The Ubiquitin Ligase CHIP Accelerates Papillary Thyroid Carcinoma Metastasis via the Transgelin-Matrix Metalloproteinase-9 Axis.

Abstract

The carboxyl-terminus of Hsp70-interacting protein (CHIP) plays crucial roles in tumorigenesis and immunity, with previous studies suggesting a double-edged sword in thyroid cancer. However, its precise functions and underlying molecular mechanisms in thyroid cancer remained unclear. Here, we demonstrate through immunohistochemistry (IHC) that CHIP expression progressively increases from normal thyroid tissue to primary papillary thyroid carcinoma (PTC) and lymph node metastases, with CHIP levels positively correlating with lymph node metastasis (P = 0.006). Moreover, CHIP overexpression enhanced thyroid cancer cell migration and invasion without significantly affecting cell viability. Tandem mass tag (TMT)-based LC-MS/MS analysis revealed that CHIP-regulated differentially expressed proteins, notably transgelin, were predominantly associated with metastasis-related pathways. Western blot, qPCR, and TCGA-THCA cohort data confirmed that CHIP regulates transgelin expression at the protein but not the genetic level. Mechanistically, CHIP promotes extracellular matrix degradation through the transgelin-matrix metalloproteinase-9 (MMP-9) axis, thereby facilitating PTC progression. Collectively, our findings indicate that CHIP expression was closely related to the progression and metastasis of PTC, suggesting that CHIP functions as a novel tumor oncoprotein in PTC via the transgelin-MMP-9 signaling axis.