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Loss of microRNA-27b contributes to breast cancer stem cell generation by activating ENPP1.

Takahashi RU, Miyazaki H, Takeshita F, Yamamoto Y, Minoura K, Ono M, Kodaira M, Tamura K, Mori M, Ochiya T - Nat Commun (2015)

Bottom Line: Here, we identified microRNA-27b (miR-27b) as a key regulator for the generation of a side-population in breast cancer cells that showed CSC properties, and also found that the anti-type II diabetes (T2D) drug metformin reduced this side-population via miR-27b-mediated repression of ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1), which is involved in T2D development.ENPP1 induced the generation of the side-population via upregulation of the ABCG2 transporter.ENPP1 was also identified as a substrate of the 26S proteasome, the activity of which is downregulated in CSCs.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Tokyo 104-0045, Japan.

ABSTRACT
Cancer stem cells (CSCs) have been identified in various types of cancer; however, the mechanisms by which cells acquire CSC properties such as drug resistance and tumour seeding ability are not fully understood. Here, we identified microRNA-27b (miR-27b) as a key regulator for the generation of a side-population in breast cancer cells that showed CSC properties, and also found that the anti-type II diabetes (T2D) drug metformin reduced this side-population via miR-27b-mediated repression of ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1), which is involved in T2D development. ENPP1 induced the generation of the side-population via upregulation of the ABCG2 transporter. ENPP1 was also identified as a substrate of the 26S proteasome, the activity of which is downregulated in CSCs. Overall, these results demonstrate that a T2D-associated gene plays an important role in tumour development and that its expression is strictly controlled at the mRNA and protein levels.

No MeSH data available.


Related in: MedlinePlus

MiR-27b regulates the tumour seeding ability of breast cancer cells.(a) Flow cytometric analyses of MCF7-luc Zs-DR-27bs cells transfected with LNA-NC or LNA-miR-27b. (b) Overview of the method used to analyse the CSC properties of docetaxel-treated MCF7-luc cell derivatives. (c) Bioluminescent images of tumours in NOD/SCID mice injected with docetaxel (DOC)-treated MCF7-luc cell derivatives. Representative images are shown for each cohort. (d) The numbers of animals with detectable tumours in the groups injected with the MCF7-luc cell derivatives.
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f3: MiR-27b regulates the tumour seeding ability of breast cancer cells.(a) Flow cytometric analyses of MCF7-luc Zs-DR-27bs cells transfected with LNA-NC or LNA-miR-27b. (b) Overview of the method used to analyse the CSC properties of docetaxel-treated MCF7-luc cell derivatives. (c) Bioluminescent images of tumours in NOD/SCID mice injected with docetaxel (DOC)-treated MCF7-luc cell derivatives. Representative images are shown for each cohort. (d) The numbers of animals with detectable tumours in the groups injected with the MCF7-luc cell derivatives.

Mentions: To confirm that MCF7 cells in the SP fraction show downregulation of miR-27b, the expression levels of Zs-DR and the sizes of the SP fraction were determined in MCF7-luc Zs-DR-27bs cells transfected with LNA-miR-27b or LNA-NC. In both cell types, the SP fraction of the Zs-DR-positive cells was three- to fourfold larger than that of the Zs-DR-negative cells (Fig. 3a). Notably, unlike LNA-NC, LNA-miR-27b caused a drastic increase in the number of Zs-DR-positive cells that showed the SP phenotype (Fig. 3a).


Loss of microRNA-27b contributes to breast cancer stem cell generation by activating ENPP1.

Takahashi RU, Miyazaki H, Takeshita F, Yamamoto Y, Minoura K, Ono M, Kodaira M, Tamura K, Mori M, Ochiya T - Nat Commun (2015)

MiR-27b regulates the tumour seeding ability of breast cancer cells.(a) Flow cytometric analyses of MCF7-luc Zs-DR-27bs cells transfected with LNA-NC or LNA-miR-27b. (b) Overview of the method used to analyse the CSC properties of docetaxel-treated MCF7-luc cell derivatives. (c) Bioluminescent images of tumours in NOD/SCID mice injected with docetaxel (DOC)-treated MCF7-luc cell derivatives. Representative images are shown for each cohort. (d) The numbers of animals with detectable tumours in the groups injected with the MCF7-luc cell derivatives.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490376&req=5

f3: MiR-27b regulates the tumour seeding ability of breast cancer cells.(a) Flow cytometric analyses of MCF7-luc Zs-DR-27bs cells transfected with LNA-NC or LNA-miR-27b. (b) Overview of the method used to analyse the CSC properties of docetaxel-treated MCF7-luc cell derivatives. (c) Bioluminescent images of tumours in NOD/SCID mice injected with docetaxel (DOC)-treated MCF7-luc cell derivatives. Representative images are shown for each cohort. (d) The numbers of animals with detectable tumours in the groups injected with the MCF7-luc cell derivatives.
Mentions: To confirm that MCF7 cells in the SP fraction show downregulation of miR-27b, the expression levels of Zs-DR and the sizes of the SP fraction were determined in MCF7-luc Zs-DR-27bs cells transfected with LNA-miR-27b or LNA-NC. In both cell types, the SP fraction of the Zs-DR-positive cells was three- to fourfold larger than that of the Zs-DR-negative cells (Fig. 3a). Notably, unlike LNA-NC, LNA-miR-27b caused a drastic increase in the number of Zs-DR-positive cells that showed the SP phenotype (Fig. 3a).

Bottom Line: Here, we identified microRNA-27b (miR-27b) as a key regulator for the generation of a side-population in breast cancer cells that showed CSC properties, and also found that the anti-type II diabetes (T2D) drug metformin reduced this side-population via miR-27b-mediated repression of ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1), which is involved in T2D development.ENPP1 induced the generation of the side-population via upregulation of the ABCG2 transporter.ENPP1 was also identified as a substrate of the 26S proteasome, the activity of which is downregulated in CSCs.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Tokyo 104-0045, Japan.

ABSTRACT
Cancer stem cells (CSCs) have been identified in various types of cancer; however, the mechanisms by which cells acquire CSC properties such as drug resistance and tumour seeding ability are not fully understood. Here, we identified microRNA-27b (miR-27b) as a key regulator for the generation of a side-population in breast cancer cells that showed CSC properties, and also found that the anti-type II diabetes (T2D) drug metformin reduced this side-population via miR-27b-mediated repression of ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1), which is involved in T2D development. ENPP1 induced the generation of the side-population via upregulation of the ABCG2 transporter. ENPP1 was also identified as a substrate of the 26S proteasome, the activity of which is downregulated in CSCs. Overall, these results demonstrate that a T2D-associated gene plays an important role in tumour development and that its expression is strictly controlled at the mRNA and protein levels.

No MeSH data available.


Related in: MedlinePlus