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MiR-133a Is Functionally Involved in Doxorubicin-Resistance in Breast Cancer Cells MCF-7 via Its Regulation of the Expression of Uncoupling Protein 2.

Yuan Y, Yao YF, Hu SN, Gao J, Zhang LL - PLoS ONE (2015)

Bottom Line: Previous studies indicate that mitochondria uncoupling protein 2 (UCP-2) is involved in the development of chemotherapy resistance in colon cancer and lung cancer cells.In the present study we found that lower level of miR133a is accompanied by increased expression of UCP-2 in Doxorubicin-resistant breast cancer cell cline MCF-7/Dox as compared with its parental cell line MCF-7.In this study we showed that: 1) exogenous expression of miR133a in MCF-7/Dox cells can sensitize their reaction to the treatment of Doxorubicin, which is coincided with reduced expression of UCP-2; 2) knockdown of UCP-2 in MCF-7/Dox cells can also sensitize their reaction to the treatment of Doxorubicin; 3) intratumoral delivering of miR133a can restore Doxorubicin treatment response in Doxorubicin-resistant xenografts in vivo, which is concomitant with the decreased expression of UCP-2.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemotherapy, Jiangsu Cancer Hospital and Research Institute, Nanjing, Jiangsu, People's Republic of China.

ABSTRACT
The development of novel targeted therapies holds promise for conquering chemotherapy resistance, which is one of the major hurdles in current breast cancer treatment. Previous studies indicate that mitochondria uncoupling protein 2 (UCP-2) is involved in the development of chemotherapy resistance in colon cancer and lung cancer cells. In the present study we found that lower level of miR133a is accompanied by increased expression of UCP-2 in Doxorubicin-resistant breast cancer cell cline MCF-7/Dox as compared with its parental cell line MCF-7. We postulated that miR133a might play a functional role in the development of Doxorubicin-resistant in breast cancer cells. In this study we showed that: 1) exogenous expression of miR133a in MCF-7/Dox cells can sensitize their reaction to the treatment of Doxorubicin, which is coincided with reduced expression of UCP-2; 2) knockdown of UCP-2 in MCF-7/Dox cells can also sensitize their reaction to the treatment of Doxorubicin; 3) intratumoral delivering of miR133a can restore Doxorubicin treatment response in Doxorubicin-resistant xenografts in vivo, which is concomitant with the decreased expression of UCP-2. These findings provided direct evidences that the miR133a/UCP-2 axis might play an essential role in the development of Doxorubicin-resistance in breast cancer cells, suggesting that the miR133a/UCP-2 signaling cohort could be served as a novel therapeutic target for the treatment of chemotherapy resistant in breast cancer.

No MeSH data available.


Related in: MedlinePlus

MiR133a helps to increase Doxorubicin treatment response inDoxorubicin-resistant in vivo via its decreasing the expression of UCP-2.(A) Tumor growth curve in the nude mice treated with Doxorubicin intraperitoneally (i.p.) (4 mg/kg, twice per week) combined with intratumoral injection of pre-miR133a, scramble or saline for four weeks. (B) Expressions levels of miR-133a were detected by real-time PCR analysis in tumor tissues. (C) Expression levels of UCP-2 in tumor tissues were determined by real-time PCR (Left) and Western blot analysis (Right), respectively. Each bar represents the mean ± SEM. All the results shown were repeated in three independent experiments. **, P < 0.01; and***, P < 0.001 significantly different from the respective control group.
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pone.0129843.g004: MiR133a helps to increase Doxorubicin treatment response inDoxorubicin-resistant in vivo via its decreasing the expression of UCP-2.(A) Tumor growth curve in the nude mice treated with Doxorubicin intraperitoneally (i.p.) (4 mg/kg, twice per week) combined with intratumoral injection of pre-miR133a, scramble or saline for four weeks. (B) Expressions levels of miR-133a were detected by real-time PCR analysis in tumor tissues. (C) Expression levels of UCP-2 in tumor tissues were determined by real-time PCR (Left) and Western blot analysis (Right), respectively. Each bar represents the mean ± SEM. All the results shown were repeated in three independent experiments. **, P < 0.01; and***, P < 0.001 significantly different from the respective control group.

Mentions: Based on the findings that exogenous expression of miR-133a in breast cancer cells attenuated its Doxorubicin resistance in vitro possibly by reducing the expression of UCP-2, we further explored the effect of overexpressing miR133a in tumor xenografts in vivo. The results showed that pre-miR-133a, but not scramble or saline, could enhance the inhibition effect of Doxorubicin in tumor growth (Fig 4A). The higher expression level of miR133a in tumor xenografts delivered with pre-miR133a as compared with that in tumor xenografts delivered with scramble and saline were validated by real-time PCR, which is concomitant with decreased expression of UCP-2 in mRNA and protein levels (Fig 4B). These in vivo findings coincided with what was found in vitro, provided direct evidences that the miR133a/UCP-2 axis might be a novel therapeutic target for conquering Doxorubicin resistance in current breast cancer treatment.


