Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-01-2016 | Original Article – Clinical Oncology

Retinoic acid-related orphan receptor C isoform 2 expression and its prognostic significance for non-small cell lung cancer

Authors: Qi Huang, Jinshuo Fan, Xin Qian, Zhilei Lv, Xiuxiu Zhang, Jieli Han, Feng Wu, Caiyun Chen, Jiao Du, Mengfei Guo, Guorong Hu, Yang Jin

Published in: Journal of Cancer Research and Clinical Oncology | Issue 1/2016

Abstract

Background

Retinoic acid-related orphan receptor C isoform 2 (RORC2) is regarded as a pathogenic factor for autoimmune and inflammatory diseases and tumours. Previous studies have primarily focused on RORC2 expression in IL-17-producing immune cells but not in carcinoma cells; thus, little is known about the roles of RORC2 in the progression of human non-small cell lung cancer (NSCLC). In this study, we analysed the expression of RORC2 and its participation in tumour progression in NSCLC.

Methods

RORC2 expression in NSCLC and adjacent normal lung tissues was assessed via quantitative real-time PCR (qRT-PCR) and immunohistochemistry. RORC2 expression in NSCLC cell lines was examined by qRT-PCR, Western blotting and flow cytometry. The effects of inhibiting RORC2 activity on the proliferation of NSCLC cells were evaluated. The prognostic value of RORC2 for NSCLC was revealed based on Kaplan–Meier analysis.

Results

High RORC2 expression was observed in lung cancer tissues and was significantly related to age (p = 0.013) and regional lymph node metastasis (p = 0.009). RORC2 expression was higher in the A549, H460, SPC-A1 and H1299 cell lines than in a control cell line. In addition, cell proliferation was decreased in NSCLC cells upon the blocking of RORC2 activity using a specific inhibitor. High RORC2 expression correlated with worse overall survival (p = 0.030).

Conclusions

Our study suggests that RORC2 is expressed by lung cancer cells and greatly contributes to tumour cell proliferation and overall survival in NSCLC. These findings strongly imply that RORC2 is associated with tumour progression.

Available only for authorised users

André E, Gawlas K, Steinmayr M, Becker-André M (1998) A novel isoform of the orphan nuclear receptor ROR_β is specifically expressed in pineal gland and retina. Gene 216:277–283PubMedCrossRef

Balabko L et al (2014) Increased expression of the Th17-IL-6R/pSTAT3/BATF/RorgammaT-axis in the tumoural region of adenocarcinoma as compared to squamous cell carcinoma of the lung. Sci Rep 4:7396. doi:10.1038/srep07396 PubMedPubMedCentralCrossRef

Burgler S et al (2009) Differentiation and functional analysis of human T(H)17 cells. J Allergy Clin Immunol 123:588–595. doi:10.1016/j.jaci.2008.12.017 PubMedCrossRef

Burgler S, Mantel PY, Bassin C, Ouaked N, Akdis CA, Schmidt-Weber CB (2010) RORC2 is involved in T cell polarization through interaction with the FOXP3 promoter. J Immunol 184:6161–6169. doi:10.4049/jimmunol.0903243 PubMedCrossRef

Cheang MC et al (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101:736–750. doi:10.1093/jnci/djp082 PubMedPubMedCentralCrossRef

Chen X et al (2010) Increased IL-17-producing cells correlate with poor survival and lymphangiogenesis in NSCLC patients. Lung Cancer 69:348–354. doi:10.1016/j.lungcan.2009.11.013 PubMedCrossRef

Chu S, Zhong X, Zhang J, Lao Q, He Z, Bai J (2011) The expression of Foxp3 and ROR gamma t in lung tissues from normal smokers and chronic obstructive pulmonary disease patients. Int Immunopharmacol 11:1780–1788. doi:10.1016/j.intimp.2011.06.010 PubMedCrossRef

Cirée A et al (2004) Expression and activity of IL-17 in cutaneous T-cell lymphomas (mycosis fungoides and Sezary syndrome). Int J Cancer 112:113–120PubMedCrossRef

Cording S, Medvedovic J, Cherrier M, Eberl G (2014) Development and regulation of RORgammat innate lymphoid cells. FEBS Lett. doi:10.1016/j.febslet.2014.03.034 PubMed

He YW (2000) The role of orphan nuclear receptor in thymocyte differentiation and lymphoid organ development. Immunol Res 22:71–82. doi:10.1385/ir:22:2-3:71 PubMedCrossRef

He YW, Deftos ML, Ojala EW, Bevan MJ (1998) RORgamma t, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells. Immunity 9:797–806PubMedPubMedCentralCrossRef

