Top

Journal of Ovarian Research

Published in:

Open Access 01-12-2017 | Research

Increased RHAMM expression relates to ovarian cancer progression

Authors: Stephanie T. Buttermore, Mitchel S. Hoffman, Ambuj Kumar, Anne Champeaux, Santo V. Nicosia, Patricia A. Kruk

Published in: Journal of Ovarian Research | Issue 1/2017

Abstract

Background

Elevated hyaluronan-mediated motility receptor (RHAMM) has been reported to contribute to disease progression, aggressive phenotype and poor prognosis in multiple cancer types, however, RHAMM’s role in ovarian cancer (OC) has not been elucidated. Therefore, we sought to evaluate the role for RHAMM in epithelial OC.

Results

Despite little to no expression in normal ovarian surface epithelium, western immunoblotting, immunohistochemical staining and enzyme linked immunosorbent assay showed elevated RHAMM levels in clinical tissue sections, omental metastasis and urine specimens of serous OC patients, as well as in cell lysates. We also found that RHAMM levels increase with increasing grade and stage in serous OC tissues and that RHAMM localizes to the apical cell surface and inclusion cysts. Apical localization of RHAMM suggested protein secretion which was validated by detection of significantly elevated urinary RHAMM levels (p < 0.0001) in OC patients (116.66 pg/mL) compared with normal controls (8.16 pg/mL). Likewise, urinary RHAMM levels decreased following cytoreductive surgery in OC patients suggesting the source of urinary RHAMM from tumor tissue. Lastly, we validated RHAMM levels in OC cell lysate and found at least 12× greater levels compared to normal ovarian surface epithelial cells.

Conclusion

This pilot study shows, for the first time, that RHAMM may contribute to OC disease and could potentially be used as a prognostic marker.

Institute NC. Surveillance, epidemiology and end results program. http://seer.cancer.gov/. Accessed 26 June 2016.

Cannistra SA. Cancer of the ovary. N Engl J Med. 2004;351(24):2519–29. doi:10.1056/NEJMra041842.CrossRefPubMed

Entwistle J, Hall CL, Turley EA. HA receptors: regulators of signalling to the cytoskeleton. J Cell Biochem. 1996;61(4):569–77. doi:10.1002/(SICI)1097-4644(19960616)61:4<569::AID-JCB10>3.0.CO;2-B. CrossRefPubMed

Zhang S, Chang MC, Zylka D, Turley S, Harrison R, Turley EA. The hyaluronan receptor RHAMM regulates extracellular-regulated kinase. J Biol Chem. 1998;273(18):11342–8.CrossRefPubMed

Gust KM, Hofer MD, Perner SR, et al. RHAMM (CD168) is overexpressed at the protein level and may constitute an immunogenic antigen in advanced prostate cancer disease. Neoplasia. 2009;11(9):956–63. doi:10.1593/neo.09694.CrossRefPubMedPubMedCentral

Niedworok C, Kretschmer I, Röck K, et al. The impact of the receptor of hyaluronan-mediated motility (RHAMM) on human urothelial transitional cell cancer of the bladder. PLoS One. 2013;8(9):e75681. doi:10.1371/journal.pone.0075681.CrossRefPubMedPubMedCentral

Veiseh M, Kwon DH, Borowsky AD, et al. Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset. Proc Natl Acad Sci U S A. 2014;111:E1731–9. doi:10.1073/pnas.1402383111.CrossRefPubMedPubMedCentral

Koelzer VH, Huber B, Mele V, et al. Expression of the hyaluronan-mediated motility receptor RHAMM in tumor budding cells identifies aggressive colorectal cancers. Hum Pathol. 2015;46(11):1573–81. doi:10.1016/j.humpath.2015.07.010.

Coulson-Thomas VJ, Gesteira TF, Hascall V, Kao W. Umbilical cord mesenchymal stem cells suppress host rejection: the role of the glycocalyx. J Biol Chem. 2014;289(34):23465–81. doi:10.1074/jbc.M114.557447.CrossRefPubMedPubMedCentral

10.

Wang C, Thor AD, Moore DH, et al. 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. 1998;4(3):567 LP-576. http://clincancerres.aacrjournals.org/content/4/3/567.abstract.

11.

Assmann V, Gillett CE, Poulsom R, Ryder K, Hart IR, Hanby AM. 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. 2001;195(2):191–6. doi:10.1002/path.941.CrossRefPubMed

12.

