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.
Highlights
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in western countries
Patient survival is correlated to RHAMM expression in tumor cells
We re-tested the ability of RHAMM expression to predict survival in a new, well characterized colorectal cancer cohort
Summary
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in western countries. Over a third of the patients diagnosed with CRC will die within 5 years, mostly from widespread metastatic disease [1, 2]. Targeted therapy approaches are currently only being used to treat patients with metastatic CRC, outlining the need to identify additional therapeutic targets which may help to prevent tumor dissemination. RHAMM (Receptor for Hyaluronic Acid Mediated Motility/HMMR/CD168) was first characterized as a protein involved in cell locomotion. In response to hyaluronic acid (HA), TGF-β or PDGF [5], RHAMM can activate various signaling cascades. RHAMM can target MEK1 and ERK1/2 to the cytoskeleton and nucleus, regulating mitotic spindle integrity, cell cycle progression, and expression of genes governing reorganization and degradation of the extracellular matrix (ECM). It is functionally linked to key centrosomal proteins such as the Aurora kinase A [10,11,12], and is essential for bipolar spindle formation and cell division fidelity [13, 14]
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