Limits...
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

Evaluation of ENPP1 expression in breast cancer specimens.(a) Evaluation of ENPP1 mRNA expression in the clinical samples. The y axis displays the expression level of ENPP1 relative to that of GAPDH and the x axis displays the expression level of miR-27b normalized to that of RNU6B. (b) Evaluation of ENPP1 mRNA expression in breast cancer clinical samples classified by luminal-type. Expression levels were normalized to those of GAPDH. Comparisons between groups were performed using unpaired t-tests. (c) Kaplan–Meier representations of the probabilities of recurrence-free survival in 112 breast cancer cases classified according to the expression levels of ABCG2 and ENPP1. The P-values were calculated using log rank tests.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4490376&req=5

f9: Evaluation of ENPP1 expression in breast cancer specimens.(a) Evaluation of ENPP1 mRNA expression in the clinical samples. The y axis displays the expression level of ENPP1 relative to that of GAPDH and the x axis displays the expression level of miR-27b normalized to that of RNU6B. (b) Evaluation of ENPP1 mRNA expression in breast cancer clinical samples classified by luminal-type. Expression levels were normalized to those of GAPDH. Comparisons between groups were performed using unpaired t-tests. (c) Kaplan–Meier representations of the probabilities of recurrence-free survival in 112 breast cancer cases classified according to the expression levels of ABCG2 and ENPP1. The P-values were calculated using log rank tests.

Mentions: Finally, the diagnostic value of ENPP1 expression was evaluated by a qRT–PCR analysis of a subset of primary human breast cancer specimens. As shown in Fig. 1a, miR-27b expression was low in a subset of the tumour specimens; therefore, ENPP1 expression was determined in these 26 samples and 9 non-tumour controls. A qRT–PCR analysis revealed elevated ENPP1 expression in breast cancer tissues that had lower miR-27b expression than normal tissues (Fig. 9a). ENPP1 mRNA expression was also significantly higher in 53 human primary luminal-type breast tumours than 15 normal controls (Fig. 9b). In addition, we evaluated the prognostic value of ABCG2 and ENPP1 expression in a public clinical microarray database of breast tumours from 112 luminal A patients (tumour grade 3)47. Although elevated expression of ABCG2 or ENPP1 was not correlated with recurrence of breast cancer, co-expression of ABCG2 and ENPP1 was moderately associated with poor prognosis (HR=1.84; P=0.062; Fig. 9c).


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)

Evaluation of ENPP1 expression in breast cancer specimens.(a) Evaluation of ENPP1 mRNA expression in the clinical samples. The y axis displays the expression level of ENPP1 relative to that of GAPDH and the x axis displays the expression level of miR-27b normalized to that of RNU6B. (b) Evaluation of ENPP1 mRNA expression in breast cancer clinical samples classified by luminal-type. Expression levels were normalized to those of GAPDH. Comparisons between groups were performed using unpaired t-tests. (c) Kaplan–Meier representations of the probabilities of recurrence-free survival in 112 breast cancer cases classified according to the expression levels of ABCG2 and ENPP1. The P-values were calculated using log rank tests.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f9: Evaluation of ENPP1 expression in breast cancer specimens.(a) Evaluation of ENPP1 mRNA expression in the clinical samples. The y axis displays the expression level of ENPP1 relative to that of GAPDH and the x axis displays the expression level of miR-27b normalized to that of RNU6B. (b) Evaluation of ENPP1 mRNA expression in breast cancer clinical samples classified by luminal-type. Expression levels were normalized to those of GAPDH. Comparisons between groups were performed using unpaired t-tests. (c) Kaplan–Meier representations of the probabilities of recurrence-free survival in 112 breast cancer cases classified according to the expression levels of ABCG2 and ENPP1. The P-values were calculated using log rank tests.
Mentions: Finally, the diagnostic value of ENPP1 expression was evaluated by a qRT–PCR analysis of a subset of primary human breast cancer specimens. As shown in Fig. 1a, miR-27b expression was low in a subset of the tumour specimens; therefore, ENPP1 expression was determined in these 26 samples and 9 non-tumour controls. A qRT–PCR analysis revealed elevated ENPP1 expression in breast cancer tissues that had lower miR-27b expression than normal tissues (Fig. 9a). ENPP1 mRNA expression was also significantly higher in 53 human primary luminal-type breast tumours than 15 normal controls (Fig. 9b). In addition, we evaluated the prognostic value of ABCG2 and ENPP1 expression in a public clinical microarray database of breast tumours from 112 luminal A patients (tumour grade 3)47. Although elevated expression of ABCG2 or ENPP1 was not correlated with recurrence of breast cancer, co-expression of ABCG2 and ENPP1 was moderately associated with poor prognosis (HR=1.84; P=0.062; Fig. 9c).

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