Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

miR-296 regulation of a cell polarity–cell plasticity module controls tumor progression

Abstract

The expression of small, non-coding RNA or microRNAs (miR), is frequently deregulated in human cancer, but how these pathways affect disease progression is still largely elusive. Here, we report on a miR, miR-296, which is progressively lost during tumor progression and correlates with metastatic disease in colorectal, breast, lung, gastric, parathyroid, liver and bile ducts cancers. Functionally, miR-296 controls a global cell motility gene signature in epithelial cells by transcriptionally repressing the cell polarity–cell plasticity module, Scribble (Scrib). In turn, loss of miR-296 causes aberrantly increased and mislocalized Scrib in human tumors, resulting in exaggerated random cell migration and tumor cell invasiveness. Re-expression of miR-296 in MDA-MB231 cells inhibits tumor growth in vivo. Finally, miR-296 or Scrib levels predict tumor relapse in hepatocellular carcinoma patients. These data identify miR-296 as a global repressor of tumorigenicity and uncover a previously unexplored exploitation of Scrib in tumor progression in humans.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Assemat E, Bazellieres E, Pallesi-Pocachard E, Le Bivic A, Massey-Harroche D . (2008). Polarity complex proteins. Biochim Biophys Acta 1778: 614–630.

    Article  CAS  Google Scholar 

  • Augello C, Caruso L, Maggioni M, Donadon M, Montorsi M, Santambrogio R et al. (2009). Inhibitors of apoptosis proteins (IAPs) expression and their prognostic significance in hepatocellular carcinoma. BMC Cancer 9: 125.

    Article  Google Scholar 

  • Bahri S, Wang S, Conder R, Choy J, Vlachos S, Dong K et al. (2010). The leading edge during dorsal closure as a model for epithelial plasticity: Pak is required for recruitment of the Scribble complex and septate junction formation. Development 137: 2023–2032.

    Article  CAS  Google Scholar 

  • Bartel DP . (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281–297.

    Article  CAS  Google Scholar 

  • Bauer M, Su G, Casper C, He R, Rehrauer W, Friedl A . (2010). Heterogeneity of gene expression in stromal fibroblasts of human breast carcinomas and normal breast. Oncogene 9: 1732–1740.

    Article  Google Scholar 

  • Bilder D, Li M, Perrimon N . (2000). Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289: 113–116.

    Article  CAS  Google Scholar 

  • Calin GA, Croce CM . (2006). MicroRNA signatures in human cancers. Nat Rev Cancer 6: 857–866.

    Article  CAS  Google Scholar 

  • Dow LE, Elsum IA, King CL, Kinross KM, Richardson HE, Humbert PO . (2008). Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling. Oncogene 27: 5988–6001.

    Article  CAS  Google Scholar 

  • Dow LE, Kauffman JS, Caddy J, Zarbalis K, Peterson AS, Jane SM et al. (2007). The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge. Oncogene 26: 2272–2282.

    Article  CAS  Google Scholar 

  • Etienne-Manneville S . (2008). Polarity proteins in migration and invasion. Oncogene 27: 6970–6980.

    Article  CAS  Google Scholar 

  • Gardiol D, Zacchi A, Petrera F, Stanta G, Banks L . (2006). Human discs large and scrib are localized at the same regions in colon mucosa and changes in their expression patterns are correlated with loss of tissue architecture during malignant progression. Int J Cancer 119: 1285–1290.

    Article  CAS  Google Scholar 

  • Garzon R, Calin GA, Croce CM . (2009). MicroRNAs in cancer. Annu Rev Med 60: 167–179.

    Article  CAS  Google Scholar 

  • Hanahan D . (1988). Dissecting multistep tumorigenesis in transgenic mice. Annu Rev Genet 22: 479–519.

    Article  CAS  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    Article  CAS  Google Scholar 

  • Hong L, Han Y, Zhang H, Li M, Gong T, Sun L et al. (2010). The prognostic and chemotherapeutic value of miR-296 in esophageal squamous cell carcinoma. Ann Surg 251: 1056–1063.

    Article  Google Scholar 

  • Houbaviy HB, Murray MF, Sharp PA . (2003). Embryonic stem cell-specific microRNAs. Dev Cell 5: 351–358.

    Article  CAS  Google Scholar 

  • Humbert PO, Grzeschik NA, Brumby AM, Galea R, Elsum I, Richardson HE . (2008). Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module. Oncogene 27: 6888–6907.

    Article  CAS  Google Scholar 

  • Kamei Y, Kito K, Takeuchi T, Imai Y, Murase R, Ueda N et al. (2007). Human scribble accumulates in colorectal neoplasia in association with an altered distribution of beta-catenin. Hum Pathol 38: 1273–1281.

    Article  CAS  Google Scholar 

  • Kim SW, Kim JW, Kim YT, Kim JH, Kim S, Yoon BS et al. (2007). Analysis of chromosomal changes in serous ovarian carcinoma using high-resolution array comparative genomic hybridization: potential predictive markers of chemoresistant disease. Genes Chromosomes Cancer 46: 1–9.

    Article  CAS  Google Scholar 

  • Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D et al. (2005). MicroRNA expression profiles classify human cancers. Nature 435: 834–838.

