiating stem cell population in human renal carcinomas. FASEB J. 2008;22(10):3696–705.

    Article  CAS  PubMed  Google Scholar 

  62. Zhong Y, Guan K, Guo S, Zhou C, Wang D, Ma W, et al. Spheres derived from the human SK-RC-42 renal cell carcinoma cell line are enriched in cancer stem cells. Cancer Lett. 2010;299(2):150–60.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to Elham Kalantari for her excellent technical assistance.

Funding

This research was supported by a Grant of the Iran University of Medical Sciences (Grant #25166).

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Authors and Affiliations

  1. Oncopathology Research Centre, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next TO Milad Tower, Tehran, 14496-14530, Iran

    Arezoo Rasti, Zahra Madjd, Maryam Abolhasani, Mitra Mehrazma, Leili Saeednejad Zanjani & Mojgan Asgari

  2. Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran

    Zahra Madjd

  3. Hasheminejad Kidney Center, Iran University of Medical Sciences, (IUMS), Tehran, Iran

    Maryam Abolhasani, Mitra Mehrazma & Mojgan Asgari

  4. Department of Biostatistics, School of Public Health, Iran University of Medical Sciences (IUMS), Tehran, Iran

    Leila Janani

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  1. Arezoo Rasti
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Correspondence to Zahra Madjd or Maryam Abolhasani.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This research study was approved by the Iran University of Medical Sciences Research Ethics Committee.

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Rasti, A., Madjd, Z., Abolhasani, M. et al. Cytoplasmic expression of Twist1, an EMT-related transcription factor, is associated with higher grades renal cell carcinomas and worse progression-free survival in clear cell renal cell carcinoma. Clin Exp Med 18, 177–190 (2018). https://doi.org/10.1007/s10238-017-0481-2

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