Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression

Mol Cancer. 2019 May 9;18(1):92. doi: 10.1186/s12943-019-1018-y.


The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We previously screened genes upregulated in human hepatocellular carcinomas for their metastatic function in a mouse model of pancreatic neuroendocrine tumor (PNET) and identified that human RHAMMB promoted liver metastasis. It was unknown whether RHAMMB is upregulated in pancreatic cancer or contributes to its progression. In this study, we found that RHAMM protein was frequently upregulated in human PNETs. We investigated alternative splicing isoforms, RHAMMA and RHAMMB, by RNA-Seq analysis of primary PNETs and liver metastases. RHAMMB, but not RHAMMA, was significantly upregulated in liver metastases. RHAMMB was crucial for in vivo metastatic capacity of mouse and human PNETs. RHAMMA, carrying an extra 15-amino acid-stretch, did not promote metastasis in spontaneous and experimental metastasis mouse models. Moreover, RHAMMB was substantially higher than RHAMMA in pancreatic ductal adenocarcinoma (PDAC). RHAMMB, but not RHAMMA, correlated with both higher EGFR expression and poorer survival of PDAC patients. Knockdown of EGFR abolished RHAMMB-driven PNET metastasis. Altogether, our findings suggest a clinically relevant function of RHAMMB, but not RHAMMA, in promoting PNET metastasis in part through EGFR signaling. RHAMMB can thus serve as a prognostic factor for pancreatic cancer.

Keywords: Isoforms; Metastasis; PDAC; PNETs; Pancreatic cancer; RHAMM.

Publication types

  • Letter
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alternative Splicing
  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Line, Tumor
  • Disease Progression
  • ErbB Receptors / metabolism
  • Extracellular Matrix Proteins / genetics*
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hyaluronan Receptors / genetics*
  • Hyaluronan Receptors / metabolism
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Liver Neoplasms / secondary*
  • Male
  • Mice
  • Neoplasm Transplantation
  • Neuroendocrine Tumors / genetics
  • Neuroendocrine Tumors / metabolism
  • Neuroendocrine Tumors / pathology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Prognosis
  • Signal Transduction
  • Survival Analysis
  • Up-Regulation*


  • Biomarkers, Tumor
  • Extracellular Matrix Proteins
  • Hyaluronan Receptors
  • hyaluronan-mediated motility receptor
  • EGFR protein, human
  • ErbB Receptors