The hyaluronan-mediated motility receptor RHAMM promotes growth, invasiveness and dissemination of colorectal cancer

// Valentina Mele 1, * , Lena Sokol 2, * , Viktor Hendrik Kölzer 3 , Dennis Pfaff 4 , Manuele Giuseppe Muraro 5 , Irene Keller 6 , Zahnd Stefan 2 , Irene Centeno 2 , Luigi Maria Terracciano 7 , Heather Dawson 8 , Inti Zlobec 2 , Giandomenica Iezzi 1, * and Alessandro Lugli 9, * 1 Cancer Immunotherapy, Department of Biomedicine, University of Basel, Basel, Switzerland 2 Translational Research Unit, Institute of Pathology, University of Bern, Bern, Switzerland 3 Cantonal Hospital Baselland, Institute of Pathology, Liestal, Switzerland 4 Cell Signaling, Department of Biomedicine, University of Basel, Basel, Switzerland 5 Oncology Surgery and Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland 6 Department of Clinical Research and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland 7 Molecular Pathology Division, Institute of Pathology, University Hospital, Basel, Switzerland 8 Clinical Pathology Division, Institute of Pathology, University of Bern, Bern, Switzerland 9 Clinical Pathology, Institute of Pathology, University Hospital, Basel, Switzerland * Equally contributing first/last authors Correspondence to: Alessandro Lugli, email: alessandro.lugli@pathology.unibe.ch Keywords: RHAMM, colorectal cancer, metastasis, invasion, proliferation Received: March 02, 2017 Accepted: July 06, 2017 Published: August 03, 2017 ABSTRACT In colorectal cancer (CRC), RHAMM is an independent adverse prognostic factor. The aim of the study was therefore to investigate on the role of RHAMM as a potential direct driver of cell proliferation and migration in CRC cell lines and to identify pathways dependent on RHAMM in human CRC. Proliferation, cell cycle alterations and invasive capacity were tested in two RHAMM- and control- knockdown CRC cell lines by flow cytometry and in vitro assays. Tumorigenicity and metastasis formation was assessed in immunodeficient mice. RNA-Seq and immunohistochemistry was performed on six RHAMM+/- primary CRC tumors. In vitro , silencing of RHAMM inhibited CRC cell migration and invasion by 50% (p<0.01). In vivo , RHAMM knockdown resulted in slower growth, lower tumor size (p<0.001) and inhibition of metastasis (p<0.001). Patients with RHAMM-high CRC had a worse prognosis (p=0.040) and upregulated pathways for cell cycle progression and adhesion turnover. RHAMM overexpression is correlated with increased migration and invasion of CRC cells, leads to larger, fast growing tumors, and its downregulation essentially abolishes metastasis in mouse models. RHAMM is therefore a promising therapeutic target in all CRC stages as its inhibition affects growth and dissemination of the primary CRC as well as the metastases.