    Article  CAS  Google Scholar 

  • Nagasaka K, Pim D, Massimi P, Thomas M, Tomaić V, Subbaiah VK et al. (2010). The cell polarity regulator hScrib controls ERK activation through a KIM site-dependent interaction. Oncogene 23: 5311–5321.

    Article  Google Scholar 

  • Naylor TL, Greshock J, Wang Y, Colligon T, Yu QC, Clemmer V et al. (2005). High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization. Breast Cancer Res 7: R1186–R1198.

    Article  CAS  Google Scholar 

  • Olson P, Lu J, Zhang H, Shai A, Chun MG, Wang Y et al. (2009). MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer. Genes Dev 23: 2152–2165.

    Article  CAS  Google Scholar 

  • Osmani N, Vitale N, Borg JP, Etienne-Manneville S . (2006). Scrib controls Cdc42 localization and activity to promote cell polarization during astrocyte migration. Curr Biol 16: 2395–2405.

    Article  CAS  Google Scholar 

  • Ouyang Z, Zhan W, Dan L . (2010). hScrib, a human homolog of Drosophila neoplastic tumor suppressor, is involved in the progress of endometrial cancer. Oncol Res 18: 593–599.

    Article  Google Scholar 

  • Pedersen IM, Cheng G, Wieland S, Volinia S, Croce CM, Chisari FV et al. (2007). Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449: 919–922.

    Article  CAS  Google Scholar 

  • Petrie RJ, Doyle AD, Yamada KM . (2009). Random versus directionally persistent cell migration. Nat Rev Mol Cell Biol 10: 538–549.

    Article  CAS  Google Scholar 

  • Phua DC, Humbert PO, Hunziker W . (2009). Vimentin regulates scribble activity by protecting it from proteasomal degradation. Mol Biol Cell 20: 2841–2855.

    Article  CAS  Google Scholar 

  • Romagnoli S, Fasoli E, Vaira V, Falleni M, Pellegrini C, Catania A et al. (2009). Identification of potential therapeutic targets in malignant mesothelioma using cell-cycle gene expression analysis. Am J Pathol 174: 762–770.

    Article  CAS  Google Scholar 

  • Seike M, Goto A, Okano T, Bowman ED, Schetter AJ, Horikawa I et al. (2009). MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers. Proc Natl Acad Sci USA 106: 12085–12090.

    Article  CAS  Google Scholar 

  • Tay Y, Zhang J, Thomson AM, Lim B, Rigoutsos I . (2008). MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 455: 1124–1128.

    Article  CAS  Google Scholar 

  • Valastyan S, Reinhardt F, Benaich N, Calogrias D, Szasz AM, Wang ZC et al. (2009). A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell 137: 1032–1046.

    Article  CAS  Google Scholar 

  • Wei JJ, Wu X, Peng Y, Shi G, Olca B, Yang X et al. (2010). Regulation of HMGA1 expression by microRNA296 affects prostate cancer growth and invasion. Clin Cancer Res 17: 1297–1305.

    Article  Google Scholar 

  • Woo HG, Park ES, Lee JS, Lee YH, Ishikawa T, Kim YJ et al. (2009). Identification of potential driver genes in human liver carcinoma by genomewide screening. Cancer Res 69: 4059–4066.

    Article  CAS  Google Scholar 

  • Wu M, Pastor-Pareja JC, Xu T . (2010). Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature 463: 545–548.

    Article  CAS  Google Scholar 

  • Wurdinger T, Tannous BA, Saydam O, Skog J, Grau S, Soutschek J et al. (2008). miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells. Cancer Cell 14: 382–393.

    Article  CAS  Google Scholar 

  • Yang H, Gu J, Wang KK, Zhang W, Xing J, Chen Z et al. (2009). MicroRNA expression signatures in Barrett's esophagus and esophageal adenocarcinoma. Clin Cancer Res 15: 5744–5752.

    Article  CAS  Google Scholar 

  • Zhan L, Rosenberg A, Bergami KC, Yu M, Xuan Z, Jaffe AB et al. (2008). Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell 135: 865–878.

    Article  CAS  Google Scholar 

  • Zhang H, Li Y, Lai M . (2010). The microRNA network and tumor metastasis. Oncogene 29: 937–948.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Riccardo Ghidoni, Michele Samaja and Massimo Locati for availability of laboratory equipment and reagents, Patrizia Doi and Delfina Tosi for technical help. AF is supported by a fellowship of the Doctorate School of Molecular Medicine at Università degli Studi di Milano. This work was supported by grants from the Fondazione Invernizzi (to GC), Fondazione Berlucchi (to SB), and from National Institutes of Health grants HL54131, CA140043, CA78810 and CA118005 (to DCA).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S Bosari.

Ethics declarations

Competing interests

The authors declare no conflicts of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vaira, V., Faversani, A., Dohi, T. et al. miR-296 regulation of a cell polarity–cell plasticity module controls tumor progression. Oncogene 31, 27–38 (2012). https://doi.org/10.1038/onc.2011.209

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.209

Keywords

This article is cited by

Search

Quick links