Prognostic value of the miRNA-27a and PPAR/RXRα signaling axis in patients with thyroid carcinoma
Abstract
The authors aimed to evaluate the prognostic value of miRNA-27a (miR-27a), peroxisome proliferator-activated receptor alpha/gamma (PPARα/γ) and retinoid X receptor alpha (RXRα) tissue expression in patients with thyroid carcinoma. The expression levels were quantified in 174 archived thyroid specimens using real-time quantitative PCR. Downregulation of miR-27a was associated with lymph node stage and multifocality. PPARα expression was associated with histopathological type, tumor size and lymph node invasion. Moreover, RXRα expression was lower in patients who underwent total/subtotal thyroidectomy or received radioactive iodine treatment. Patients with upregulated miR-27a and downregulated RXRα showed a higher frequency of advanced lymph node stage and relapse by cluster analysis. Both miR-27a and PPARα/RXRα showed association with different poor prognostic indices in thyroid cancer patients.
Graphical abstract
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68(6), 394–424 (2018).
- 2. Role of emerging environmental risk factors in thyroid cancer: a brief review. Int. J. Environ. Res. Public Health 16(7), 1185 (2019).
- 3. . Current knowledge of germline genetic risk factors for the development of non-medullary thyroid cancer. Genes 10(7), 482 (2019).
- 4. . The role of microRNAs in different types of thyroid carcinoma: a comprehensive analysis to find new miRNA supplementary therapies. J. Endocrinol. Invest. 41(3), 269–283 (2018). • Highlights the functional role and aberrant expression of miRNAs in different types of thyroid carcinoma and the potential implication for future targeted therapy.
- 5. . Thyroid cancer. Lancet 388(10061), 2783–2795 (2016).
- 6. . Nutritional and environmental factors in thyroid carcinogenesis. Int. J. Environ. Res. Public Health 15(8), 1735 (2018).
- 7. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26(1), 1–133 (2016).
- 8. . Recurrence of papillary thyroid cancer after optimized surgery. Gland. Surg. 4(1), 52–62 (2015).
- 9. . Molecular fine-needle aspiration biopsy diagnosis of thyroid nodules by tumor specific mutations and gene expression patterns. Mol. Cell Endocrinol. 322(1–2), 29–37 (2010).
- 10. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19(11), 1167–1214 (2009).
- 11. . An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 104(6), 947–953 (1988).
- 12. Identification of genes differentially expressed in benign versus malignant thyroid tumors. Clin. Cancer Res. 14(11), 3327–3337 (2008).
- 13. . MiR-221, a potential prognostic biomarker for recurrence in papillary thyroid cancer. World J. Surg. Oncol. 15(1), 11 (2017).
- 14. . MicroRNA: biogenesis, function and role in cancer. Curr. Genomics 11(7), 537–561 (2010).
- 15. . MicroRNA-196a2 biomarker and targetome network analysis in solid tumors. Mol. Diagn. Ther. 20(6), 559–577 (2016).
- 16. . MicroRNA-34a: a key regulator in the hallmarks of renal cell carcinoma. Oxid. Med. Cell Longev. 2017, 3269379 (2017).
- 17. MicroRNA-target cross-talks: key players in glioblastoma multiforme. Tumour Biol. 39(11), 1010428317726842 (2017).
- 18. . Deregulated microRNA signature following glioblastoma irradiation. Cancer Control 26(1), 1073274819847226 (2019).
- 19. . Evaluation of miRNA-196a2 and apoptosis-related target genes: ANXA1, DFFA and PDCD4 expression in gastrointestinal cancer patients: a pilot study. PLoS ONE 12(11), e0187310 (2017).
- 20. . Noncoding RNAs orchestrate cell growth, death and drug resistance in renal cell carcinoma. Epigenomics 12(3), 199–219 (2020).
- 21. MicroRNA deregulation in human thyroid papillary carcinomas. Endocr. Relat. Cancer 13(2), 497–508 (2006).
- 22. . MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. J. Clin. Endocrinol. Metab. 93(5), 1600–1608 (2008). • One of the first to discuss that various histopathological types of thyroid tumors have distinct miRNA profiles that further differ within the same tumor type, reflecting specific oncogenic mutations.
