Abstract
The receptor for hyaluronan (HA)-mediated motility (RHAMM) is a HA-binding protein located in the cytoskeleton and centrosome. RHAMM has multiple functions that manifest with different cellular localizations, for example, modulation of growth factor receptor, regulation of cell signaling pathways, and mitotic spindle assembly. In addition, its increased expression has major roles in tumorigenesis and can induce genomic instability and cancer progression. In head and neck cancers, increased expression of RHAMM is associated with high proliferation of cancer cells and decreased survival. CD44, a cell-adhesion molecule and HA receptor, can modulate intracellular signaling by forming complexes with RHAMM to promote invasion and metastasis of cancer cells. In this review, we provide an overview of the biological functions of RHAMM in non-neoplastic cells and cancer cells, as well as its association with CD44, and also introduce studies that particularly implicate RHAMM in the pathogenesis of head and neck cancers.
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Abbreviations
- HA:
-
Hyaluronan
- RHAMM:
-
Receptor for hyaluronan-mediated motility
- ERK:
-
Extracellular-regulated kinase
- SCC:
-
Squamous cell carcinoma
- CSC:
-
Cancer stem cell
References
Anttila MA, Tammi RH, Tammi MI et al (2000) High levels of stromal hyaluronan predict poor disease outcome in epithelial ovarian cancer. Cancer Res 60:150–155
Arnaoutov A, Dasso M (2003) The Ran GTPase regulates kinetochore function. Dev Cell 5:99–111
Assmann V, Marshall JF, Fieber C et al (1998) The human hyaluronan receptor RHAMM is expressed as an intracellular protein in breast cancer cells. J Cell Sci 111:1685–1694
Assmann V, Jenkinson D, Marshall JF et al (1999) The intracellular hyaluronan receptor RHAMM/IHABP interacts with microtubules and actin filaments. J Cell Sci 112:3943–3954
Assmann V, Gillett CE, Poulsom R et al (2001) The pattern of expression of the microtubule-binding protein RHAMM/IHABP in mammary carcinoma suggests a role in the invasive behaviour of tumour cells. J Pathol 195:191–196
Auvinen P, Tammi R, Parkkinen J et al (2000) Hyaluronan in peritumoural stroma and malignant cells associates with breast cancer spreading and predicts survival. Am J Pathol 156:529–536
Bajorath J, Greenfield B, Munro SB et al (1998) Identification of CD44 residues important for hyaluronan binding and delineation of the binding site. J Biol Chem 273:338–343
Banerji S, Ni J, Wang SX et al (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144:789–801
Benitez A, Yates TJ, Lopez LE et al (2011) Targeting hyaluronidase for cancer therapy: antitumor activity of sulfated hyaluronic acid in prostate cancer cells. Cancer Res 71:4085–4095
Benitez A, Yates TJ, Shamaldevi N et al (2013) Dietary supplement hymecromone and sorafenib: a novel combination for the control of renal cell carcinoma. J Urol 190:285–290
Biddle A, Liang X, Gammon L et al (2011) Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res 71:5317–5326
Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737
Chi A, Shirodkar SP, Escudero DO et al (2012) Molecular characterization of kidney cancer: association of hyaluronic acid family with histological subtypes and metastasis. Cancer 118:2394–2402
Cho RJ, Huang M, Campbell MJ et al (2001) Transcriptional regulation and function during the human cell cycle. Nat Genet 27:48–54
Choudhary M, Zhang X, Stojkovic P et al (2007) Putative role of hyaluronan and its related genes, HAS2 and RHAMM, in human early preimplantation embryogenesis and embryonic stem cell characterization. Stem Cells 25:3045–3057
Cohen EE, Lingen MW, Vokes EE (2004) The expanding role of systemic therapy in head and neck cancer. J Clin Oncol 22:1743–1752
Crainie M, Belch AR, Mant MJ et al (1999) Overexpression of the receptor for hyaluronan-mediated motility (RHAMM) characterizes the malignant clone in multiple myeloma: identification of three distinct RHAMM variants. Blood 93:1684–1696
