Skip to main content

Advertisement

SpringerLink
Log in

Expression and clinical significance of Shh/Gli-1 in papillary thyroid carcinoma

  • Research Article
  • Published:
Tumor Biology

Abstract

The Sonic Hedgehog (Shh) pathway affects cancer initiation, progression, and metastasis, but its role in papillary thyroid carcinoma (PTC) remains elusive. To characterize expression and clinical significance of Shh and the transcription factor Gli-1—the key elements of the Shh pathway in PTC tissues—we immunohistochemically examined Shh/Gli-1 expression in PTC tissues from 142 patients, along with adjacent non-cancerous tissues as controls. We reviewed 142 patients’ clinical characteristics and analyzed their relationship with expression of Shh/Gli-1. Shh and Gli-1 were expressed in 64.1 % (91/142) and 47.9 % (68/142) in PTC tissues, respectively, compared with 16.9 % (24/142) and 9.2 % (13/142) of adjacent non-cancerous tissues. Gli-1 expression was significantly associated with patients’ ages (P < 0.05) and lymph node metastasis (P < 0.01). Increased Shh and Gli-1 expression was significantly associated with tumor-node-metastasis (TNM) stage (P < 0.01). Shh and Gli-1 were expressed in 79.2 and 60.4 %, respectively, of PTC tumors larger than 10 mm. Shh was significantly associated with tumor size (P < 0.01). Shh and Gli-1 were expressed in 72.5 and 65.2 %, respectively, of patients with lymph node metastasis. Overall, we found increased expression of the main initiator Shh and transcription factor Gli-1 in Shh pathway in PTC tissues. The expression of Shh/Gli-1 was significantly associated with tumor size, clinical staging, and lymph node metastasis, indicating that aberrant activation of the Shh pathway is important to PTC occurrence and progression. Potentially, Shh/Gli-1 could be a diagnostic indicator and a marker of therapeutic response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Wang L et al. The Sonic hedgehog pathway mediates carbamylated erythropoietin-enhanced proliferation and differentiation of adult neural progenitor cells. J Biol Chem. 2007;282(44):32462–70.

    Article  CAS  PubMed  Google Scholar 

  2. Karhadkar SS et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 2004;431(7009):707–12.

    Article  CAS  PubMed  Google Scholar 

  3. Watkins DN et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature. 2003;422(6929):313–7.

    Article  CAS  PubMed  Google Scholar 

  4. Thayer SP et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425(6960):851–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Ohta M et al. p53-Independent negative regulation of p21/cyclin-dependent kinase-interacting protein 1 by the sonic hedgehog-glioma-associated oncogene 1 pathway in gastric carcinoma cells. Cancer Res. 2005;65(23):10822–9.

    Article  CAS  PubMed  Google Scholar 

  6. Lees CW, Satsangi J. Hedgehog, paneth cells, and colon cancer: a cautionary note for the use of systemic agonists/antagonists. Gastroenterology. 2006;131(5):1657–8.

    Article  PubMed  Google Scholar 

  7. Huang SH et al. Activation of the hedgehog pathway in human hepatocellular carcinomas. Carcinogenesis. 2006;27(7):1334–40.

    Article  CAS  PubMed  Google Scholar 

  8. Jung YM et al. Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis. Hepatology. 2007;45(5):1091–6.

    Article  PubMed  Google Scholar 

  9. Nelson KK et al. Expression of the Sonic Hedgehog pathway molecules in synchronous follicular adenoma and papillary carcinoma of the thyroid gland in predicting malignancy. Surgery. 2010;148(4):654–60.

    Article  PubMed  Google Scholar 

  10. Woodruff SL et al. Global variation in the pattern of differentiated thyroid cancer. American Journal of Surgery. 2010;200(4):462–6.

