Expression and role of nestin in human cervical intraepithelial neoplasia and cervical cancer

Sato,Atsuki; Ishiwata,Toshiyuki; Matsuda,Yoko; Yamamoto,Tetsushi; Asakura,Hirobumi; Takeshita,Toshiyuki; Naito,Zenya

doi:10.3892/ijo.2012.1473

Expression and role of nestin in human cervical intraepithelial neoplasia and cervical cancer

Authors:
- Atsuki Sato
- Toshiyuki Ishiwata
- Yoko Matsuda
- Tetsushi Yamamoto
- Hirobumi Asakura
- Toshiyuki Takeshita
- Zenya Naito
View Affiliations

Affiliations: Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo 113-8602, Japan, Division of Reproductive Medicine, Perinatology and Gynecologic Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
Published online on: May 10, 2012 https://doi.org/10.3892/ijo.2012.1473
Pages: 441-448
Copyright: © Sato et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Nestin expression reportedly correlates with aggressive growth, metastasis, poor prognosis and presence of cancer stem cells (CSCs) in various tumors. In this study, we determined the expression and role of nestin in cervical intraepithelial neoplasia (CIN) and cervical cancer. We performed immunohistochemical and in situ hybridization analyses of nestin in 26 cases for each stage of CIN and 55 cervical cancer tissue samples. To examine the role of nestin in cervical cancer cells, we stably transfected expression vectors containing nestin cDNA into ME-180 cells. We studied the effects of increased nestin expression on cell proliferation, cell motility, invasion as well as sphere and soft agar formation. Nestin was not localized in the squamous epithelium in normal cervical tissues, but it was weakly expressed in the basal squamous epithelium of CIN 1. In CIN 2, nestin was localized to the basal to lower 2/3 of the squamous epithelium, whereas in CIN 3, it was localized to the majority of the squamous epithelium. Nestin was detected in all cases of invasive cervical cancer. Nestin mRNA was expressed in both ME-180 and CaSki cells. Growth rate, cell motility and invasion ability of stably nestin-transfected ME-180 cells were not different from empty vector-transfected ME-180 (mock cells). However, the nestin-transfected ME-180 cells formed more colonies and spheres compared to the mock cells. These findings suggest that nestin plays important roles in carcinogenesis and tumor formation of cervical cancer cells. Nestin may closely correlate with regulation of CSCs.

