Associations of the BRAF V600E Mutation and PAQR3 Protein Expression with Papillary Thyroid Carcinoma Clinicopathological Features


The BRAFV600E mutation is the most prevalent genetic event in patients with papillary thyroid cancer (PTC). However, no study has investigated the expression of PAQR3 in papillary thyroid tissues in relation to the BRAFV600E mutation and the clinicopathological features of PTC patients. Furthermore, the potential associations of the BRAFV600E mutation, PAQR3 expression and clinicopathological parameters in the cancerous tissues of PTC patients have not been investigated. This study was conducted on 60 patients with PTC who were treated surgically at our institution from 2017 to 2018. PCR was used to amplify DNA by the amplification refractory mutation system (ARMS) method to detect BRAFV600E gene mutations. In addition, immunohistochemical techniques were utilized to assess PAQR3 expression in tumor tissue sections. The BRAFV600E mutation was associated with lymph node metastasis (LNM, p < 0.05) but not with other clinicopathological features. Low PAQR3 expression was associated with extrathyroidal extension and LNM (χ2 = 7.143, p = 0.009; χ2 = 6.459, p = 0.014, respectively). Furthermore, a statistically significant association was observed between chronic lymphocytic thyroiditis and LNM (χ2 = 5.275, p = 0.0250). A linear relationship between the BRAFV600E mutation and PAQR3 protein expression has not been identified. These factors may be independent risk factors of extrathyroidal extension and LNM in PTC and be used to indicate the invasiveness of PTC tumors. Higher quality, multivariate analyses based on larger samples from around the world are urgently needed to further validate and revise our findings in the future.

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  1. 1.

    Cvejic D, Selemetjev S, Savin S, Paunovic I, Tatic S (2009) Changes in the balance between proliferation and apoptosis during the progression of malignancy in thyroid tumours. Eur J Histochem 53:65–71

    CAS  Article  Google Scholar 

  2. 2.

    Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA (2003) High prevalence of braf mutations in thyroid cancer genetic evidence for constitutive activation of the ret/ptc-ras-braf signaling pathway in papillary thyroid carcinoma. Cancer Res 63:1454–1457

    CAS  PubMed  Google Scholar 

  3. 3.

    Gu LQ, Li FY, Zhao L, Liu Y, Zhao YJ (2009) Braf v600e mutation and x-linked inhibitor of apoptosis expression in papillary thyroid carcinoma. Thyroid 19:347–354

  4. 4.

    Mathur A, Moses W, Rahbari R, Khanafshar E, Duh Q, Clark O et al (2011) Higher rate of braf mutation in papillary thyroid cancer over time. Cancer 117:4390–4395

    CAS  Article  Google Scholar 

  5. 5.

    Xing M (2005) Braf mutation in thyroid cancer. Endocr Relat Cancer 12:245–262

  6. 6.

    Whipple CA, Boni A, Fisher JL, Hampton TH, Ernstoff MS (2016) The mitogen-activated protein kinase pathway plays a critical role in regulating immunological properties of BRAF mutant cutaneous melanoma cells. Melanoma Res 26:223–235

    CAS  Article  Google Scholar 

  7. 7.

    Ji H, Wang Z, Perera SA et al (2007) Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models. Cancer Res 67:4933–4939

    CAS  Article  Google Scholar 

  8. 8.

    Tang YT, Hu T, Arterburn M, Boyle B, Bright JM, Emtage PC et al (2005) PAQR proteins: a novel membrane receptor family defined by an ancient7-transmembrane pass motif. J Mol Evol 61:372–380

    CAS  Article  Google Scholar 

  9. 9.

    Feng L, Xie X, Ding Q, Luo X, He J, Fan F et al (2007) Spatial regulation of Raf kinase signaling by RKTG. Proc Natl Acad Sci 104:14348–14353

    CAS  Article  Google Scholar 

  10. 10.

    Fan F, Feng L, He J, Wang X, Jiang X, Zhang Y et al (2008) RKTG sequesters B-Raf to the Golgi apparatus and inhibits the proliferation and tumorigenicity of human malignant melanoma cells. Carcinogenesis 29:1157–1163

    CAS  Article  Google Scholar 

  11. 11.

