Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion by targeting focal adhesion pathways in cervical squamous cell carcinoma

Yamamoto,Noriko; Kinoshita,Takashi; Nohata,Nijiro; Itesako,Toshihiko; Yoshino,Hirofumi; Enokida,Hideki; Nakagawa,Masayuki; Shozu,Makio; Seki,Naohiko

doi:10.3892/ijo.2013.1851

Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion by targeting focal adhesion pathways in cervical squamous cell carcinoma

Authors:
- Noriko Yamamoto
- Takashi Kinoshita
- Nijiro Nohata
- Toshihiko Itesako
- Hirofumi Yoshino
- Hideki Enokida
- Masayuki Nakagawa
- Makio Shozu
- Naohiko Seki
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Affiliations: Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan, Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan, Department of Obstetrics and Gynecology Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
Published online on: March 7, 2013 https://doi.org/10.3892/ijo.2013.1851
Pages: 1523-1532
Copyright: © Yamamoto et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Cervical cancer is one of the most common cancers in women. More than 275,100 women die from cervical cancer each year. Cervical squamous cell carcinoma (cervical SCC), one of the most frequent types of cervical cancers, is associated with high-risk human papilloma virus (HPV), although HPV infection alone may not be enough to induce malignant transformation. MicroRNAs (miRNAs), a class of small non-coding RNAs, regulate protein-coding gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. A growing body of evidence suggests that miRNAs contribute to cervical SCC progression, development and metastasis. miRNA expression signatures in SCC (hypopharyngeal SCC and esophageal SCC) revealed that miR-218 expression was significantly reduced in cancer tissues compared with adjacent non-cancerous epithelium, suggesting that miR-218 is a candidate tumor suppressor. The aim of this study was to investigate the functional significance of miR-218 in cervical SCC and to identify novel miR‑218-mediated cancer pathways in cervical SCC. Restoration of miR-218 significantly inhibited cancer cell migration and invasion in both HPV-positive and HPV-negative cervical SCC cell lines. These data indicated that miR-218 acts as a tumor suppressor in cervical SCC. Our in silico analysis showed that miR-218 appeared to be an important modulator of tumor cell processes through suppression of many targets, particularly those involved in focal adhesion signaling pathways. Gene expression data indicated that LAMB3, a laminin protein known to influence cell differentiation, migration, adhesion, proliferation and survival, was upregulated in cervical SCC clinical specimens, and silencing studies demonstrated that LAMB3 functioned as an oncogene in cervical SCC. The identification of novel tumor-suppressive miR-218-mediated molecular pathways has provided new insights into cervical SCC oncogenesis and metastasis.

