Abstract
Papillary thyroid cancer (PTC) is the most prevalent endocrine neoplasia. The increased incidence of PTC in patients with thyroiditis and the frequent immune infiltrate found in PTC suggest that inflammation might be a risk factor for PTC development. The CXCR3-ligand system is involved in thyroid inflammation and CXCR3 has been found upregulated in many tumors, suggesting its pro-tumorigenic role under the inflammatory microenvironment. CXCR3 ligands (CXCL4, CXCL9, CXCL10 and CXCL11) trigger antagonistic responses partly due to the presence of two splice variants, CXCR3A and CXCR3B. Whereas CXCR3A promotes cell proliferation, CXCR3B induces apoptosis. However, the relation between CXCR3 variant expression with chronic inflammation and PTC development remains unknown. Here, we characterized the expression pattern of CXCR3 variants and their ligands in benign tumors and PTC. We found that CXCR3A and CXCL10 mRNA levels were increased in non-metastatic PTC when compared to non-neoplastic tissue. This increment was also observed in a PTC epithelial cell line (TPC-1). Although elevated protein levels of both isoforms were detected in benign and malignant tumors, the CXCR3A expression remained greater than CXCR3B and promoted proliferation in Nthy-ori-3-1 cells. In non-metastatic PTC, inflammation was conditioning for the CXCR3 ligands increased availability. Consistently, CXCL10 was strongly induced by interferon gamma in normal and tumor thyrocytes.Our results suggest that persistent inflammation upregulates CXCL10 expression favoring tumor development via enhanced CXCR3A-CXCL10 signaling. These findings may help to further understand the contribution of inflammation as a risk factor in PTC development and set the basis for potential therapeutic studies.
Highlights
Thyroid cancer has one of the fastest growths in incidence when compared to other malignant and endocrine neoplasia [1, 2], where papillary thyroid cancer (PTC) represents approximately 80% of thyroid malignancies [3, 4]
CXCR3 expression was analyzed by immunohistochemistry in 30 Papillary thyroid cancer (PTC) tumors (14 nonmetastatic PTC and 16 metastatic PTC (MPTC) and in their contralateral tissue
We report a progressive increase in protein balance of CXCR3 variants when comparing control tissue to benign tumors and malignant thyroid neoplasia where CXCR3A was always the predominant isoform
Summary
Thyroid cancer has one of the fastest growths in incidence when compared to other malignant and endocrine neoplasia [1, 2], where papillary thyroid cancer (PTC) represents approximately 80% of thyroid malignancies [3, 4]. Specific chronic inflammatory conditions that increase the risk of cancer development by promoting the infiltration of inflammatory cells to premalignant lesions and the oncogene signaling that initiate cancer by inducing the inflammation-related genes expression are known mechanisms that link inflammation with cancer [9]. The higher incidence of PTC in patients with chronic lymphocytic thyroiditis or Hashimoto autoimmune thyroiditis (HT) [15,16,17] has suggested a role of inflammation as a predisposing factor in the development of thyroid cancer [18,19,20]. In the absence of typical signs of HT, poorly differentiated and anaplastic thyroid carcinomas, which are associated with a worse prognosis, generally exhibit a reduced lymphocytic infiltrate compared to PTCs [11]. There is still no clear evidence whether thyroid inflammation promotes tumor development and/or plays a protective role against thyroid cancer progression
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