He G et al (2013) [Th17 cells and IL-17 are increased in patients with brain metastases from the primary lung cancer]. Chin J Lung Cancer 16:476–481. doi:10.3779/j.issn.1009-3419.2013.09.07

Hirota K, Martin B, Veldhoen M (2010) Development, regulation and functional capacities of Th17 cells. Semin Immunopathol 32:3–16. doi:10.1007/s00281-009-0187-y PubMedCrossRef

Jetten AM, Kang HS, Takeda Y (2013) Retinoic acid-related orphan receptors alpha and gamma: key regulators of lipid/glucose metabolism, inflammation, and insulin sensitivity. Front Endocrinol 4:1. doi:10.3389/fendo.2013.00001 CrossRef

Kato T et al (2001) Expression of IL-17 mRNA in ovarian cancer. Biochem Biophys Res Commun 282:735–738PubMedCrossRef

Katsetos CD et al (1998) Cellular distribution of retinoic acid receptor-alpha protein in serous adenocarcinomas of ovarian, tubal, and peritoneal origin: comparison with estrogen receptor status. Am J Pathol 153:469–480PubMedPubMedCentralCrossRef

Kim WG, Zhu X, Kim DW, Zhang L, Kebebew E, Cheng SY (2013) Reactivation of the silenced thyroid hormone receptor beta gene expression delays thyroid tumor progression. Endocrinology 154:25–35. doi:10.1210/en.2012-1728 PubMedPubMedCentralCrossRef

Kirshberg S et al (2011) Involvement of CCR6/CCL20/IL-17 axis in NSCLC disease progression. PLoS One 6:e24856. doi:10.1371/journal.pone.0024856 PubMedPubMedCentralCrossRef

Klose CS, Hoyler T, Kiss EA, Tanriver Y, Diefenbach A (2012) Transcriptional control of innate lymphocyte fate decisions. Curr Opin Immunol 24:290–296. doi:10.1016/j.coi.2012.04.004 PubMedCrossRef

Kobold S et al (2013) Interleukin-22 is frequently expressed in small- and large-cell lung cancer and promotes growth in chemotherapy-resistant cancer cells. J Thorac Oncol 8:1032–1042. doi:10.1097/JTO.0b013e31829923c8 PubMedCrossRef

Kumar N et al (2012) Identification of SR2211: a potent synthetic RORgamma-selective modulator. ACS Chem Biol 7:672–677. doi:10.1021/cb200496y PubMedPubMedCentralCrossRef

Kurebayashi S, Ueda E, Sakaue M, Patel DD, Medvedev A, Zhang F, Jetten AM (2000) Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc Natl Acad Sci USA 97:10132–10137PubMedPubMedCentralCrossRef

Laudet V (1997) Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor. J Mol Endocrinol 19:207–226PubMedCrossRef

Li XB et al (2011) The orphan nuclear receptor EAR2 is overexpressed in colorectal cancer and it regulates survivability of colon cancer cells. Cancer Lett 309:137–144. doi:10.1016/j.canlet.2011.05.025 PubMedCrossRef

Li Q, Han Y, Fei G, Guo Z, Ren T, Liu Z (2012) IL-17 promoted metastasis of non-small-cell lung cancer cells. Immunol Lett 148:144–150. doi:10.1016/j.imlet.2012.10.011 PubMedCrossRef

Lin A et al (2010) Clinical relevance and functional implications for human leucocyte antigen-g expression in non-small-cell lung cancer. J Cell Mol Med 14:2318–2329. doi:10.1111/j.1582-4934.2009.00858.x PubMedPubMedCentralCrossRef

Moll J et al (1994) Analysis of molecular functions of the tumor metastasis promoting surface molecule CD44v4-v7 using transgenic mice. Princess Takamatsu Symp 24:142–151PubMed

Mond M, Alexiadis M, Eriksson N, Davis MJ, Muscat GE, Fuller PJ, Gilfillan C (2014) Nuclear receptor expression in human differentiated thyroid tumors. Thyroid 24:1000–1011. doi:10.1089/thy.2013.0509 PubMedCrossRef

Numasaki M et al (2005) IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. J Immunol 175:6177–6189PubMedCrossRef

Ohoka N, Kato S, Takahashi Y, Hayashi H, Sato R (2009) The orphan nuclear receptor RORalpha restrains adipocyte differentiation through a reduction of C/EBPbeta activity and perilipin gene expression. Mol Endocrinol 23:759–771. doi:10.1210/me.2008-0277 PubMedCrossRef