View Figures

View References

1	Phongsavan K, Phengsavanh A, Wahlstrom R and Marions L: Women’s perception of cervical cancer and its prevention in rural Laos. Int J Gynecol Cancer. 20:821–826. 2010.
2	Wang X, Liu R, Ma B, et al: High dose rate versus low dose rate intracavity brachytherapy for locally advanced uterine cervix cancer. Cochrane Database Syst Rev. CD0075632010.
3	Agarwal SM, Raghav D, Singh H and Raghava GP: CCDB: a curated database of genes involved in cervix cancer. Nucleic Acids Res. 39:D975–D979. 2011. View Article : Google Scholar : PubMed/NCBI
4	Kawase R, Ishiwata T, Matsuda Y, et al: Expression of fibroblast growth factor receptor 2 IIIc in human uterine cervical intraepithelial neoplasia and cervical cancer. Int J Oncol. 36:331–340. 2010.
5	Lendahl U, Zimmerman LB and McKay RD: CNS stem cells express a new class of intermediate filament protein. Cell. 60:585–595. 1990. View Article : Google Scholar : PubMed/NCBI
6	Kawamoto M, Ishiwata T, Cho K, et al: Nestin expression correlates with nerve and retroperitoneal tissue invasion in pancreatic cancer. Hum Pathol. 40:189–198. 2009. View Article : Google Scholar : PubMed/NCBI
7	Ishiwata T, Teduka K, Yamamoto T, Kawahara K, Matsuda Y and Naito Z: Neuroepithelial stem cell marker nestin regulates the migration, invasion and growth of human gliomas. Oncol Rep. 26:91–99. 2011.PubMed/NCBI
8	Marvin MJ, Dahlstrand J, Lendahl U and McKay RD: A rod end deletion in the intermediate filament protein nestin alters its subcellular localization in neuroepithelial cells of transgenic mice. J Cell Sci. 111:1951–1961. 1998.PubMed/NCBI
9	Sjoberg G, Edstrom L, Lendahl U and Sejersen T: Myofibers from Duchenne/Becker muscular dystrophy and myositis express the intermediate filament nestin. J Neuropathol Exp Neurol. 53:416–423. 1994. View Article : Google Scholar : PubMed/NCBI
10	Steinert PM, Chou YH, Prahlad V, et al: A high molecular weight intermediate filament-associated protein in BHK-21 cells is nestin, a type VI intermediate filament protein. Limited co-assembly in vitro to form heteropolymers with type III vimentin and type IV alpha-internexin. J Biol Chem. 274:9881–9890. 1999. View Article : Google Scholar
11	Sejersen T and Lendahl U: Transient expression of the intermediate filament nestin during skeletal muscle development. J Cell Sci. 106:1291–1300. 1993.PubMed/NCBI
12	Frojdman K, Pelliniemi LJ, Lendahl U, Virtanen I and Eriksson JE: The intermediate filament protein nestin occurs transiently in differentiating testis of rat and mouse. Differentiation. 61:243–249. 1997. View Article : Google Scholar : PubMed/NCBI
13	Terling C, Rass A, Mitsiadis TA, Fried K, Lendahl U and Wroblewski J: Expression of the intermediate filament nestin during rodent tooth development. Int J Dev Biol. 39:947–956. 1995.PubMed/NCBI
14	Kachinsky AM, Dominov JA and Miller JB: Myogenesis and the intermediate filament protein, nestin. Dev Biol. 165:216–228. 1994. View Article : Google Scholar : PubMed/NCBI
15	Ishizaki M, Ishiwata T, Adachi A, et al: Expression of nestin in rat and human glomerular podocytes. J Submicrosc Cytol Pathol. 38:193–200. 2006.PubMed/NCBI
16	Yang J, Bian W, Gao X, Chen L and Jing N: Nestin expression during mouse eye and lens development. Mech Dev. 94:287–291. 2000. View Article : Google Scholar : PubMed/NCBI
17	Almazan G, Vela JM, Molina-Holgado E and Guaza C: Re-evaluation of nestin as a marker of oligodendrocyte lineage cells. Microsc Res Tech. 52:753–765. 2001. View Article : Google Scholar : PubMed/NCBI
18	Amoh Y, Li L, Yang M, et al: Nascent blood vessels in the skin arise from nestin-expressing hair-follicle cells. Proc Natl Acad Sci USA. 101:13291–13295. 2004. View Article : Google Scholar : PubMed/NCBI
19	Lardon J, Rooman I and Bouwens L: Nestin expression in pancreatic stellate cells and angiogenic endothelial cells. Histochem Cell Biol. 117:535–540. 2002. View Article : Google Scholar : PubMed/NCBI