Koelzer VH, Bettina H, Valentina M, et al. Expression of the hyaluronan acid mediated motility receptor RHAMM in tumor budding cells identifies aggressive colorectal cancers. Hum Pathol Accept Publ 2015. doi:10.1016/j.humpath.2015.07.010.

13.

Hamilton SR, Fard SF, Paiwand FF, et al. The hyaluronan receptors CD44 and Rhamm (CD168) form complexes with ERK1,2 that sustain high basal motility in breast cancer cells. J Biol Chem. 2007;282(22):16667–80. doi:10.1074/jbc.M702078200.CrossRefPubMedPubMedCentral

14.

Przybycin CG, Kurman RJ, Ronnett BM, Shih LM, Vang R. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol. 2010;34(10):1407–16. doi:10.1097/PAS.0b013e3181ef7b16.CrossRefPubMed

15.

Brachova P, Thiel KW, Leslie KK. The consequence of oncomorphic TP53 mutations in ovarian cancer. Int J Mol Sci. 2013;14(9):19257–75. doi:10.3390/ijms140919257.CrossRefPubMedPubMedCentral

16.

Sohr S, Engeland K. RHAMM is differentially expressed in the cell cycle and downregulated by the tumor suppressor p53. Cell Cycle. 2008;7(21):3448–60. doi:10.4161/cc.7.21.7014.CrossRefPubMed

17.

Turley EA, Noble PW, Bourguignon LYW. Signaling properties of hyaluronan receptors. J Biol Chem. 2002;277(7):4589–92. doi:10.1074/jbc.R100038200.CrossRefPubMed

18.

Nikitovic D, Tzardi M, Berdiaki A, Tsatsakis A, Tzanakakis GN. Cancer microenvironment and inflammation: role of hyaluronan. Front Immunol. 2015;6:169. doi:10.3389/fimmu.2015.00169.CrossRefPubMedPubMedCentral

19.

Valle M, Federici O, Carboni F, et al. Postoperative infections after cytoreductive surgery and HIPEC for peritoneal carcinomatosis: proposal and results from a prospective protocol study of prevention, surveillance and treatment. Eur J Surg Oncol. 2014;40(8):950–6. doi:10.1016/j.ejso.2013.10.015.CrossRefPubMed

20.

Tolg C, McCarthy JB, Yazdani A, Turley EA. Hyaluronan and RHAMM in wound repair and the “Cancerization” of Stromal tissues. Biomed Res Int. 2014;2014:103923. doi:10.1155/2014/103923.CrossRefPubMedPubMedCentral

21.

Pories SE, Zurakowski D, Roy R, et al. Urinary metalloproteinases: noninvasive biomarkers for breast cancer risk assessment. Cancer Epidemiol Biomark Prev. 2008;17(5):1034–42. doi:10.1158/1055-9965.EPI-07-0365.CrossRef

22.

Donadio C, Lucchesi A, Ardini M, Cosio S, Gadducci A. Renal impairment in patients with ovarian cancer. Eur J Obstet Gynecol Reprod Biol. 2003;106(2):198-202. doi:10.1016/S0301-2115(02)00234-8.

23.

Maxwell CA, McCarthy J, Turley E. Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions? J Cell Sci. 2008;121:925–32. doi:10.1242/jcs.022038.CrossRefPubMed

24.

Assmann V, Marshall JF, Fieber C, Hofmann M, Hart IR. The human hyaluronan receptor RHAMM is expressed as an intracellular protein in breast cancer cells. J Cell Sci. 1998;1694: 1685-1694.

Title: Increased RHAMM expression relates to ovarian cancer progression
Authors: Stephanie T. Buttermore
Mitchel S. Hoffman
Ambuj Kumar
Anne Champeaux
Santo V. Nicosia
Patricia A. Kruk
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Ovarian Research / Issue 1/2017
Electronic ISSN: 1757-2215
DOI: https://doi.org/10.1186/s13048-017-0360-1

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Increased RHAMM expression relates to ovarian cancer progression

Abstract

Background

Results

Conclusion

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2017

MicroRNA-205 promotes cell invasion by repressing TCF21 in human ovarian cancer

Anatomical organization and neural pathways of the ovarian plexus nerve in rats

Circulating cell-free DNA and circulating tumor cells, the “liquid biopsies” in ovarian cancer

Effects of a single 20 mg dose of letrozole on ovarian function post dominant follicle selection: an exploratory randomized controlled trial

Does serum CA125 have clinical value for follow-up monitoring of postoperative patients with epithelial ovarian cancer? Results of a 12-year study

The aberrant upstream pathway regulations of CDK1 protein were implicated in the proliferation and apoptosis of ovarian cancer cells