Du YC, Chou CK, Klimstra DS et al (2011) Receptor for hyaluronan-mediated motility isoform B promotes liver metastasis in a mouse model of multistep tumorigenesis and a tail vein assay for metastasis. Proc Natl Acad Sci USA 108:16753–16758
Dunsch AK, Hammond D, Lloyd J et al (2012) Dynein light chain 1 and a spindle-associated adaptor promote dynein asymmetry and spindle orientation. J Cell Biol 198:1039–1054
Entwhistle J, Zhang S, Yang B et al (1995) Cloning and characterization of the gene encoding the hyaluronan receptor RHAMM: the role of a secreted isoform in the regulation of focal adhesion formation. Gene 163:233–238
Entwistle J, Hall CL, Turley EA et al (1996) HA receptors: regulators of signalling to the cytoskeleton. J Cell Biochem 61:569–577
Eyers PA, Erikson E, Chen LG et al (2003) A novel mechanism for activation of the protein kinase Aurora A. Curr Biol 13:691–697
Giannopoulos K, Li L, Bojarska-Junak A et al (2006) Expression of RHAMM/CD168 and other tumor-associated antigens in patients with B-cell chronic lymphocytic leukemia. Int J Oncol 29:95–103
Giannopoulos K, Mertens D, Bühler A et al (2009) The candidate immunotherapeutical target, the receptor for hyaluronic acid-mediated motility, is associated with proliferation and shows prognostic value in B-cell chronic lymphocytic leukemia. Leukemia 23:519–527
Giannopoulos K, Dmoszynska A, Kowal M et al (2010) Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia. Leukemia 24:798–805
Greiner J, Ringhoffer M, Taniguchi M et al (2004) mRNA expression of leukemia-associated antigens in patients with acute myeloid leukemia for the development of specific immunotherapies. Int J Cancer 108:704–711
Greiner J, Li L, Ringhoffer M et al (2005) Identification and characterization of epitopes of the receptor for hyaluronic acid-mediated motility (RHAMM/CD168) recognized by CD8+ T cells of HLA-A2-positive patients with acute myeloid leukemia. Blood 106:938–945
Greiner J, Bullinger L, Guinn BA et al (2008) Leukemia-associated antigens are critical for the proliferation of acute myeloid leukemia cells. Clin Cancer Res 14:7161–7166
Groen AC, Cameron LA, Coughlin M et al (2004) XRHAMM functions in ran-dependent microtubule nucleation and pole formation during anastral spindle assembly. Curr Biol 4:1801–1811
Gruss OJ, Carazo-Salas RE, Schatz CA et al (2001) Ran induces spindle assembly by reversing the inhibitory effect of importin α on TPX2 activity. Cell 104:83–93
Hall CL, Wang C, Lange LA et al (1994) Hyaluronan and the hyaluronan receptor RHAMM promote focal adhesion turnover and transient tyrosine kinase activity. J Cell Biol 126:575–588
Hall CL, Yang B, Yang X (1995) Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. Cell 82:19–26
Hall CL, Lange LA, Prober DA et al (1996) pp60(c-src) is required for cell locomotion regulated by the hyaluronan receptor RHAMM. Oncogene 13:2213–2224
Hamilton SR, Fard SF, Paiwand FF et al (2007) The hyaluronan receptors CD44 and Rhamm (CD168) form complexes with ERK1,2 that sustain high basal motility in breast cancer cells. J Biol Chem 282:16667–16680
Hardwick C, Hoare K, Owens R et al (1992) Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility. J Cell Biol 117:1343–1350
Hatano H, Shigeishi H, Kudo Y et al (2011) RHAMM/ERK interaction induces proliferative activities of cementifying fibroma cells through a mechanism based on the CD44–EGFR. Lab Invest 91:379–391
Hershko A (1997) Roles of ubiquitin-mediated proteolysis in cell cycle control. Curr Opin Cell Biol 9:788–799
Hofmann M, Assmann V, Fieber C et al (1998a) Problems with RHAMM: a new link between surface adhesion and oncogenesis? Cell 95:591–592; author reply 592–593
Hofmann M, Fieber C, Assmann V et al (1998b) Identification of IHABP, a 95 kDa intracellular hyaluronate binding protein. J Cell Sci 111:1673–1684
Hung MC (1997) Interaction between the adhesion receptor, CD44, and the oncogene product, p185HER2, promotes human ovarian tumor cell activation. J Biol Chem 272:27913–27918