20	Takano T, Rutka JT and Becker LE: Overexpression of nestin and vimentin in ependymal cells in hydrocephalus. Acta Neuropathol. 92:90–97. 1996. View Article : Google Scholar : PubMed/NCBI
21	Eaker EY and Sallustio JE: The distribution of novel intermediate filament proteins defines subpopulations of myenteric neurons in rat intestine. Gastroenterology. 107:666–674. 1994. View Article : Google Scholar : PubMed/NCBI
22	Yamada H, Takano T, Ito Y, et al: Expression of nestin mRNA is a differentiation marker in thyroid tumors. Cancer Lett. 280:61–64. 2009. View Article : Google Scholar : PubMed/NCBI
23	Strojnik T, Rosland GV, Sakariassen PO, Kavalar R and Lah T: Neural stem cell markers, nestin and musashi proteins, in the progression of human glioma: correlation of nestin with prognosis of patient survival. Surg Neurol. 68:133–144. 2007. View Article : Google Scholar : PubMed/NCBI
24	Brychtova S, Fiuraskova M, Hlobilkova A, Brychta T and Hirnak J: Nestin expression in cutaneous melanomas and melanocytic nevi. J Cutan Pathol. 34:370–375. 2007. View Article : Google Scholar : PubMed/NCBI
25	Tsujimura T, Makiishi-Shimobayashi C, Lundkvist J, et al: Expression of the intermediate filament nestin in gastrointestinal stromal tumors and interstitial cells of Cajal. Am J Pathol. 158:817–823. 2001. View Article : Google Scholar : PubMed/NCBI
26	Li H, Cherukuri P, Li N, et al: Nestin is expressed in the basal/myoepithelial layer of the mammary gland and is a selective marker of basal epithelial breast tumors. Cancer Res. 67:501–510. 2007. View Article : Google Scholar : PubMed/NCBI
27	Kleeberger W, Bova GS, Nielsen ME, et al: Roles for the stem cell associated intermediate filament Nestin in prostate cancer migration and metastasis. Cancer Res. 67:9199–9206. 2007. View Article : Google Scholar : PubMed/NCBI
28	Dahlstrand J, Collins VP and Lendahl U: Expression of the class VI intermediate filament nestin in human central nervous system tumors. Cancer Res. 52:5334–5341. 1992.PubMed/NCBI
29	Ma YH, Mentlein R, Knerlich F, Kruse ML, Mehdorn HM and Held-Feindt J: Expression of stem cell markers in human astrocytomas of different WHO grades. J Neurooncol. 86:31–45. 2008. View Article : Google Scholar : PubMed/NCBI
30	Klein WM, Wu BP, Zhao S, Wu H, Klein-Szanto AJ and Tahan SR: Increased expression of stem cell markers in malignant melanoma. Mod Pathol. 20:102–107. 2007. View Article : Google Scholar : PubMed/NCBI
31	Florenes VA, Holm R, Myklebost O, Lendahl U and Fodstad O: Expression of the neuroectodermal intermediate filament nestin in human melanomas. Cancer Res. 54:354–356. 1994.PubMed/NCBI
32	Liu C, Chen B, Zhu J, et al: Clinical implications for nestin protein expression in breast cancer. Cancer Sci. 101:815–819. 2010. View Article : Google Scholar : PubMed/NCBI
33	Matsuda Y, Naito Z, Kawahara K, Nakazawa N, Korc M and Ishiwata T: Nestin is a novel target for suppressing pancreatic cancer cell migration, invasion and metastasis. Cancer Biol Ther. 11:512–523. 2011. View Article : Google Scholar : PubMed/NCBI
34	Guzman-Ramirez N, Voller M, Wetterwald A, et al: In vitro propagation and characterization of neoplastic stem/progenitor-like cells from human prostate cancer tissue. Prostate. 69:1683–1693. 2009. View Article : Google Scholar : PubMed/NCBI
35	Kasper S: Exploring the origins of the normal prostate and prostate cancer stem cell. Stem Cell Rev. 4:193–201. 2008. View Article : Google Scholar : PubMed/NCBI
36	Hombach-Klonisch S, Paranjothy T, Wiechec E, et al: Cancer stem cells as targets for cancer therapy: selected cancers as examples. Arch Immunol Ther Exp (Warsz). 56:165–180. 2008. View Article : Google Scholar : PubMed/NCBI
37	Okuno K, Ohta S, Kato H, Taga T, Sugita K and Takeuchi Y: Expression of neural stem cell markers in malignant rhabdoid tumor cell lines. Oncol Rep. 23:485–492. 2010.PubMed/NCBI
