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

TitleFunction and clinical relevance of RHAMM isoforms in pancreatic tumor progression.
Publication TypeJournal Article
Year of Publication2019
AuthorsChoi S, Wang D, Chen X, Tang LH, Verma A, Chen Z, Kim BJung, Selesner L, Robzyk K, Zhang G, Pang S, Han T, Chan CS, Fahey TJ, Elemento O, Du Y-CNancy
JournalMol Cancer
Date Published2019 05 09
KeywordsAlternative 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

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 RHAMM promoted liver metastasis. It was unknown whether RHAMM 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, RHAMM and RHAMM, by RNA-Seq analysis of primary PNETs and liver metastases. RHAMM, but not RHAMM, was significantly upregulated in liver metastases. RHAMM was crucial for in vivo metastatic capacity of mouse and human PNETs. RHAMM, carrying an extra 15-amino acid-stretch, did not promote metastasis in spontaneous and experimental metastasis mouse models. Moreover, RHAMM was substantially higher than RHAMM in pancreatic ductal adenocarcinoma (PDAC). RHAMM, but not RHAMM, correlated with both higher EGFR expression and poorer survival of PDAC patients. Knockdown of EGFR abolished RHAMM-driven PNET metastasis. Altogether, our findings suggest a clinically relevant function of RHAMM, but not RHAMM, in promoting PNET metastasis in part through EGFR signaling. RHAMM can thus serve as a prognostic factor for pancreatic cancer.

Alternate JournalMol. Cancer
PubMed ID31072393
PubMed Central IDPMC6506944
Grant ListR21 CA173348 / CA / NCI NIH HHS / United States
U01 DK072473 / DK / NIDDK NIH HHS / United States
R01 CA204916 / CA / NCI NIH HHS / United States
UL1 TR002384 / TR / NCATS NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States