Format

Send to

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

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

Author information

1
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Box 69, New York, NY, 10065, USA.
2
Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
3
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
4
Caryl and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, 10065, USA.
5
Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, 10065, USA.
6
Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, 10065, USA.
7
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA.
8
Department of Surgery, Weill Cornell Medicine, New York, NY, 10065, USA.
9
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Box 69, New York, NY, 10065, USA. nad2012@med.cornell.edu.
10
Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, 10065, USA. nad2012@med.cornell.edu.

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.

KEYWORDS:

Isoforms; Metastasis; PDAC; PNETs; Pancreatic cancer; RHAMM

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center