Vol 72, No 1 (2021)
Original paper
Published online: 2020-10-28

open access

Page views 1126
Article views/downloads 731
Get Citation

Connect on Social Media

Connect on Social Media

Aberrant expression of semaphorin 6B affects cell phenotypes in thyroid carcinoma by activating the Notch signalling pathway

Xiu-Juan Lv1, Xin Chen1, Yan Wang1, Shan Yu1, Lin Pang1, Chao Huang2
Pubmed: 33125690
Endokrynol Pol 2021;72(1):29-36.


Introduction: Numerous semaphorins have been widely clarified to be involved in the development of multiple cancers. However, semaphorin 6B (SEMA6B) has not yet been extensively reported in cancers, especially in thyroid carcinoma.

Material and methods: Thyroid carcinoma RNA-Seq dataset from the TCGA database was used to assess the expression of SEMA6B in tissues, as well as its clinical significance. We adopted qRT-PCR and western blot analyses to measure the mRNA and protein expression of SEMA6B in thyroid carcinoma cells. The biological roles of SEMA6B in thyroid carcinoma cells were examined through cell counting kit 8, clone formation, and Transwell assays. Also, GSEA was used to identify the gene sets modulated by SEMA6B, which is further verified by western blot.

Results: According to the public dataset from the TCGA database, we found that the expression of SEMA6B was upregulated in thyroid carcinoma tissues compared to adjacent non-tumour tissues, and a high level of SEMA6B resulted in a poorer prognosis compared to the low-level SEMA6B group. Functional experiments showed that silencing SEMA6B suppressed the B-CPAP cells viability, invasiveness, and motility, whereas up-regulating SEMA6B in FTC-133 cells led to opposite outcomes. Furthermore, knockdown of SEMA6B in B-CPAP cells could significantly elevate the protein expression of NUMB and reduce the expression of NOTCH1, HES1, and Cyclin D1. Conversely, overexpression of SEMA6B in FTC-133 cells presented opposite results on the protein expression of these Notch signalling pathway-related markers.

Conclusions: Our findings demonstrated that SEMA6B exerts a tumourigenic effect in thyroid carcinoma partly by activating Notch signalling pathway, which provides a possible biomarker for the therapeutic intervention in thyroid carcinoma.

