ZNRF3 is downregulated in papillary thyroid carcinoma and suppresses the proliferation and invasion of papillary thyroid cancer cells

Tumour Biol. 2016 Sep;37(9):12665-12672. doi: 10.1007/s13277-016-5250-4. Epub 2016 Jul 22.


Zinc and ring finger 3 (ZNRF3) is a transmembrane E3 ubiquitin ligase that has emerged as an important regulator of cancer development; however, its cancer-related function remains controversial. Here, we investigated the possible role of ZNRF3 in thyroid carcinoma (TC). We found that ZNRF3 is downregulated in papillary thyroid carcinoma (PTC) compared to normal thyroid tissues and inversely correlated with the degree of cell differentiation. Overexpression of ZNRF3 significantly suppressed cell malignant behaviors, including cell proliferation, migration, and invasion in vitro, as well as tumor growth in vivo. Consistent with recent studies showing that ZNRF3 is involved in the Wnt/β-catenin pathway, ZNRF3 overexpression negatively regulated β-catenin activation, modulating PTC cell behaviors. Clinical specimens revealed a significant inverse correlation between ZNRF3 and β-catenin mRNA levels. Taken together, these results provide insight into a potential tumor suppressor role of ZNRF3 in PTC progression, and may have potential clinical relevance for the prognosis and treatment of PTC.

Keywords: Invasion; Papillary thyroid carcinomas; Proliferation; ZNRF3.

MeSH terms

  • Animals
  • Blotting, Western
  • Carcinoma, Papillary / genetics*
  • Carcinoma, Papillary / metabolism
  • Carcinoma, Papillary / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics*
  • Down-Regulation*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology
  • Transplantation, Heterologous
  • Tumor Burden / genetics
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Wnt Signaling Pathway / genetics
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • beta Catenin
  • Ubiquitin-Protein Ligases
  • ZNRF3 protein, human