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1.	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2.	Walboomers JM, Jacobs MV, Manos MM, et al: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 189:12–19. 1999. View Article : Google Scholar : PubMed/NCBI
3.	Muñoz N, Bosch FX, De Sanjosé S, et al: Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 348:518–527. 2003.
4.	Clifford GM, Smith JS, Plummer M, Muñoz N and Franceschi S: Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer. 88:63–73. 2003. View Article : Google Scholar : PubMed/NCBI
5.	Band V, Dalal S, Delmolino L and Androphy EJ: Enhanced degradation of p53 protein in HPV-6 and BPV-1 E6-immortalized human mammary epithelial cells. EMBO J. 12:1847–1852. 1993.PubMed/NCBI
6.	Lechnerl MS, Mackl DH, Finicle AB, Crook T, Vousden KH and Laiminsl LA: Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription. EMBO J. 11:3045–3052. 1992.
7.	Thomas M, Pim D and Banks L: The role of the E6-p53 interaction in the molecular pathogenesis of HPV. Oncogene. 18:7690–7700. 1999. View Article : Google Scholar : PubMed/NCBI
8.	Münger K and Howley PM: Human papillomavirus immortalization and transformation functions. Virus Res. 89:213–228. 2002.PubMed/NCBI
9.	Filipowicz W, Bhattacharyya SN and Sonenberg N: Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 9:102–114. 2008. View Article : Google Scholar : PubMed/NCBI
10.	Nelson KM and WEiss GJ: MicroRNAs and cancer: past, present, and potential future. Mol Cancer Ther. 7:3655–3660. 2008. View Article : Google Scholar : PubMed/NCBI
11.	Esquela-Kerscher A and Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar
12.	Kikkawa N, Hanazawa T, Fujimura L, et al: miR-489 is a tumour-suppressive miRNA target PTPN11 in hypopharyngeal squamous cell carcinoma (HSCC). Br J Cancer. 103:877–884. 2010. View Article : Google Scholar : PubMed/NCBI
13.	Nohata N, Hanazawa T, Kikkawa N, et al: Tumour suppressive microRNA-874 regulates novel cancer networks in maxillary sinus squamous cell carcinoma. Br J Cancer. 105:833–841. 2011. View Article : Google Scholar : PubMed/NCBI
14.	Kano M, Seki N, Kikkawa N, et al: miR-145, miR-133a and miR-133b: tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int J Cancer. 127:2804–2814. 2010. View Article : Google Scholar : PubMed/NCBI
15.	Moriya Y, Nohata N, Kinoshita T, et al: Tumor suppressive microRNA-133a regulates novel molecular networks in lung squamous cell carcinoma. J Hum Genet. 57:38–45. 2012. View Article : Google Scholar
16.	Hidaka H, Seki N, Yoshino H, Yamasaki T, et al: Tumor suppressive microRNA-1285 regulates novel molecular targets: aberrant expression and functional significance in renal cell carcinoma. Oncotarget. 3:44–57. 2012.PubMed/NCBI
17.	Ichimi T, Enokida H, Okuno Y, et al: Identification of novel microRNA targets based on microRNA signatures in bladder cancer. Int J Cancer. 125:345–352. 2009. View Article : Google Scholar : PubMed/NCBI
18.	Yoshino H, Chiyomaru T, Enokida H, et al: The tumoursuppressive function of miR-1 and miR-133a targeting TAGLN2 in bladder cancer. Br J Cancer. 104:808–818. 2011. View Article : Google Scholar : PubMed/NCBI
19.	Kinoshita T, Hanazawa T, Nohata N, et al: Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion through targeting laminin-332 in head and neck squamous cell carcinoma. Oncotarget. 3:1386–1400. 2012.PubMed/NCBI
20.	Alajez NM, Lenarduzzi M, Ito E, et al: MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the SLIT2-ROBO1 pathway. Cancer Res. 71:2381–2391. 2011. View Article : Google Scholar : PubMed/NCBI
21.	Uesugi A, Kozaki K-I, Tsuruta T, et al: The tumor suppressive microRNA miR-218 targets the mTOR component Rictor and inhibits AKT phosphorylation in oral cancer. Cancer Res. 71:5765–5678. 2011. View Article : Google Scholar : PubMed/NCBI
22.	Tie J, Pan Y, Zhao L, et al: MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet. 6:e10008792010. View Article : Google Scholar : PubMed/NCBI
23.	Tatarano S, Chiyomaru T, Kawakami K, et al: miR-218 on the genomic loss region of chromosome 4p15.31 functions as a tumor suppressor in bladder cancer. Int J Oncol. 39:13–21. 2011.PubMed/NCBI
24.	Martinez I, Gardiner AS, Board KF, Monzon FA, Edwards RP and Khan SA: Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells. Oncogene. 27:2575–2582. 2008. View Article : Google Scholar : PubMed/NCBI
25.	Gravitt PE, Peyton CL, Alessi TQ, et al: Improved amplification of genital human papillomaviruses. J Clin Microbiol. 38:357–361. 2000.PubMed/NCBI
26.	Mattick JS: RNA regulation: a new genetics? Nat Rev Genet. 5:316–323. 2004. View Article : Google Scholar
27.	Lee J-W, Choi CH, Choi J-J, et al: Altered MicroRNA expression in cervical carcinomas. Clin Cancer Res. 14:2535–2542. 2008. View Article : Google Scholar : PubMed/NCBI
28.	Wang X, Tang S, Le S-Y, et al: Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth. PLoS One. 3:e25572008. View Article : Google Scholar : PubMed/NCBI
29.	Pereira PM, Marques JP, Soares AR, Carreto L and Santos MAS: MicroRNA expression variability in human cervical tissues. PLoS One. 5:e117802010. View Article : Google Scholar : PubMed/NCBI
30.	Li Y, Wang F, Xu J, et al: Progressive miRNA expression profiles in cervical carcinogenesis and identification of HPV-related target genes for miR-29. J Pathol. 224:484–495. 2011. View Article : Google Scholar : PubMed/NCBI
31.	Rao Q, Zhou H, Peng Y, Li J and Lin Z: Aberrant microRNA expression in human cervical carcinomas. Med Oncol. 29:1242–1248. 2012. View Article : Google Scholar : PubMed/NCBI
32.	Li Y, Liu J, Yuan C, Cui B, Zou X and Qiao Y: High-risk human papillomavirus reduces the expression of microRNA-218 in women with cervical intraepithelial neoplasia. J Int Med Res. 38:1730–1736. 2010. View Article : Google Scholar : PubMed/NCBI
33.	Chiyomaru T, Enokida H, Kawakami K, et al: Functional role of LASP1 in cell viability and its regulation by microRNAs in bladder cancer. Urologic Oncol. 30:434–443. 2012. View Article : Google Scholar : PubMed/NCBI
34.	Bartel DP, Lee R and Feinbaum R: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
35.	Guess CM and Quaranta V: Defining the role of laminin-332 in carcinoma. Matrix Biol. 28:445–455. 2009. View Article : Google Scholar : PubMed/NCBI
36.	Marinkovich MP: Laminin 332 in squamous-cell carcinoma. Nat Rev Cancer. 7:370–380. 2007. View Article : Google Scholar : PubMed/NCBI
37.	Carter WG, Ryan MC and Gahr PJ: Epiligrin, a new cell adhesion ligand for integrinα3β1 in epithelial basement membranes. Cell. 65:599–610. 1991.
38.	Schenk S, Hintermann E, Bilban M, et al: Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution. J Cell Biol. 161:197–209. 2003. View Article : Google Scholar : PubMed/NCBI
39.	Okamoto O, Bachy S, Odenthal U, et al: Normal human keratinocytes bind to the alpha3LG4/5 domain of unprocessed laminin-5 through the receptor syndecan-1. J Biol Chem. 278:44168–44177. 2003. View Article : Google Scholar : PubMed/NCBI
40.	Mizejewski GJ: Role of integrins in cancer: survey of expression patterns. Proc Soc Exp Biol Med. 222:124–138. 1999. View Article : Google Scholar : PubMed/NCBI