Upregulation of the signal transducers and activators of transcription 3 (STAT3) pathway in lymphatic metastases of papillary thyroid cancer.

Papillary thyroid cancer (PTC) has an impressive propensity for lymphatic spread. Signal transducers and activators of transcription 3 (STAT3), constitutively activated in many different cancers, may play a role in PTC lymphatic metastases. We examined 49 patients with PTC, 22 with and 27 without lymphatic metastases. All patients had a total thyroidectomy with lymph node dissection to document true node negative cases. The level of STAT3 expression in benign, non-neoplastic thyroid tissue is barely detectable by immunohistochemistry. Only 11 of the 35 (31%) specimens exhibited weak immunostainingfor STAT3 and pSTAT3 was found weakly positive in 3 of 35 (9%) benign specimens. Expression of STAT3 in all PTC primary tumors was 98% (40/41) and thus significantly higher than corresponding benign thyroid tissue (p=0.0001). pSTAT3 was found in 37% of primary tumors (15/41) and this was significantly higher than pSTAT3 expression in benign tissue (p=0.006). Comparing node-positive and node-negative primary tumors, there was no difference in staining intensity for STAT3 where strong (2+) staining was seen 12/19 node-positive tumors and 13/22 node-negative tumors (p=1). Regarding pSTAT3 expression in primary PTC tumors, node negative cases (n=22) exhibited significantly less staining compared to node positive cases (n=19). Only 4 of 22 (18%) cases in the node-negative group were weakly (1+) positive for pSTAT3 while 12 of 19 (58%) cases in the node-positive group were positive (p=0.011) with 45% of these specimens exhibiting strong (2+) staining. Lymphatic metastases were highly positive (>93%) for both STAT3 and pSTAT3. The STAT3 pathway is ubiquitous in PTC and activated pSTAT3 is significantly upregulated in PTC tumors with metastatic disease. This study is the first to suggest a potential role for activated pSTAT3 in lymphatic metastases in thyroid cancer.

[1]  X. F. Wang,et al.  Silencing STAT3 may inhibit cell growth through regulating signaling pathway, telomerase, cell cycle, apoptosis and angiogenesis in hepatocellular carcinoma: potential uses for gene therapy. , 2011, Neoplasma.

[2]  Steven J. M. Jones,et al.  Diagnostic utility of galectin-3 in thyroid cancer. , 2010, The American journal of pathology.

[3]  R. Udelsman.  Treatment of persistent or recurrent papillary carcinoma of the thyroid--the good, the bad, and the unknown. , 2010, The Journal of clinical endocrinology and metabolism.

[4]  S. Pai,et al.  Reoperation for recurrent/persistent well-differentiated thyroid cancer. , 2010, Otolaryngologic clinics of North America.

[5]  J. Turkson,et al.  Constitutively active Stat3 enhances neu-mediated migration and metastasis in mammary tumors via upregulation of Cten. , 2010, Cancer research.

[6]  Zuojie Luo,et al.  Assessment of biomarkers for clinical diagnosis of papillary thyroid carcinoma with distant metastasis. , 2010, The International journal of biological markers.

[7]  Sang Hyuk Lee,et al.  Expression of cell-cycle regulators (cyclin D1, cyclin E, p27kip1, p57kip2) in papillary thyroid carcinoma , 2010, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[8]  T. Carling,et al.  Controversy surrounding the role for routine central lymph node dissection for differentiated thyroid cancer , 2010, Current opinion in oncology.

[9]  Stephanie L. Lee,et al.  Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. , 2009, Thyroid : official journal of the American Thyroid Association.

[10]  Suyun Huang,et al.  STAT3 as a central regulator of tumor metastases. , 2009, Current molecular medicine.

[11]  L. Rotstein.  The role of lymphadenectomy in the management of papillary carcinoma of the thyroid , 2009, Journal of surgical oncology.

[12]  Hua-Qin Wang,et al.  Significance of survivin, caspase-3, and VEGF expression in thyroid carcinoma , 2009, Clinical and Experimental Medicine.

[13]  S. Hauptmann,et al.  Lymph node dissection in the lateral neck for completion in central node-positive papillary thyroid cancer. , 2009, Surgery.

[14]  H. Dralle,et al.  Surgical approaches in thyroid cancer and lymph-node metastases. , 2008, Best practice & research. Clinical endocrinology & metabolism.

[15]  O. Stoeltzing,et al.  Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes , 2008, Molecular Cancer Therapeutics.

[16]  Steven J. M. Jones,et al.  Biomarker panel diagnosis of thyroid cancer: a critical review , 2008, Expert review of anticancer therapy.

[17]  F. Consorti,et al.  Survivin and cyclin D1 are jointly expressed in thyroid papillary carcinoma and microcarcinoma. , 2008, Oncology reports.

[18]  Yuri E Nikiforov,et al.  Thyroid carcinoma: molecular pathways and therapeutic targets , 2008, Modern Pathology.

[19]  L. Bastholt,et al.  Papillary microcarcinoma of the thyroid gland: Is the immunohistochemical expression of cyclin D1 or galectin-3 in primary tumour an indicator of metastatic disease? , 2008, Acta oncologica.

[20]  Hyunji Lee,et al.  Modulatory role of phospholipase D in the activation of signal transducer and activator of transcription (STAT)-3 by thyroid oncogenic kinase RET/PTC , 2008, BMC Cancer.

[21]  D. McMillin,et al.  Bcl-2 overexpression in thyroid carcinoma cells increases sensitivity to Bcl-2 homology 3 domain inhibition. , 2007, The Journal of clinical endocrinology and metabolism.

[22]  Suyun Huang.  Regulation of Metastases by Signal Transducer and Activator of Transcription 3 Signaling Pathway: Clinical Implications , 2007, Clinical Cancer Research.

[23]  R. DeLellis.  Pathology and genetics of thyroid carcinoma , 2006, Journal of surgical oncology.

[24]  S. Sidhu,et al.  Routine ipsilateral level VI lymphadenectomy reduces postoperative thyroglobulin levels in papillary thyroid cancer. , 2006, Surgery.

[25]  R. Bast,et al.  The role of constitutively active signal transducer and activator of transcription 3 in ovarian tumorigenesis and prognosis , 2006, Cancer.

[26]  J. Mackey,et al.  Signal transducers and activators of transcription-3 up-regulates tissue inhibitor of metalloproteinase-1 expression and decreases invasiveness of breast cancer. , 2006, The American journal of pathology.

[27]  P. Hall,et al.  Clinically significant prognostic factors for differentiated thyroid carcinoma , 2006, Cancer.

[28]  Jung Hun Song,et al.  Activation of signal transducer and activator of transcription 3 by oncogenic RET/PTC (rearranged in transformation/papillary thyroid carcinoma) tyrosine kinase: roles in specific gene regulation and cellular transformation. , 2003, Molecular endocrinology.

[29]  R. Hinze,et al.  Pattern of Nodal Metastasis for Primary and Reoperative Thyroid Cancer , 2001, World Journal of Surgery.

[30]  J. Shah,et al.  Impact of lymph node metastasis in differentiated carcinoma of the thyroid: A matched‐pair analysis , 1996, Head & neck.

[31]  H. Wanebo,et al.  Recurrent Thyroid Cancer Role of Surgery Versus Radioactive Iodine (I131) , 1994, Annals of Surgery.