Ishigami S, Ueno S, Nishizono Y et al (2011) Prognostic impact of CD168 expression in gastric cancer. BMC Cancer 11:106
Jiang J, Mohan P, Maxwell CA (2013) The cytoskeletal protein RHAMM and ERK1/2 activity maintain the pluripotency of murine embryonic stem cells. PLoS One 8:e73548
Joukov V, Groen AC, Prokhorova T et al (2006) The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly. Cell 127:539–552
Korkes F, Castro MG, Zequi SD et al (2013) RHAMM immunohistochemical expression and androgen deprivation in normal peritumoural, hyperplasic and neoplastic prostate tissue. BJU Int. doi:10.1111/bju.12339 [Epub ahead of print]
Kosunen A, Ropponen K, Kellokoski J et al (2004) Reduced expression of hyaluronan is a strong indicator of poor survival in oral squamous cell carcinoma. Oral Oncol 40:257–263
Kramer MW, Escudero DO, Lokeshwar SD et al (2011) Association of hyaluronic acid family members (HAS1, HAS2, and HYAL-1) with bladder cancer diagnosis and prognosis. Cancer 117:1197–1209
Kufer TA, Silljé HH, Körner R et al (2002) Human TPX2 is required for targeting Aurora-A kinase to the spindle. J Cell Biol 1586:617–623
Laurent TC, Fraser JR (1992) Hyaluronan. FASEB J 6:2397–2404
Li H, Guo L, Li JW et al (2000) Expression of hyaluronan receptors CD44 and RHAMM in stomach cancers: relevance with tumor progression. Int J Oncol 17:927–932
Line A, Slucka Z, Stengrevics A et al (2002) Characterisation of tumour-associated antigens in colon cancer. Cancer Immunol Immunother 51:574–582
Lipponen P, Aaltomaa S, Tammi R et al (2001) High stromal hyaluronan level is associated with poor differentiation and metastasis in prostate cancer. Eur J Cancer 37:849–856
Lokeshwar VB, Selzer MG (2000) Differences in hyaluronic acid-mediated functions and signaling in arterial, microvessel, and vein-derived human endothelial cells. J Biol Chem 275:27641–27649
Lugli A, Zlobec I, Günthert U et al (2006) Overexpression of the receptor for hyaluronic acid mediated motility is an independent adverse prognostic factor in colorectal cancer. Mod Pathol 9:1302–1309
Lynn BD, Li X, Cattini PA et al (2001) Sequence, protein expression and extracellular-regulated kinase association of the hyaladherin RHAMM (receptor for hyaluronan mediated motility) in PC12 cells. Neurosci Lett 306:49–52
Maxwell CA, Keats JJ, Crainie M et al (2003) RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability. Mol Biol Cell 14:2262–2276
Maxwell CA, Rasmussen E, Zhan F et al (2004) RHAMM expression and isoform balance predict aggressive disease and poor survival in multiple myeloma. Blood 104:1151–1158
Maxwell CA, Keats JJ, Belch AR et al (2005) Receptor for hyaluronan-mediated motility correlates with centrosome abnormalities in multiple myeloma and maintains mitotic integrity. Cancer Res 65:850–860
Maxwell CA, McCarthy J, Turley E (2008) Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions? J Cell Sci 121:925–932
Maxwell CA, Benítez J, Gómez-Baldó L et al (2011) Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. PLoS Biol 9:e1001199
Mohan P, Castellsague J, Jiang J et al (2013) Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition. Oncotarget 4:80–93
Mohapatra S, Yang X, Wright JA et al (1996) Soluble hyaluronan receptor RHAMM induces mitotic arrest by suppressing Cdc2 and cyclin B1 expression. J Exp Med 183:1663–1668
Nagel S, Hirschmann P, Dirnhofer S et al (2010) Coexpression of CD44 variant isoforms and receptor for hyaluronic acid-mediated motility (RHAMM, CD168) is an International Prognostic Index and C-MYC gene status-independent predictor of poor outcome in diffuse large B-cell lymphomas. Exp Hematol 38:38–45
Nagy JI, Hacking J, Frankenstein UN et al (1995) Requirement of the hyaluronan receptor RHAMM in neurite extension and motility as demonstrated in primary neurons and neuronal cell lines. J Neurosci 5:241–252
Naor D, Nedvetzki S, Walmsley M et al (2007) CD44 involvement in autoimmune inflammations: the lesson to be learned from CD44-targeting by antibody or from knockout mice. Ann N Y Acad Sci 1110:233–247
