HSP47 promotes metastasis of breast cancer by interacting with myosin IIA via the unfolded protein response transducer IRE1α

Oncogene. 2020 Jun;39(23):4519-4537. doi: 10.1038/s41388-020-1311-7. Epub 2020 May 4.

Abstract

Breast cancer (BC) is an aggressive cancer that is a leading cause of cancer-associated death in women worldwide. Although increased expression of heat shock protein 47 (HSP47), a collagen-specific chaperone, is associated with the high malignancy of BC, its role in BC remains largely unclear. Here we show that a small population of high-invasive BC cells expresses HSP47 and that HSP47-positive high-invasive BC cells have a high metastatic potential that is completely abolished by disruption of HSP47. HSP47 interacts with non-muscle myosin IIA (NMIIA) via the unfolded protein response transducer IRE1α, resulting in enhancement of the metastatic potential of high-invasive BC cells by augmenting the contractile force of actin filaments. Ablation of NMIIA abrogates the metastatic potential of HSP47-positive high-invasive BC cells. We further show that forced expression of NMIIA confers a high metastatic potential on low-invasive BC cells in which HSP47 but not NMIIA is expressed. Overall, our study indicates that HSP47 acts as a stimulator for metastasis of BC cells and suggest that HSP47 may be a candidate for a therapeutic target against BC.

MeSH terms

  • Animals
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Endoribonucleases / metabolism*
  • Extracellular Matrix / metabolism
  • Female
  • HSP47 Heat-Shock Proteins / genetics
  • HSP47 Heat-Shock Proteins / metabolism*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Metastasis / pathology
  • Nonmuscle Myosin Type IIA / genetics
  • Nonmuscle Myosin Type IIA / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Tumor Microenvironment / physiology
  • Unfolded Protein Response / physiology

Substances

  • HSP47 Heat-Shock Proteins
  • RNA, Small Interfering
  • SERPINH1 protein, human
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • Endoribonucleases
  • Nonmuscle Myosin Type IIA