38	Bortolomai I, Canevari S, Facetti I, et al: Tumor initiating cells: development and critical characterization of a model derived from the A431 carcinoma cell line forming spheres in suspension. Cell Cycle. 9:1194–1206. 2010. View Article : Google Scholar : PubMed/NCBI
39	Singh SK, Clarke ID, Hide T and Dirks PB: Cancer stem cells in nervous system tumors. Oncogene. 23:7267–7273. 2004. View Article : Google Scholar : PubMed/NCBI
40	Bentivegna A, Conconi D, Panzeri E, et al: Biological heterogeneity of putative bladder cancer stem-like cell populations from human bladder transitional cell carcinoma samples. Cancer Sci. 101:416–424. 2010. View Article : Google Scholar : PubMed/NCBI
41	Jimeno A, Feldmann G, Suarez-Gauthier A, et al: A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development. Mol Cancer Ther. 8:310–314. 2009. View Article : Google Scholar : PubMed/NCBI
42	Kurban G, Ishiwata T, Kudo M, Yokoyama M, Sugisaki Y and Naito Z: Expression of keratinocyte growth factor receptor (KGFR/FGFR2 IIIb) in human uterine cervical cancer. Oncol Rep. 11:987–991. 2004.PubMed/NCBI
43	Naito Z, Ishiwata T, Kurban G, et al: Expression and accumulation of lumican protein in uterine cervical cancer cells at the periphery of cancer nests. Int J Oncol. 20:943–948. 2002.PubMed/NCBI
44	Aarimaa V, Kaariainen M, Vaittinen S, et al: Restoration of myofiber continuity after transection injury in the rat soleus. Neuromuscul Disord. 14:421–428. 2004. View Article : Google Scholar : PubMed/NCBI
45	Holmin S, Almqvist P, Lendahl U and Mathiesen T: Adult nestin-expressing subependymal cells differentiate to astrocytes in response to brain injury. Eur J Neurosci. 9:65–75. 1997. View Article : Google Scholar : PubMed/NCBI
46	Lin RC, Matesic DF, Marvin M, McKay RD and Brustle O: Re-expression of the intermediate filament nestin in reactive astrocytes. Neurobiol Dis. 2:79–85. 1995. View Article : Google Scholar : PubMed/NCBI
47	Niki T, Pekny M, Hellemans K, et al: Class VI intermediate filament protein nestin is induced during activation of rat hepatic stellate cells. Hepatology. 29:520–527. 1999. View Article : Google Scholar : PubMed/NCBI
48	El-Helou V, Dupuis J, Proulx C, et al: Resident nestin+ neural-like cells and fibers are detected in normal and damaged rat myocardium. Hypertension. 46:1219–1225. 2005.
49	Wiese C, Rolletschek A, Kania G, et al: Nestin expression - a property of multi-lineage progenitor cells? Cell Mol Life Sci. 61:2510–2522. 2004. View Article : Google Scholar : PubMed/NCBI
50	Teranishi N, Naito Z, Ishiwata T, et al: Identification of neovasculature using nestin in colorectal cancer. Int J Oncol. 30:593–603. 2007.PubMed/NCBI
51	Hammes LS, Tekmal RR, Naud P, et al: Up-regulation of VEGF, c-fms and COX-2 expression correlates with severity of cervical cancer precursor (CIN) lesions and invasive disease. Gynecol Oncol. 110:445–451. 2008. View Article : Google Scholar : PubMed/NCBI
52	Soufla G, Sifakis S, Baritaki S, Zafiropoulos A, Koumantakis E and Spandidos DA: VEGF, FGF2, TGFB1 and TGFBR1 mRNA expression levels correlate with the malignant transformation of the uterine cervix. Cancer Lett. 221:105–118. 2005. View Article : Google Scholar : PubMed/NCBI
53	Kuramoto H, Hongo A, Liu YX, et al: Immunohistochemical evaluation of insulin-like growth factor I receptor status in cervical cancer specimens. Acta Med Okayama. 62:251–259. 2008.PubMed/NCBI
54	Feng D, Peng C, Li C, et al: Identification and characterization of cancer stem-like cells from primary carcinoma of the cervix uteri. Oncol Rep. 22:1129–1134. 2009.PubMed/NCBI
55	Gu W, Yeo E, McMillan N and Yu C: Silencing oncogene expression in cervical cancer stem-like cells inhibits their cell growth and self-renewal ability. Cancer Gene Ther. 18:897–905. 2011. View Article : Google Scholar : PubMed/NCBI