- 23. The role of microRNA genes in papillary thyroid carcinoma. Proc. Natl Acad. Sci. U S A 102(52), 19075–19080 (2005).
- 24. Differential expression of miRNAs in papillary thyroid carcinoma compared to multinodular goiter using formalin fixed paraffin embedded tissues. Endocr. Pathol. 18(3), 163–173 (2007).
- 25. . MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma. Mod. Pathol. 21(9), 1139–1146 (2008).
- 26. MicroRNA-222 and microRNA-146b are tissue and circulating biomarkers of recurrent papillary thyroid cancer. Cancer 119(24), 4358–4365 (2013).
- 27. . MiR-27a: a novel biomarker and potential therapeutic target in tumors. J. Cancer 10(12), 2836–2848 (2019). •• Discusses the role of miR-27a in tumor biology and clinical significance in detail, offering novel insights into molecular targeting therapy for human cancers.
- 28. Adipose tissue-secreted miR-27a promotes liver cancer by targeting FOXO1 in obese individuals. Onco. Targets Ther. 8, 735–744 (2015).
- 29. . Androgen-regulated processing of the oncomir miR-27a, which targets prohibitin in prostate cancer. Hum. Mol. Genet. 21(14), 3112–3127 (2012).
- 30. . Proteomic screening identifies calreticulin as a miR-27a direct target repressing MHC class I cell surface exposure in colorectal cancer. Cell Death Dis. 7(2), e2120 (2016).
- 31. . MiR-27a regulates the sensitivity of breast cancer cells to cisplatin treatment via BAK-SMAC/DIABLO-XIAP axis. Tumour Biol. 37(5), 6837–6845 (2016).
- 32. . B4GALT3 up-regulation by miR-27a contributes to the oncogenic activity in human cervical cancer cells. Cancer Lett. 375(2), 284–292 (2016).
- 33. . Effects of miR-27a upregulation on thyroid cancer cells migration, invasion, and angiogenesis. Genet. Mol. Res. 15(4), (2016).
- 34. . Pax-8-PPAR-gamma fusion protein in thyroid carcinoma. Nat. Rev. Endocrinol. 10(10), 616–623 (2014).
- 35. . The role of the PAX8/PPARgamma fusion oncogene in thyroid cancer. PPAR Res. 2008, 672829 (2008).
- 36. Underexpression of peroxisome proliferator-activated receptor (PPAR) gamma in PAX8/PPARgamma-negative thyroid tumours. Br. J. Cancer 91(4), 732–738 (2004).
- 37. . Underexpression of PPARgamma is associated with aneuploidy and lower differentiation of thyroid tumours of follicular origin. Oncol. Rep. 22(4), 907–913 (2009).
- 38. PPARgamma promotes growth and invasion of thyroid cancer cells. PPAR Res. 2011, 171765 (2011).
- 39. Antitumor effects of peroxisome proliferator activate receptor gamma ligands on anaplastic thyroid carcinoma. Int. J. Oncol. 24(1), 89–95 (2004).
- 40. PPARalpha agonist-induced rodent tumors: modes of action and human relevance. Crit. Rev. Toxicol. 33(6), 655–780 (2003).
- 41. . Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat. Rev. Cancer. 4(1), 61–70 (2004).
- 42. . MRNA expression pattern of retinoic acid and retinoid X nuclear receptor subtypes in human thyroid papillary carcinoma. Oncol. Rep. 30(5), 2371–2378 (2013).
- 43. Retinoic acid receptor and retinoid X receptor subtype expression for the differential diagnosis of thyroid neoplasms. Eur. J. Endocrinol. 160(4), 631–638 (2009).
- 44. . Retinoid X receptor-gamma and peroxisome proliferator-activated receptor-gamma expression predicts thyroid carcinoma cell response to retinoid and thiazolidinedione treatment. Mol. Cancer Ther. 3(8), 1011–1020 (2004).
- 45. . The new TNM staging system for thyroid cancer and the risk of disease downstaging. Front. Endocrinol.(Lausanne) 9, 541 (2018).
- 46. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin. Chem. 55(4), 611–622 (2009).
- 47. . Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 25(4), 402–408 (2001).