Article available in PDF format

View PDF Download PDF file


  1. Zhang H, Hu N. Telomerase reverse transcriptase induced thyroid carcinoma cell proliferation through PTEN/AKT signaling pathway. Mol Med Rep. 2018; 18(2): 1345–1352.
  2. Piraino P, Sepúlveda A, Lillo R, et al. [Thyroid cancer. Report of 85 cases]. Rev Med Chil. 2000; 128(4): 405–410.
  3. Wang Y, Wang Y, Wang W. Increasing incidence of thyroid cancer in shanghai, China, 1983–2007. Nature Precedings. 2011.
  4. Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid cancer in the United States, 1988-2005. Cancer. 2009; 115(16): 3801–3807.
  5. DeSantis CE, Ma J, Gaudet MM, et al. Cancer statistics, 2019. CA Cancer J Clin. 2019; 69(1): 7–34.
  6. Chen WQ, Li H, Sun KX, et al. [Report of Cancer Incidence and Mortality in China, 2014]. Zhonghua Zhong Liu Za Zhi. 2018; 40(1): 5–13.
  7. Chmielik E, Rusinek D, Oczko-Wojciechowska M, et al. Heterogeneity of Thyroid Cancer. Pathobiology. 2018; 85(1–2): 117–129.
  8. Cabanillas M, McFadden D, Durante C. Thyroid cancer. Lancet. 2016; 388(10061): 2783–2795.
  9. Kumar A, Bal CS. Differentiated thyroid cancer. Indian J Pediatr. 2003; 70(9): 707–713.
  10. Sampson E, Brierley JD, Le LW, et al. Clinical management and outcome of papillary and follicular (differentiated) thyroid cancer presenting with distant metastasis at diagnosis. Cancer. 2007; 110(7): 1451–1456.
  11. Smith VA, Sessions RB, Lentsch EJ. Cervical lymph node metastasis and papillary thyroid carcinoma: does the compartment involved affect survival? Experience from the SEER database. J Surg Oncol. 2012; 106(4): 357–362.
  12. Liu FH, Kuo SF, Hsueh C, et al. Postoperative recurrence of papillary thyroid carcinoma with lymph node metastasis. J Surg Oncol. 2015; 112(2): 149–154.
  13. Alto LT, Terman JR. Semaphorins and their Signaling Mechanisms. Methods Mol Biol. 2017; 1493: 1–25.
  14. Neufeld G, Mumblat Y, Smolkin T, et al. The role of the semaphorins in cancer. Cell Adh Migr. 2016; 10(6): 652–674.
  15. Gurrapu S, Tamagnone L. Transmembrane semaphorins: Multimodal signaling cues in development and cancer. Cell Adh Migr. 2016; 10(6): 675–691.
  16. Gu C, Giraudo E. The role of semaphorins and their receptors in vascular development and cancer. Exp Cell Res. 2013; 319(9): 1306–1316.
  17. Ge C, Li Q, Wang L, et al. The role of axon guidance factor semaphorin 6B in the invasion and metastasis of gastric cancer. J Int Med Res. 2013; 41(2): 284–292.
  18. D'Apice L, Costa V, Valente C, et al. Analysis of SEMA6B gene expression in breast cancer: identification of a new isoform. Biochim Biophys Acta. 2013; 1830(10): 4543–4553.
  19. Braune EB, Lendahl U. Notch — a goldilocks signaling pathway in disease and cancer therapy. Discov Med. 2016; 21(115): 189–196.
  20. de Matos PS, Ferreira AP, de Oliveira Facuri F, et al. Usefulness of HBME-1, cytokeratin 19 and galectin-3 immunostaining in the diagnosis of thyroid malignancy. Histopathology. 2005; 47(4): 391–401.
  21. Xiang RH, Hensel CH, Garcia DK, et al. Isolation of the human semaphorin III/F gene (SEMA3F) at chromosome 3p21, a region deleted in lung cancer. Genomics. 1996; 32(1): 39–48.
  22. Xiang R, Davalos AR, Hensel CH, et al. Semaphorin 3F gene from human 3p21.3 suppresses tumor formation in nude mice. Cancer Res. 2002; 62(9): 2637–2643.
  23. Tse C, Xiang RH, Bracht T, et al. Human Semaphorin 3B (SEMA3B) located at chromosome 3p21.3 suppresses tumor formation in an adenocarcinoma cell line. Cancer Res. 2002; 62(2): 542–6.
  24. Meda C, Molla F, De Pizzol M, et al. Semaphorin 4A exerts a proangiogenic effect by enhancing vascular endothelial growth factor-A expression in macrophages. J Immunol. 2012; 188(8): 4081–4092.
  25. Basile JR, Barac A, Zhu T, et al. Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res. 2004; 64(15): 5212–5224.
  26. Sadanandam A, Varney ML, Singh S, et al. High gene expression of semaphorin 5A in pancreatic cancer is associated with tumor growth, invasion and metastasis. Int J Cancer. 2010; 127(6): 1373–1383.
  27. Segarra M, Ohnuki H, Maric D, et al. Semaphorin 6A regulates angiogenesis by modulating VEGF signaling. Blood. 2012; 120(19): 4104–4115.
  28. Correa RG, Sasahara RM, Bengtson MH, et al. Human semaphorin 6B [(HSA)SEMA6B], a novel human class 6 semaphorin gene: alternative splicing and all-trans-retinoic acid-dependent downregulation in glioblastoma cell lines. Genomics. 2001; 73(3): 343–348.
  29. Zhao J, Tang H, Zhao H, et al. SEMA6A is a prognostic biomarker in glioblastoma. Tumour Biol. 2015; 36(11): 8333–8340.
  30. Dhanabal M, Wu F, Alvarez E, et al. Recombinant semaphorin 6A-1 ectodomain inhibits in vivo growth factor and tumor cell line-induced angiogenesis. Cancer Biol Ther. 2005; 4(6): 659–668.
  31. Li L, Tang P, Li S, et al. Notch signaling pathway networks in cancer metastasis: a new target for cancer therapy. Med Oncol. 2017; 34(10): 180.
  32. Yamashita AS, Geraldo MV, Fuziwara CS, et al. Notch pathway is activated by MAPK signaling and influences papillary thyroid cancer proliferation. Transl Oncol. 2013; 6(2): 197–205.
  33. Piana S, Zanetti E, Bisagni A, et al. Expression of NOTCH1 in thyroid cancer is mostly restricted to papillary carcinoma. Endocr Connect. 2019; 8(8): 1089–1096.
  34. Luo Z, Mu L, Zheng Y, et al. NUMB enhances Notch signaling by repressing ubiquitination of NOTCH1 intracellular domain. J Mol Cell Biol. 2020; 12(5): 345–358.
  35. Kageyama R, Ohtsuka T, Shimojo H, et al. Dynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition. Nat Neurosci. 2008; 11(11): 1247–1251.
  36. Li Li, Zhao F, Lu J, et al. Notch-1 signaling promotes the malignant features of human breast cancer through NF-κB activation. PLoS One. 2014; 9(4): e95912.