Relaxin-2 is a novel biomarker for differentiated thyroid carcinoma in humans

• Published in: Biochemical pharmacology Vol. 225; p. 116323
• Main Authors: Kotwal, Anupam, Simpson, Ronda, Whiteman, Nicholas, Swanson, Benjamin, Yuil-Valdes, Ana, Fitch, Madelyn, Nguyen, Joshua, Elhag, Salma, Shats, Oleg, Goldner, Whitney, Bennett, Robert
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.07.2024
• Subjects: Adult; Aged; Antigens, CD - genetics; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - genetics; Antigens, Differentiation, Myelomonocytic - metabolism; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Carcinogenesis; Cell Line, Tumor; Female; Humans; Macrophages; Male; Middle Aged; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Peptide - genetics; Receptors, Peptide - metabolism; Relaxin; Relaxin - genetics; Relaxin - metabolism; Thyroid carcinoma; Thyroid Neoplasms - diagnosis; Thyroid Neoplasms - genetics; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Tumor microenvironment; RET; RNA; PDTC; HRP; PTEN; DNase; Macrophages; Carcinogenesis; Thyroid carcinoma; STR; SD; TPOAb; NRAS; TNM; FFPE; RLN; AJCC; qPCR; GUSB; INSL; HRAS; TSA; TBP; DAB; TBS; Tumor microenvironment; TMA; BRAF; EDTA; TME; Relaxin; ATA; ECM; Tris; ATC; MMP; DTC; iCaRe2; DNA; RXFP; TTBS; IRB; TCCR; GAPDH; TP53; PCR; PTC; TIMP
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2024.116323

[Display omitted] Relaxin’s role in differentiated thyroid cancer (DTC) has been suggested but its characterization in a large clinical sample remains limited. We performed immunohistochemistry for relaxin-2 (RLN2), CD68 (total macrophages), CD163 (M2 macrophages) on tissue microarrays from 181 subjects with non-distant metastatic DTC, and 185 subjects with benign thyroid tissue. Mean pixels/area for each marker was compared between tumor and adjacent tissue via paired-t test and between DTC and benign subjects via t-test assuming unequal variances. RNA qPCR was performed for expression of RLN2, RLN1, and RXFP1 in cell lines. Amongst 181 cases, the mean age was 46 years, 75 % were females. Tumoral tissue amongst the DTC cases demonstrated higher mean expression of RLN2 (53.04 vs. 9.79; p < 0.0001) compared to tumor-adjacent tissue. DTC tissue also demonstrated higher mean expression of CD68 (14.46 vs. 4.79; p < 0.0001), and CD163 (23.13 vs. −0.73; p < 0.0001) than benign thyroid. These markers did not differ between tumor-adjacent and benign thyroid tissue groups; and amongst cases, did not differ by demographic or clinicopathologic features. RLN1 and RXFP1 expression was detected in a minority of the cell lines, while RLN2 was expressed by 6/7 cell lines. In conclusion, widespread RLN2 expression in DTC tissue and most cell lines demonstrates that RLN2 acts in a paracrine manner, and that RLN1 and RXFP1 are probably not involved in thyroid cancer cell signaling. RLN2 is a biomarker for thyroid carcinogenesis, being associated with but not secreted by immunosuppressive macrophages. These findings will guide further investigations for therapeutic avenues against thyroid cancer.