- 48. MRNA expression in papillary and anaplastic thyroid carcinoma: molecular anatomy of a killing switch. PLoS ONE 7(10), e37807 (2012).
- 49. Transcriptomic signature associated with carcinogenesis and aggressiveness of papillary thyroid carcinoma. Theranostics 8(16), 4345–4358 (2018). • Explored a comprehensive transcriptomic signature associated with the carcinogenesis and aggressive behavior of papillary thyroid cancer that would facilitate the prognosis and development of new therapeutic strategies for this type of cancer.
- 50. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl Acad. Sci. U S A 105(30), 10513–10518 (2008).
- 51. . MicroRNAs in cancer: biomarkers, functions and therapy. Trends Mol. Med. 20(8), 460–469 (2014).
- 52. MiR-27a promotes hepatocellular carcinoma cell proliferation through suppression of its target gene peroxisome proliferator-activated receptor gamma. Chin. Med. J. 128(7), 941–947 (2015).
- 53. . MiR-27a controls triacylglycerol synthesis in bovine mammary epithelial cells by targeting peroxisome proliferator-activated receptor gamma. J. Dairy Sci. 100(5), 4102–4112 (2017).
- 54. MiR-27a is a negative regulator of adipocyte differentiation via suppressing PPARgamma expression. Biochem. Biophys. Res. Commun. 392(3), 323–328 (2010).
- 55. MiR-27a-3p targeting RXRα promotes colorectal cancer progression by activating Wnt/β-catenin pathway. Oncotarget 8(47), 82991–83008 (2017).
- 56. MicroRNA-27a contributes to rhabdomyosarcoma cell proliferation by suppressing RARA and RXRA. PLoS ONE 10(4), e0125171 (2015).
- 57. . Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer. World J. Gastroenterol. 22(8), 2441 (2016).
- 58. . MicroRNAs-dependent regulation of PPARs in metabolic diseases and cancers. PPAR Res. 2017, 7058424 (2017). • Uncovered the regulation of PPARs by miRNAs in the context of metabolic disorders, inflammation and cancer.
- 59. Retinoid X receptor α in human liver is regulated by miR-34a. Biochem. Pharmacol. 90(2), 179–187 (2014).
- 60. PPARgamma ligand (thiazolidinedione) induces growth arrest and differentiation markers of human pancreatic cancer cells. Int. J. Oncol. 17(6), 1157–1221 (2000).
- 61. Inhibitory effects of peroxisome poliferator-activated receptor gamma on thyroid carcinoma cell growth. J. Clin. Endocrinol. Metab. 87(10), 4728–4735 (2002).
- 62. PPARgamma inhibits hepatocellular carcinoma metastases in vitro and in mice. Br. J. Cancer 106(9), 1486 (2012).
- 63. Colorectal cancer expression of peroxisome proliferator-activated receptor γ (PPARG, PPARgamma) is associated with good prognosis. Gastroenterology 136(4), 1242–1250 (2009).
- 64. Pioglitazone induces a proadipogenic antitumor response in mice with PAX8-PPARgamma fusion protein thyroid carcinoma. Endocrinology 152(11), 4455–4465 (2011).
- 65. . PPAR-γ receptor ligands: novel therapy for pituitary adenomas. J. Clin. Invest. 111(9), 1381–1388 (2003).
- 66. Gain fat—lose metastasis: converting invasive breast cancer cells into adipocytes inhibits cancer metastasis. Cancer Cell 35(1), 17–32.e6 (2019).
- 67. . Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr. Biol. 11(10), 764–768 (2001).
- 68. . PPAR-γ agonists as antineoplastic agents in cancers with dysregulated IGF axis. Front. Endocrinol. (Lausanne) 8, 31 (2017).
- 69. Loss of the peroxisome proliferation-activated receptor gamma (PPARγ) does not affect mammary development and propensity for tumor formation but leads to reduced fertility. J. Biol. Chem. 277(20), 17830–17835 (2002).
- 70. Mutational analysis of the peroxisome proliferator-activated receptor γ gene in human malignancies. Cancer Res. 61(13), 5307–5310 (2001).
- 71. . Cross-tissue analysis of gene and protein expression in normal and cancer tissues. Sci. Rep. 6(1), 1–6 (2016).