Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression

Molecular Cancer

Olivier Elemento¹  Akanksha Verma¹  Soyoung Choi²  Leigh Selesner²  Bu Jung Kim²  Sharon Pang²  Xiang Chen²  George Zhang²  Yi-Chieh Nancy Du³  Laura H. Tang⁴  Kenneth Robzyk⁴  Thomas J. Fahey⁵  Zhengming Chen⁶  Dunrui Wang⁷  Chang S. Chan⁸  Teng Han⁹ 

[1] Caryl and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, 10065, New York, NY, USA;Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Box 69, 10065, New York, NY, USA;Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Box 69, 10065, New York, NY, USA;Weill Cornell Graduate School of Medical Sciences, Cornell University, 10065, New York, NY, USA;Department of Pathology, Memorial Sloan Kettering Cancer Center, 10065, New York, NY, USA;Department of Surgery, Weill Cornell Medicine, 10065, New York, NY, USA;Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, 10065, New York, NY, USA;Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA;Rutgers Cancer Institute of New Jersey, 08903, New Brunswick, NJ, USA;Weill Cornell Graduate School of Medical Sciences, Cornell University, 10065, New York, NY, USA;

关键词: RHAMM;    Isoforms;    Pancreatic cancer;    PNETs;    PDAC;    Metastasis;   

DOI  :  10.1186/s12943-019-1018-y

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY