Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression. uri icon

Overview

abstract

  • 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.

publication date

  • May 9, 2019

Research

keywords

  • Carcinoma, Pancreatic Ductal
  • Extracellular Matrix Proteins
  • Hyaluronan Receptors
  • Liver Neoplasms
  • Neuroendocrine Tumors
  • Pancreatic Neoplasms
  • Up-Regulation

Identity

PubMed Central ID

  • PMC6506944

Scopus Document Identifier

  • 85065543542

Digital Object Identifier (DOI)

  • 10.1093/hmg/ddu610

PubMed ID

  • 31072393

Additional Document Info

volume

  • 18

issue

  • 1