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

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.