miR-150 promotes human breast cancer growth and malignant behavior by targeting the pro-apoptotic purinergic P2X7 receptor

PLoS One. 2013 Dec 2;8(12):e80707. doi: 10.1371/journal.pone.0080707. eCollection 2013.

Abstract

The P2X7 receptor regulates cell growth through mediation of apoptosis. Low level expression of P2X7 has been linked to cancer development because tumor cells harboring a defective P2X7 mechanism can escape P2X7 pro-apoptotic control. microRNAs (miRNAs) function as negative regulators of post-transcriptional gene expression, playing major roles in cellular differentiation, proliferation, and metastasis. In this study, we found that miR-150 was over-expressed in breast cancer cell lines and tissues. In these breast cancer cell lines, blocking the action of miR-150 with inhibitors leads to cell death, while ectopic expression of the miR-150 results in increased cell proliferation. We deploy a microRNA sponge strategy to inhibit miR-150 in vitro, and the result demonstrates that the 3'-untranslated region (3'UTR) of P2X7 receptor contains a highly conserved miR-150-binding motif and its direct interaction with miR-150 down-regulates endogenous P2X7 protein levels. Furthermore, our findings demonstrate that miR-150 over-expression promotes growth, clonogenicity and reduces apoptosis in breast cancer cells. Meanwhile, these findings can be decapitated in nude mice with breast cancer xenografts. Finally, these observations strengthen our working hypothesis that up-regulation of miR-150 in breast cancer is inversely associated with P2X7 receptor expression level. Together, these findings establish miR-150 as a novel regulator of P2X7 and a potential therapeutic target for breast cancer.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Apoptosis*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Female
  • HEK293 Cells
  • Heterografts
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Neoplasm Transplantation
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism*
  • Receptors, Purinergic P2X7 / biosynthesis*
  • Receptors, Purinergic P2X7 / genetics

Substances

  • 3' Untranslated Regions
  • MIRN150 microRNA, human
  • MicroRNAs
  • Neoplasm Proteins
  • RNA, Neoplasm
  • Receptors, Purinergic P2X7

Grant support

This work was supported by grants from the National Natural Science Foundation of China (81102020, 81172526, 81272897, 81072177), Guangdong Natural Science Foundation (S2011040000385, 10151503102000019). This work was also supported by Key Laboratory of malignant tumor gene regulation and target therapy of Guangdong Higher Education Institutes, Sun Yat-sen University (KLB09001). The funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.