Ortiz MA, Piedrafita FJ, Pfahl M, Maki R (1995) TOR: a new orphan receptor expressed in the thymus that can modulate retinoid and thyroid hormone signals. Mol Endocrinol 9:1679–1691. doi:10.1210/mend.9.12.8614404 PubMed

Pages F et al (1999) Control of tumor development by intratumoral cytokines. Immunol Lett 68:135–139PubMedCrossRef

Purwar R et al (2012) Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 18:1248–1253. doi:10.1038/nm.2856 PubMedCrossRef

Raichur S, Lau P, Staels B, Muscat GE (2007) Retinoid-related orphan receptor gamma regulates several genes that control metabolism in skeletal muscle cells: links to modulation of reactive oxygen species production. J Mol Endocrinol 39:29–44. doi:10.1677/jme.1.00010 PubMedCrossRef

Reppert S, Boross I, Koslowski M, Tureci O, Koch S, Lehr HA, Finotto S (2011) A role for T-bet-mediated tumour immune surveillance in anti-IL-17A treatment of lung cancer. Nat Commun 2:600. doi:10.1038/ncomms1609 PubMedCrossRef

Schaeren-Wierners N, André E, Kapfhammer JP, Becker-André M (1997) The ExDression pattern of the orphan nuclear receptor RORβ in the developing and adult rat nervous system suggests a role in the processing of sensory information and in circadian rhythm. Eur J Neurosci 9:2687–2701CrossRef

Siegel R et al (2012) Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 62:220–241. doi:10.3322/caac.21149 PubMedCrossRef

Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics. CA Cancer J Clin 64:9–29. doi:10.3322/caac.21208 PubMedCrossRef

Slominski AT et al (2014) RORalpha and ROR gamma are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB J 28:2775–2789. doi:10.1096/fj.13-242040 PubMedPubMedCentralCrossRef

Steiner GE, Newman ME, Paikl D, Stix U, Memaran-Dagda N, Lee C, Marberger MJ (2003) Expression and function of pro-inflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate. Prostate 56:171–182PubMedCrossRef

Tomida S et al (2009) Relapse-related molecular signature in lung adenocarcinomas identifies patients with dismal prognosis. J Clin Oncol 27:2793–2799. doi:10.1200/jco.2008.19.7053 PubMedCrossRef

Ueda E, Kurebayashi S, Sakaue M, Backlund M, Koller B, Jetten AM (2002) High incidence of T-cell lymphomas in mice deficient in the retinoid-related orphan receptor RORgamma. Cancer Res 62:901–909PubMed

Unutmaz D (2009) RORC2: the master of human Th17 cell programming. Eur J Immunol 39(6):1452–1455. doi:10.1002/eji.200939540 PubMedCrossRef

Vacca M, Degirolamo C, Massafra V, Polimeno L, Mariani-Costantini R, Palasciano G, Moschetta A (2013) Nuclear receptors in regenerating liver and hepatocellular carcinoma. Mol Cell Endocrinol 368:108–119. doi:10.1016/j.mce.2012.06.025 PubMedCrossRef

Yao J, Liu L, Yang M (2014) Interleukin-23 receptor genetic variants contribute to susceptibility of multiple cancers. Gene 533:21–25. doi:10.1016/j.gene.2013.09.054 PubMedCrossRef

Title: Retinoic acid-related orphan receptor C isoform 2 expression and its prognostic significance for non-small cell lung cancer
Authors: Qi Huang
Jinshuo Fan
Xin Qian
Zhilei Lv
Xiuxiu Zhang
Jieli Han
Feng Wu
Caiyun Chen
Jiao Du
Mengfei Guo
Guorong Hu
Yang Jin
Publication date: 01-01-2016
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 1/2016
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-015-2040-0

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Retinoic acid-related orphan receptor C isoform 2 expression and its prognostic significance for non-small cell lung cancer

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

Morphological and molecular features of oral fluid-derived exosomes: oral cancer patients versus healthy individuals

Drastic morphological and molecular differences between lymph node micrometastatic tumors and macrometastatic tumors of lung adenocarcinoma

How staging of thin melanoma is changed after the introduction of TNM 7th edition: a population-based analysis

Role of dihydrotestosterone (DHT) on TGF-β1 signaling pathway in epithelial ovarian cancer cells

Long-term follow-up of the AML97 study for patients aged 60 years and above with acute myeloid leukaemia: a study of the East German Haematology and Oncology Study Group (OSHO)

Risk factors for outcome in refractory acute myeloid leukemia patients treated with a combination of fludarabine, cytarabine, and amsacrine followed by a reduced-intensity conditioning and allogeneic stem cell transplantation

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page