MiR-133a Is Functionally Involved in Doxorubicin-Resistance in Breast Cancer Cells MCF-7 via Its Regulation of the Expression of Uncoupling Protein 2.

Yuan Y, Yao YF, Hu SN, Gao J, Zhang LL - PLoS ONE (2015)

MiR133a helps to increase Doxorubicin treatment response inDoxorubicin-resistant in vivo via its decreasing the expression of UCP-2.(A) Tumor growth curve in the nude mice treated with Doxorubicin intraperitoneally (i.p.) (4 mg/kg, twice per week) combined with intratumoral injection of pre-miR133a, scramble or saline for four weeks. (B) Expressions levels of miR-133a were detected by real-time PCR analysis in tumor tissues. (C) Expression levels of UCP-2 in tumor tissues were determined by real-time PCR (Left) and Western blot analysis (Right), respectively. Each bar represents the mean ± SEM. All the results shown were repeated in three independent experiments. **, P < 0.01; and***, P < 0.001 significantly different from the respective control group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4481265&req=5

pone.0129843.g004: MiR133a helps to increase Doxorubicin treatment response inDoxorubicin-resistant in vivo via its decreasing the expression of UCP-2.(A) Tumor growth curve in the nude mice treated with Doxorubicin intraperitoneally (i.p.) (4 mg/kg, twice per week) combined with intratumoral injection of pre-miR133a, scramble or saline for four weeks. (B) Expressions levels of miR-133a were detected by real-time PCR analysis in tumor tissues. (C) Expression levels of UCP-2 in tumor tissues were determined by real-time PCR (Left) and Western blot analysis (Right), respectively. Each bar represents the mean ± SEM. All the results shown were repeated in three independent experiments. **, P < 0.01; and***, P < 0.001 significantly different from the respective control group.
Mentions: Based on the findings that exogenous expression of miR-133a in breast cancer cells attenuated its Doxorubicin resistance in vitro possibly by reducing the expression of UCP-2, we further explored the effect of overexpressing miR133a in tumor xenografts in vivo. The results showed that pre-miR-133a, but not scramble or saline, could enhance the inhibition effect of Doxorubicin in tumor growth (Fig 4A). The higher expression level of miR133a in tumor xenografts delivered with pre-miR133a as compared with that in tumor xenografts delivered with scramble and saline were validated by real-time PCR, which is concomitant with decreased expression of UCP-2 in mRNA and protein levels (Fig 4B). These in vivo findings coincided with what was found in vitro, provided direct evidences that the miR133a/UCP-2 axis might be a novel therapeutic target for conquering Doxorubicin resistance in current breast cancer treatment.

Bottom Line: Previous studies indicate that mitochondria uncoupling protein 2 (UCP-2) is involved in the development of chemotherapy resistance in colon cancer and lung cancer cells.In the present study we found that lower level of miR133a is accompanied by increased expression of UCP-2 in Doxorubicin-resistant breast cancer cell cline MCF-7/Dox as compared with its parental cell line MCF-7.In this study we showed that: 1) exogenous expression of miR133a in MCF-7/Dox cells can sensitize their reaction to the treatment of Doxorubicin, which is coincided with reduced expression of UCP-2; 2) knockdown of UCP-2 in MCF-7/Dox cells can also sensitize their reaction to the treatment of Doxorubicin; 3) intratumoral delivering of miR133a can restore Doxorubicin treatment response in Doxorubicin-resistant xenografts in vivo, which is concomitant with the decreased expression of UCP-2.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemotherapy, Jiangsu Cancer Hospital and Research Institute, Nanjing, Jiangsu, People's Republic of China.

ABSTRACT
The development of novel targeted therapies holds promise for conquering chemotherapy resistance, which is one of the major hurdles in current breast cancer treatment. Previous studies indicate that mitochondria uncoupling protein 2 (UCP-2) is involved in the development of chemotherapy resistance in colon cancer and lung cancer cells. In the present study we found that lower level of miR133a is accompanied by increased expression of UCP-2 in Doxorubicin-resistant breast cancer cell cline MCF-7/Dox as compared with its parental cell line MCF-7. We postulated that miR133a might play a functional role in the development of Doxorubicin-resistant in breast cancer cells. In this study we showed that: 1) exogenous expression of miR133a in MCF-7/Dox cells can sensitize their reaction to the treatment of Doxorubicin, which is coincided with reduced expression of UCP-2; 2) knockdown of UCP-2 in MCF-7/Dox cells can also sensitize their reaction to the treatment of Doxorubicin; 3) intratumoral delivering of miR133a can restore Doxorubicin treatment response in Doxorubicin-resistant xenografts in vivo, which is concomitant with the decreased expression of UCP-2. These findings provided direct evidences that the miR133a/UCP-2 axis might play an essential role in the development of Doxorubicin-resistance in breast cancer cells, suggesting that the miR133a/UCP-2 signaling cohort could be served as a novel therapeutic target for the treatment of chemotherapy resistant in breast cancer.

No MeSH data available.


Related in: MedlinePlus