COPS5 and LASP1 synergistically interact to downregulate 14-3-3σ expression and promote colorectal cancer progression via activating PI3K/AKT pathway

Int J Cancer. 2018 May 1;142(9):1853-1864. doi: 10.1002/ijc.31206. Epub 2017 Dec 27.

Abstract

Overexpression of LIM and SH3 protein 1 (LASP1) is required for colorectal cancer (CRC) development and progression. Here, C-Jun activation domain-binding protein-1 (Jab1), also known as COP9 signalosome subunit 5 (COPS5), was verified as a new LASP1-interacting protein through yeast two-hybrid assay. The role of COPS5 in LASP1-mediated CRC progression remains unknown. GST pull-down assay indicated that the SH3 domain of LASP1 could directly bind to MPN domain of COPS5. In vitro gain- and loss-of-function analyses revealed the stimulatory role of COPS5 on CRC cell proliferation, migration and invasion. Endogenous overexpression of COPS5 could also enhance the homing capacity of CRC cells in vivo. Further analysis showed that COPS5 and LASP1 synergistically interact to stimulate the ubiquitination and degradation of 14-3-3σ and promote colorectal cancer progression via PI3K/Akt dependent signaling pathway. Clinically, the expression of COPS5 was studied in CRC tissues and it is associated with CRC differentiation, metastasis and poor prognosis. The colocalization of LASP1 and COPS5 was demonstrated in both nonmetastatic and metastatic CRC tissues. A positive correlation was found between the expression of LASP1 and COPS5 while a negative correlation existed between 14-3-3σ and COPS5/LASP1 in most CRC samples. A combination of COPS5 and LASP1 tends to be an independent prognostic indicator for CRC patients, and this is also suitable for CRC without lymph node metastasis. The current research has further advanced our understanding on the complicated molecular mechanism underlying LASP1-mediated CRC progression, which hopefully will contribute to the development of novel diagnostic and therapeutic strategies in CRC.

Keywords: C-Jun activation domain-binding protein-1; LIM and SH3 protein 1; colorectal cancer; poor prognosis; tumor metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / biosynthesis*
  • 14-3-3 Proteins / genetics
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Biomarkers, Tumor / biosynthesis*
  • Biomarkers, Tumor / genetics
  • COP9 Signalosome Complex / genetics
  • COP9 Signalosome Complex / metabolism*
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Disease Progression
  • Down-Regulation
  • Enzyme Activation
  • Exoribonucleases / biosynthesis*
  • Exoribonucleases / genetics
  • HCT116 Cells
  • HT29 Cells
  • Heterografts
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • LIM Domain Proteins / genetics
  • LIM Domain Proteins / metabolism*
  • Mice
  • Mice, Nude
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction

Substances

  • 14-3-3 Proteins
  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • Cytoskeletal Proteins
  • Intracellular Signaling Peptides and Proteins
  • LASP1 protein, human
  • LIM Domain Proteins
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Exoribonucleases
  • SFN protein, human
  • Peptide Hydrolases
  • COPS5 protein, human
  • COP9 Signalosome Complex