Oncotarget

Research Papers:

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

Valentina Mele, Lena Sokol, Viktor Hendrik Kölzer, Dennis Pfaff, Manuele Giuseppe Muraro, Irene Keller, Zahnd Stefan, Irene Centeno, Luigi Maria Terracciano, Heather Dawson, Inti Zlobec, Giandomenica Iezzi and Alessandro Lugli _

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Oncotarget. 2017; 8:70617-70629. https://doi.org/10.18632/oncotarget.19904

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Abstract

Valentina Mele1,*, Lena Sokol2,*, Viktor Hendrik Kölzer3, Dennis Pfaff4, Manuele Giuseppe Muraro5, Irene Keller6, Zahnd Stefan2, Irene Centeno2, Luigi Maria Terracciano7, Heather Dawson8, Inti Zlobec2, Giandomenica Iezzi1,* and Alessandro Lugli9,*

1Cancer Immunotherapy, Department of Biomedicine, University of Basel, Basel, Switzerland

2Translational Research Unit, Institute of Pathology, University of Bern, Bern, Switzerland

3Cantonal Hospital Baselland, Institute of Pathology, Liestal, Switzerland

4Cell Signaling, Department of Biomedicine, University of Basel, Basel, Switzerland

5Oncology Surgery and Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland

6Department of Clinical Research and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland

7Molecular Pathology Division, Institute of Pathology, University Hospital, Basel, Switzerland

8Clinical Pathology Division, Institute of Pathology, University of Bern, Bern, Switzerland

9Clinical Pathology, Institute of Pathology, University Hospital, Basel, Switzerland

*Equally contributing first/last authors

Correspondence to:

Alessandro Lugli, email: [email protected]

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.


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