Neumann B, Walter T, Hériché JK et al (2010) Phenotypic profiling of the human genome by time-lapse microscopy reveals cell division genes. Nature 464:721–727
Niedworok C, Kretschmer I, Röck K et al (2013) The impact of the receptor of hyaluronan-mediated motility (RHAMM) on human urothelial transitional cell cancer of the bladder. PLoS One 8:e75681
Orian-Rousseau V, Chen L, Sleeman JP et al (2002) CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev 16:3074–3086
Petersen PE (2009) Oral cancer prevention and control—the approach of the World Health Organization. Oral Oncol 45:454–460
Pilarski LM, Masellis-Smith A, Belch AR et al (1994) RHAMM, a receptor for hyaluronan-mediated motility, on normal human lymphocytes, thymocytes and malignant B cells: a mediator in B cell malignancy? Leuk Lymphoma 14:363–374
Ponta H, Sherman L, Herrlich PA et al (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4:33–45
Prince ME, Sivanandan R, Kaczorowski A et al (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 104:973–978
Pujana MA, Han JD, Starita LM et al (2007) Network modeling links breast cancer susceptibility and centrosome dysfunction. Nat Genet 39:1338–1349
Rein DT, Roehrig K, Schöndorf T et al (2003) Expression of the hyaluronan receptor RHAMM in endometrial carcinomas suggests a role in tumour progression and metastasis. J Cancer Res Clin Oncol 129:161–164
Savani RC, Wang C, Yang B et al (1995) Migration of bovine aortic smooth muscle cells after wounding injury. The role of hyaluronan and RHAMM. J Clin Invest 95:1158–1168
Schmitt A, Barth TF, Beyer E et al (2009) The tumor antigens RHAMM and G250/CAIX are expressed in head and neck squamous cell carcinomas and elicit specific CD8+ T cell responses. Int J Oncol 34:629–639
Shi Y, Reiman T, Li W et al (2007) Targeting aurora kinases as therapy in multiple myeloma. Blood 109:3915–3921
Shigeishi H, Fujimoto S, Hiraoka M et al (2009a) Overexpression of the receptor for hyaluronan-mediated motility, correlates with expression of microtubule-associated protein in human oral squamous cell carcinomas. Int J Oncol 34:1565–1571
Shigeishi H, Ohta K, Hiraoka M et al (2009b) Expression of TPX2 in salivary gland carcinomas. Oncol Rep 21:341–344
Shigeishi H, Biddle A, Gammon L et al (2013) Maintenance of stem cell self-renewal in head and neck cancers requires actions of GSK3β influenced by CD44 and RHAMM. Stem Cells 31:2073–2083
Snauwaert S, Vanhee S, Goetgeluk G et al (2012) RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia. Haematologica 97:1539–1547
Sohr S, Engeland K (2008) RHAMM is differentially expressed in the cell cycle and downregulated by the tumor suppressor p53. Cell Cycle 7:3448–3460
Song L, Rape M (2010) Regulated degradation of spindle assembly factors by the anaphase-promoting complex. Mol Cell 38:369–382
Sosnowski RG, Feldman S, Feramisco JR (1993) Interference with endogenous ras function inhibits cellular responses to wounding. J Cell Biol 121:113–119
Starita LM, Machida Y, Sankaran S et al (2004) BRCA1-dependent ubiquitination of gamma-tubulin regulates centrosome number. Mol Cell Biol 24:8457–8466
Tammi R, Tammi M, Hakkinen L et al (1990) Histochemical localisation of hyaluronate in human oral epithelium using a specific hyaluronate-binding probe. Arch Oral Biol 35:219–224
Tolg C, Hamilton SR, Nakrieko KA et al (2006) Rhamm −/− fibroblasts are defective in CD44-mediated ERK1, 2 motogenic signaling, leading to defective skin wound repair. J Cell Biol 175:1017–1028
Tolg C, Hamilton SR, Morningstar L et al (2010) RHAMM promotes interphase microtubule instability and mitotic spindle integrity through MEK1/ERK1/2 activity. J Biol Chem 285:26461–26474
Tulu US, Fagerstrom C, Ferenz NP et al (2006) Molecular requirements for kinetochore-associated microtubule formation in mammalian cells. Curr Biol 16:536–541
Turley E, Moore D (1984) Hyaluronate binding proteins also bind to fibronectin, laminin and collagen. Biochem Biophys Res Commun 121:808–814
