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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.

Original publication

DOI

10.1186/s12943-019-1018-y

Type

Journal article

Journal

Mol Cancer

Publication Date

09/05/2019

Volume

18

Keywords

Isoforms, Metastasis, PDAC, PNETs, Pancreatic cancer, RHAMM, Alternative Splicing, Animals, Biomarkers, Tumor, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Disease Progression, ErbB Receptors, Extracellular Matrix Proteins, Female, Gene Expression Regulation, Neoplastic, Humans, Hyaluronan Receptors, Liver Neoplasms, Male, Mice, Neoplasm Transplantation, Neuroendocrine Tumors, Pancreatic Neoplasms, Prognosis, Signal Transduction, Survival Analysis, Up-Regulation