CD74 interacts with CD44 and enhances tumorigenesis and metastasis via RHOA-mediated cofilin phosphorylation in human breast cancer cells

Oncotarget. 2016 Oct 18;7(42):68303-68313. doi: 10.18632/oncotarget.11945.

Abstract

CD74, also known as Ii, was initially considered to participate primarily in antigen presentation. Subsequent studies have shown that CD74 is highly expressed in various types of tumor cells and has multiple roles in a variety of biological processes. CD74 is thought to promote breast cancer metastasis, but the molecular mechanism remains elusive. In the present study, our results showed that CD74 was more highly expressed on the membrane and in the cytoplasm of breast cancer tissues than in control breast tissues. Consistently, CD74 downregulation reduced MDA-MB-231 cell invasion and migration and suppressed protrusions in breast cancer cells. Moreover, CD74 overexpression promoted the phosphorylation of the actin-severing protein cofilin (CFL1), resulting in actin polymerization in breast cancer cells. CD44 was required for the up-regulation of CFL1 phosphorylation by CD74 because CD44 knockdown downregulated CD74-induced CFL1 phosphorylation, while CD74 overexpression could not rescue CFL1 phosphorylation. Moreover, RHOA is necessary for CFL1 phosphorylation and cell migration induced by CD74 in breast cancer cells. Our findings highlight the critical role of CD74 in breast cancer metastasis. New drugs and antibodies targeting CD74 may be effective strategies for breast cancer therapy.

Keywords: CD44; CD74; CFL1; RHOA.

MeSH terms

  • Adult
  • Antigens, Differentiation, B-Lymphocyte / genetics
  • Antigens, Differentiation, B-Lymphocyte / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cofilin 1 / metabolism*
  • Female
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / metabolism*
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Middle Aged
  • Neoplasm Metastasis
  • Phosphorylation
  • Protein Binding
  • RNA Interference
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Antigens, Differentiation, B-Lymphocyte
  • Cofilin 1
  • Histocompatibility Antigens Class II
  • Hyaluronan Receptors
  • invariant chain
  • rhoA GTP-Binding Protein