    Bai G, Chu J, Eli M, Bao Y, Wen H (2017) PAQR3 overexpression suppresses the aggressive phenotype of esophageal squamous cell carcinoma cells via inhibition of ERK signaling. Biomed Pharmacother 94:813–819

    CAS  Article  Google Scholar 

  12. 12.

    Ling ZQ, Guo W, Lu XX, Zhu X, Hong LL, Wang Z et al (2014) A golgi-specific protein paqr3 is closely associated with the progression, metastasis and prognosis of human gastric cancers. Ann Oncol 25:1363–1372

    CAS  Article  Google Scholar 

  13. 13.

    Ma Z, Wang Y, Piao T, Li Z, Zhang H, Liu Z, Liu J (2015) The tumor suppressor role of PAQR3 in osteosarcoma. Tumor Biol 36:3319–3324

    CAS  Article  Google Scholar 

  14. 14.

    Chen J, Wang F, Xu J, He Z, Lu Y, Wang Z (2016) The role of PAQR3 gene promoter hypermethylation in breast cancer and prognosis. Oncol Rep 36:1612–1618

    CAS  Article  Google Scholar 

  15. 15.

    Wu H, Zhang W, Ding Q, Peng G, Zou Z, Liu T et al (2014) Identification of PAQR3 as a new candidate tumor suppressor in hepatocellular carcinoma. Oncol Rep 32:2687–2695

    CAS  Article  Google Scholar 

  16. 16.

    Bai G, Yang M, Zheng C, Zhang L, Eli M (2018) Suppressor PAQR3 associated with the clinical significance and prognosis in esophageal squamous cell carcinoma. Oncol Lett 15:5703–5711

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Sun J, Zhang J, Lu J, Gao J, Liang Z (2016) BRAF V600E and TERT promoter mutations in papillary thyroid carcinoma in Chinese patients. PLoS One 11:e0153319

    Article  Google Scholar 

  18. 18.

    Guo L, Ma YQ, Yao Y et al (2019) Role of ultrasonographic features and quantified BRAFV600E mutation in lymph node metastasis in Chinese patients with papillary thyroid carcinoma. Sci Rep 9:75

    Article  Google Scholar 

  19. 19.

    Li Y, Nakamura M, Kakudo K (2009) Targeting of the BRAF gene in papillary thyroid carcinoma (review). Oncol Rep 22:671–681

    CAS  PubMed  Google Scholar 

  20. 20.

    Nasirden A, Saito T, Fukumura Y, Hara K, Akaike K, Kurisaki-Arakawa A et al (2016) In Japanese patients with papillary thyroid carcinoma, TERTpromoter mutation is associated with poor prognosis, in contrast toBRAFV600E mutation. Virchows Arch 469:687–696

    CAS  Article  Google Scholar 

  21. 21.

    Agnieszka C, Monika K, Dagmara R, Jolanta K, Michal J, Ewa S et al (2015) The risk of relapse in papillary thyroid Cancer (PTC) in the context of BRAFV600E mutation status and other prognostic factors. PLOS ONE 10:e0132821

    Article  Google Scholar 

  22. 22.

    Choi SY, Park HS, Kang MK, Lee DK, Lee KD, Lee HS et al (2013) The relationship between the BRAFV600E mutation in papillary thyroid microcarcinoma and clinicopathologic factors. World J Surg Oncol 11:1–5

    Article  Google Scholar 

  23. 23.

    Liu Z, Lv T, Xie C, Di Z (2018) BRAFV600E gene mutation is associated with bilateral malignancy of papillary thyroid Cancer. Am J Med Sci 356:130–134

    Article  Google Scholar 

  24. 24.

    Qu HJ, Qu XY, Hu Z, Lin Y, Wang JR, Zheng CF et al (2017) The synergic effect of BRAFV600E mutation and multifocality on central lymph node metastasis in unilateral papillary thyroid carcinoma. Endocr J 65:113–120

    Article  Google Scholar 

  25. 25.

