Hyaluronic acid-CD44 interactions promote BMP4/7-dependent Id1/3 expression in melanoma cells

Sci Rep. 2018 Oct 8;8(1):14913. doi: 10.1038/s41598-018-33337-7.

Abstract

BMP4/7-dependent expression of inhibitor of differentiation/DNA binding (Id) proteins 1 and 3 has been implicated in tumor progression and poor prognosis of malignant melanoma patients. Hyaluronic acid (HA), a pericellular matrix component, supports BMP7 signalling in murine chondrocytes through its receptor CD44. However, its role in regulating BMP signalling in melanoma is not clear. In this study we found that depletion of endogenously-produced HA by hyaluronidase treatment or by inhibition of HA synthesis by 4-methylumbelliferone (4-MU) resulted in reduced BMP4/7-dependent Id1/3 protein expression in mouse melanoma B16-F10 and Ret cells. Conversely, exogenous HA treatment increased BMP4/7-dependent Id1/3 protein expression. Knockdown of CD44 reduced BMP4/7-dependent Id1/3 protein expression, and attenuated the ability of exogenous HA to stimulate Id1 and Id3 expression in response to BMP. Co-IP experiments demonstrated that CD44 can physically associate with the BMP type II receptor (BMPR) ACVR2B. Importantly, we found that coordinate expression of Id1 or Id3 with HA synthases HAS2, HAS3, and CD44 is associated with reduced overall survival of cutaneous melanoma patients. Our results suggest that HA-CD44 interactions with BMPR promote BMP4/7-dependent Id1/3 protein expression in melanoma, contributing to reduced survival in melanoma patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 4 / biosynthesis*
  • Bone Morphogenetic Protein 4 / genetics
  • Bone Morphogenetic Protein 7 / biosynthesis*
  • Bone Morphogenetic Protein 7 / genetics
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Hyaluronic Acid / genetics
  • Hyaluronic Acid / metabolism*
  • Inhibitor of Differentiation Protein 1 / biosynthesis*
  • Inhibitor of Differentiation Protein 1 / genetics
  • Inhibitor of Differentiation Proteins / biosynthesis*
  • Inhibitor of Differentiation Proteins / genetics
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / metabolism*
  • Melanoma, Experimental / pathology
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology

Substances

  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Protein 7
  • Cd44 protein, mouse
  • Hyaluronan Receptors
  • Idb1 protein, mouse
  • Inhibitor of Differentiation Protein 1
  • Inhibitor of Differentiation Proteins
  • Neoplasm Proteins
  • bmp7 protein, mouse
  • Idb3 protein, mouse
  • Hyaluronic Acid