Glucose-regulated protein 94 mediates metastasis by CCT8 and the JNK pathway in hepatocellular carcinoma

Tumour Biol. 2016 Jun;37(6):8219-27. doi: 10.1007/s13277-015-4669-3. Epub 2015 Dec 30.


Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Cancer metastasis is a major obstacle in clinical cancer therapy. The mechanisms underlying the metastasis of HCC remain unclear. Glucose-regulated protein 94 (GRP94) is a key protein involved in mediating cancer progression, and it is highly expressed in HCC specimens. However, the role of GRP94 in cancer metastasis is unclear. A specific short hairpin RNA (shRNA) was employed to knock down GRP94 gene expression in HCC cell lines. Wound-healing migration, transwell migration, and invasion assays were performed to determine the migration and invasive ability of HCC cells. We demonstrated that silencing GRP94 inhibited HCC cell wound healing, migration, and invasion. Furthermore, our findings indicated that GRP94 knockdown might attenuate HCC cell metastasis by inhibiting CCT8/c-Jun/EMT signaling. Our study indicated that silencing GRP94 significantly reduced the migration and invasion abilities of HCC cells. Moreover, depleting GRP94 inhibited cell migration and invasion by downregulating CCT8/c-Jun signaling. Thus, our data suggest that the GRP94/CCT8/c-Jun/EMT signaling cascade might be a new therapeutic target for HCC.

Keywords: CCT8; GRP94; HCC; Metastasis.

MeSH terms

  • Blotting, Western
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / secondary
  • Cell Line, Tumor
  • Cell Migration Assays
  • Cell Movement / genetics
  • Chaperonin Containing TCP-1 / metabolism*
  • Gene Expression Regulation, Neoplastic / physiology*
  • Gene Knockdown Techniques
  • Gene Silencing
  • HSP70 Heat-Shock Proteins / genetics*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Membrane Proteins / genetics*
  • Neoplasm Invasiveness / genetics
  • RNA, Small Interfering
  • Wound Healing / genetics


  • HSP70 Heat-Shock Proteins
  • Membrane Proteins
  • RNA, Small Interfering
  • glucose-regulated proteins
  • JNK Mitogen-Activated Protein Kinases
  • CCT8 protein, human
  • Chaperonin Containing TCP-1