    Article  PubMed  Google Scholar 

  11. Kimura ET et al. 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 Research. 2003;63(7):1454–7.

    CAS  PubMed  Google Scholar 

  12. Xing M. BRAF mutation in thyroid cancer. Endocrine-Related Cancer. 2005;12(2):245–62.

    Article  CAS  PubMed  Google Scholar 

  13. Fagman H et al. Genetic deletion of sonic hedgehog causes hemiagenesis and ectopic development of the thyroid in mouse. American Journal of Pathology. 2004;164(5):1865–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Lum L, Beachy PA. The hedgehog response network: sensors, switches, and routers. Science. 2004;304(5678):1755–9.

    Article  CAS  PubMed  Google Scholar 

  15. Chuang PT, McMahon AP. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature. 1999;397(6720):617–21.

    Article  CAS  PubMed  Google Scholar 

  16. Altaba RI, Mas AC, Stecca B. The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends in Cell Biology. 2007;17(9):438–47.

    Article  Google Scholar 

  17. Stecca B, Altaba AI. Context-dependent regulation of the GLI code in cancer by Hedgehog and non-Hedgehog signals. Journal of Molecular Cell Biology. 2010;2(2):84–95.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Omenetti A, Diehl AM. The adventures of sonic hedgehog in development and repair. II. Sonic hedgehog and liver development, inflammation, and cancer. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2008;294(3):G595–8.

    Article  CAS  PubMed  Google Scholar 

  19. Rubin LL, de Sauvage FJ. Targeting the Hedgehog pathway in cancer. Nature Reviews Drug Discovery. 2006;5(12):1026–33.

    Article  CAS  PubMed  Google Scholar 

  20. Feldmann G et al. Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut. 2008;57(10):1420–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Koga K et al. Novel link between estrogen receptor alpha and hedgehog pathway in breast cancer. Anticancer Research. 2008;28(2A):731–9.

    CAS  PubMed  Google Scholar 

  22. Sipos JA, Mazzaferri EL. Thyroid cancer epidemiology and prognostic variables. Clinical Oncology. 2010;22(6):395–404.

    Article  CAS  PubMed  Google Scholar 

  23. Xing MZ, Haugen BR, Schlumberger M. Progress in molecular-based management of differentiated thyroid cancer. Lancet. 2013;381(9871):1058–69.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Knauf JA, Fagin JA. Role of MAPK pathway oncoproteins in thyroid cancer pathogenesis and as drug targets. Current Opinion in Cell Biology. 2009;21(2):296–303.

    Article  CAS  PubMed  Google Scholar 

  25. Xu XL et al. Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation. Endocrine-Related Cancer. 2012;19(2):167–79.

    Article  CAS  PubMed  Google Scholar 

  26. Dormoy V et al. The sonic hedgehog signaling pathway is reactivated in human renal cell carcinoma and plays orchestral role in tumor growth. Molecular Cancer. 2009;8:123. doi:10.1186/1476-4598-8-123.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Hirotsu M et al. Smoothened as a new therapeutic target for human osteosarcoma. Molecular Cancer. 2010;9:5. doi:10.1186/1476-4598-9-5.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This research was funded by the National Natural Science Foundation of China (No. 81202552) and the Natural Science Foundation of Jilin Provincial Science and Technology Department (201101046).

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Thyroid Surgery, China-Japan Union Hospital, Jilin University, Changchun, 130022, People’s Republic of China

    Xue-hai Bian, Hui Sun, Guang Zhang, Chun-hai Zhang, Xiao-li Liu & Shi-jie Li

  2. Department of Histology and Embryology, College of Basic Medical Sciences, Jilin University, Changchun, China

    Hui Xue

  3. Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China

    Jing Su

Authors
  1. Xue-hai Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chun-hai Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiao-li Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shi-jie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xue-hai Bian.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bian, Xh., Sun, H., Xue, H. et al. Expression and clinical significance of Shh/Gli-1 in papillary thyroid carcinoma. Tumor Biol. 35, 10523–10528 (2014). https://doi.org/10.1007/s13277-014-2365-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2365-3

Keywords

Search

Navigation