Abstract 5705: CHI3L1 overexpression predicts poor prognosis and drives aggressiveness in papillary thyroid cancer

Abstract Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein that is pivotal in regulating inflammation, macrophage polarization, apoptosis, and the process of carcinogenesis. While its expression is markedly increased in various cancer types, its specific role in papillary thyroid cancer (PTC) has not been fully elucidated. In our study, we assessed the expression of CHI3L1 protein in a large cohort of PTC patient samples and investigated its functional significance and underlying mechanisms in PTC cell lines. CHI3L1 over-expression was noted in 38.9% (638/1613) of PTC cases and was significantly associated with aggressive clinicopathological characteristics such as extrathyroidal extension (p < 0.0001), advanced T stage (p < 0.0001), lymph node metastasis (p < 0.0001), distant metastasis (p = 0.0003), stage IV tumors (p = 0.0007) and tumor recurrence (p < 0.0001). Interestingly, a significant association was also noted between CHI3L1 over-expression and phosphor-AKT (P = 0.0007) as well as PD-L1 (P < 0.0001). In addition, CHI3L1 was associated with shorter recurrence-free survival (p = 0.0004). Our in vitro studies revealed that inhibition of CHI3L1 reduced cell proliferation and triggered apoptosis in PTC cell lines. Notably, the downregulation of PLK1 impaired the self-renewal capacity of spheroids derived from PTC cells, indicating its role in maintaining cancer stem-like properties. Furthermore, CHI3L1 knockdown resulted in decreased expression of phosphorylated AKT and PD-L1, while its overexpression led to an upregulation of both. These findings underscore the role of CHI3L1 in PTC prognosis and promoting its progression. This study also identifies CHI3L1 as a promising therapeutic target, offering a novel strategy for managing aggressive and treatment-resistant forms of PTC. Citation Format: Pratheesh Kumar Poyil, Abdul K. Siraj, Sandeep Kumar Parvathareddy, Khadija Alobaisi, Rafia Begum, Fouad Al-Dayel, Khawla S. Al-Kuraya. CHI3L1 overexpression predicts poor prognosis and drives aggressiveness in papillary thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5705.