Turley EA, Torrance J (1985) Localization of hyaluronate and hyaluronate-binding protein on motile and non-motile fibroblasts. Exp Cell Res 161:17–28
Turley E, Moore D, Hayden J (1987) Characterization of hyaluronate binding proteins isolated from 3T3 and murine sarcoma virus transformed 3T3 cells. Biochemistry 26:2997–3005
Turley EA, Austen L, Moore D et al (1993) Ras-transformed cells express both CD44 and RHAMM hyaluronan receptors: only RHAMM is essential for hyaluronan-promoted locomotion. Exp Cell Res 207:277–282
Turley EA, Noble PW, Bourguignon LY (2002) Signaling properties of hyaluronan receptors. J Biol Chem 277:4589–4592
Tzankov A, Strasser U, Dirnhofer S et al (2011) In situ RHAMM protein expression in acute myeloid leukemia blasts suggests poor overall survival. Ann Hematol 90:901–909
Umbhauer M, Marshall CJ, Mason CS et al (1995) Mesoderm induction in Xenopus caused by activation of MAP kinase. Nature 376:58–62
Venables JP, Klinck R, Bramard A et al (2008) Identification of alternative splicing markers for breast cancer. Cancer Res 68:9525–9531
Vermorken JB, Mesia R, Rivera F et al (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127
Wang C, Thor AD, Moore DH 2nd et al (1998) The overexpression of RHAMM, a hyaluronan-binding protein that regulates ras signaling, correlates with overexpression of mitogen-activated protein kinase and is a significant parameter in breast cancer progression. Clin Cancer Res 4:567–576
Wang Z, Wu Y, Wang H et al (2014) Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proc Natl Acad Sci USA 111:E89–E98
Wittmann T, Wilm M, Karsenti E et al (2000) TPX2, A novel xenopus MAP involved in spindle pole organization. J Cell Biol 149:1405–1418
Wu LC, Wang ZW, Tsan JT et al (1996) Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet 14:430–440
Xu XM, Chen Y, Chen J et al (2003) A peptide with three hyaluronan binding motifs inhibits tumor growth and induces apoptosis. Cancer Res 63:5685–5690
Yamada Y, Itano N, Narimatsu H et al (1999) Receptor for hyaluronan-mediated motility and CD44 expressions in colon cancer assessed by quantitative analysis using real-time reverse transcriptase-polymerase chain reaction. Jpn J Cancer Res 90:987–992
Yamano Y, Uzawa K, Shinozuka K et al (2008) Hyaluronan-mediated motility: a target in oral squamous cell carcinoma. Int J Oncol 32:1001–1009
Yang CW, Su JY, Tsou AP et al (2005) Integrative genomics based identification of potential human hepatocarcinogenesis-associated cell cycle regulators: RHAMM as an example. Biochem Biophys Res Commun 330:489–497
Zang S, Chang MD, Zylka D et al (1998) The hyaluronan receptor RHAMM regulates extracellular regulated kinase. J Biol Chem 273:11342–11348
Zhou H, Kuang J, Zhong L et al (1998) Tumor amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 20:189–193
Zlobec I, Terracciano L, Tornillo L et al (2008a) Role of RHAMM within the hierarchy of well-established prognostic factors in colorectal cancer. Gut 57:1413–1419
Zlobec I, Baker K, Terracciano LM et al (2008b) RHAMM, p21 combined phenotype identifies microsatellite instability-high colorectal cancers with a highly adverse prognosis. Clin Cancer Res 4:3798–3806
Zöller M (2011) CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer 11:254–267
Acknowledgments
This work was supported by a Grant-in-aid for Scientific Research (C) (No. 11008667) from the Ministry of Education, Culture, Sports, and Technology of Japan, a Scientific Research Fund of Sugiyama Chemical and Industrial Laboratory, and the Satake Fund for Scientific Research from the Hiroshima University Supporters’ Association.
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Shigeishi, H., Higashikawa, K. & Takechi, M. Role of receptor for hyaluronan-mediated motility (RHAMM) in human head and neck cancers. J Cancer Res Clin Oncol 140, 1629–1640 (2014). https://doi.org/10.1007/s00432-014-1653-z
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DOI: https://doi.org/10.1007/s00432-014-1653-z