    Chakraborty A, Narkar A, Mukhopadhyaya R, Kane S, D’Cruz A, Rajan MGR (2012) BRAF V600E mutation in papillary thyroid carcinoma: significant association with node metastases and extra thyroidal invasion. Endocr Pathol 23:83–93

    CAS  Article  Google Scholar 

  26. 26.

    Kang SH, Pyo JY, Yang SW et al (2013) Detection of BRAF V600E mutation with thyroid tissue using pyrosequencing. Am J Clin Pathol 139:759–764

    CAS  Article  Google Scholar 

  27. 27.

    Ahn D, Park JS, Sohn JH, Kim JH, Park SK, Seo AN et al (2012) BRAF (V600E) mutation does not serve as a prognostic factor in Korean patients with papillary thyroid carcinoma. Auris Nasus Larynx 39:198–203

    Article  Google Scholar 

  28. 28.

    Kurt B, Yalçın S, Alagöz, Engin et al (2012) The relationship of the BRAF (V600E) mutation and the established prognostic factors in papillary thyroid carcinomas. Endocr Pathol 23:135–140

    CAS  Article  Google Scholar 

  29. 29.

    Givens DJ, Buchmann LO, Agarwal AM, Grimmer JF, Hunt JP (2014) BRAF V600E does not predict aggressive features of pediatric papillary thyroid carcinoma. Laryngoscope 124(9):E389–E393

    CAS  Article  Google Scholar 

  30. 30.

    Kim SJ, Lee KE, Myong JP, Park JH, Youn YK (2011) BRAF V600E mutation is associated with tumor aggres- siveness in papillary thyroid cancer. World J Surg 36:310–317

    Article  Google Scholar 

  31. 31.

    Song JY, Sun SR, Dong F, Huang T, Wu B, Zhou J (2018) Predictive value of BRAF V600E mutation for lymph node metastasis in papillary thyroid Cancer: a meta-analysis. Curr Med Sci 38:785–797

    CAS  Article  Google Scholar 

  32. 32.

    Kurtulmus N, Ertas B, Saglican Y, Kaya H, Duren M (2016) BRAF V600E mutation: has it a role in cervical lymph node metastasis of papillary thyroid Cancer? Eur Thyroid J 5:195–200

    CAS  Article  Google Scholar 

  33. 33.

    Tang KT, Lee CH (2010) BRAF mutation in papillary thyroid carcinoma: pathogenic role and clinical implications. J Chin Med Assoc 73:113–128

    CAS  Article  Google Scholar 

  34. 34.

    Li RH, Zhang AM, Li S, Li TY, Wang LJ, Zhang HR et al (2016) PAQR3 gene expression and its methylation level in colorectal cancer tissues. Oncol Lett 12:1773–1778

    CAS  Article  Google Scholar 

  35. 35.

    Zhao C, Li Y, Chen G et al (2017) Overexpression of miR-15b-5p promotes gastric cancer metastasis by regulating PAQR3. Oncol Rep 38:352–358

    CAS  Article  Google Scholar 

  36. 36.

    Guo W, You X, Xu D, Zhang Y, Wang Z, Man K et al (2016) PAQR3 enhances Twist1 degradation to suppress epithelial-mesenchymal transition and metastasis of gastric cancer cells. Carcinogenesis 37:397–407

    CAS  Article  Google Scholar 

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Correspondence to Jian Gao.

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This study was supported by grants from The Key Scientific and Technological Projects of Anhui Province in China (1604a0802073).

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Gao, J., Ma, X.P., Deng, F.S. et al. Associations of the BRAF V600E Mutation and PAQR3 Protein Expression with Papillary Thyroid Carcinoma Clinicopathological Features. Pathol. Oncol. Res. 26, 1833–1841 (2020).

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  • BRAF gene
  • PAQR3
  • Thyroid cancer
  • Papillary thyroid microcarcinoma
  • Lymph node metastasis (LNM)
  • Extrathyroidal extension