Differential expression profile of CXCR3 splicing variants is associated with thyroid neoplasia. Potential role in papillary thyroid carcinoma oncogenesis?

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.

Role of chemokine receptors in thyroid cancer and immunotherapy

“…In this scenario, we know that different CXCR3 ligands (CXCL4, CXCL9, CXCL10 and CXCL11) can trigger different and sometimes opposite responses. This is, at least in part, due to the presence of two splicing variants of the receptor: CXCR3A involved in cell proliferation and CXCR3B involved in cell apoptosis (Urra et al 2018). The first demonstration that CXCR3 is also involved in cancer was provided by Tsuchiya et al in 2004.…”

“…CXCL4, CXCL9-10-11 Normal human thyroid cells, human TPC-1 cell line, non-metastatic human PTC (Urra et al 2018) No data available No data available CXCR4 CXCL12 Normal human thyroid cells (González et al 2009), rat RET/PTC thyroid cancer cell line (Castellone et al 2004), human PTC, human ATC, human MTC, human FTC, human ARO cells (He et al 2010, Torregrossa et al 2010, 2012, Shin et al 2013 TAM (Kim et al 2016) Promotion of rat thyroid cancer cell migration (Castellone et al 2004) Promotion of in vitro human anaplastic thyroid cell migration, Association with human metastasis in vivo (Torregrossa et al 2010(Torregrossa et al , 2012) Promotion of EMT (Hwang et al 2003) CXCR7…”

Disparate roles of CXCR3A and CXCR3B in regulating progressive properties of colorectal cancer cells

“…Compared to Lv-NC infected cells, *, **, and *** represent P < 0.05, P < 0.01, P < 0.0001, respectively variants of CXCR3 exhibit differential roles in inflammations and cancers by selectively activating different signaling pathways. 18,19,30,31 In this regard, CXCR3A and CXCR3B are generally considered to exert opposite functions in cancers, 5 that is, the CXCR3A mediates signals to promote cancer cell proliferation, survival, migration and invasion, and angiostatic effects in tumors [32][33][34] ; while the CXCR3B induces signaling to suppress cancer cell growth and progression. 14,32 Therefore, CXCR3…”

“…Interestingly, CXCR3A and CXCR3B receptors are mainly bind to its ligand CXCL9 to exert their functions in tumorigenesis. Of note, it has been demonstrated that CXCL9 plays a vital role in the tumor progression and is significantly associated with the tumor differentiation, tumor invasion, lymph node metastasis, distant metastasis, and vascular invasion in many types of cancers, including CRC . In this context, CXCR3A is found to serve as a represent classical CXCR3.…”

“…Of note, it has been demonstrated that CXCL9 plays a vital role in the tumor progression and is significantly associated with the tumor differentiation, tumor invasion, lymph node metastasis, distant metastasis, and vascular invasion in many types of cancers, including CRC. [16][17][18][19][20] In this context, CXCR3A is found to serve as a represent classical CXCR3. Of importance, CRC patients with an increased CXCR3A expression showed significantly poorer prognosis than those with lower expression in colon cancer, in which CXCR3 was able to promote colon cancer metastasis to lymph nodes.…”