Over-expression of miR-451a can enhance the sensitivity of breast cancer cells to tamoxifen by regulating 14-3-3ζ, estrogen receptor α, and autophagy

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• 作者：Zhen-Ru Liu^a ; ¹ ; Yi Song^b ; ¹ ; Li-Hong Wan^a ; Yuan-Yuan Zhang^a ; ^{sarahyyzhang@hotmail.com" class="auth_mail" title="E-mail the corresponding author} ; Li-Mimg Zhou^a ; ^c ; ^{zhou1081@hotmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Breast cancer ; Tamoxifen ; Resistance ; MiR-451a ; ERα ; 14-3-3ζ ; Autophagy
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：149
• 期：Complete
• 页码：104-113
• 全文大小：1481 K

文摘

To investigate the effects and mechanisms of miR-451a in the tamoxifen (TAM) resistance of breast cancer cells.

Materials and methods

TAM sensitive cells (MCF-7) and resistant cells (LCC2) were employed in the study. The lentivirus vectors of Lv-miR-451a, Lv-miR-451a sponge, and Lv-miR-451a NC were employed to increase or decrease the expression of miR-451a, respectively. SiRNA to 14-3-3ζ was used to inhibit expression of 14-3-3ζ. MTT assay was utilized to detect breast cancer cell proliferation. AnnexinV-FITC binding assay was used to detect apoptosis. Expression of ERα, 14-3-3ζ and miR-451a were measured by qRT-PCR and Western blot analysis. Interactions between 14-3-3ζ and ERα were investigated by co-immunoprecipitation. LC3-II surface expression and intracellular autophagosomes were observed by Western blot and electron microscopy.

Key findings

Over-expression of miR-451a can enhance MCF-7 and LCC2 cell sensitivity to TAM. Opposite effects were elicited by knocking down miR-451a. TAM treatment can up-regulate 14-3-3ζ expression, and down-regulate ERα expression. 14-3-3ζ and ERα were shown to interact. Over-expression of miR-451a decreased 14-3-3ζ expression and increased ERα expression, suppressing cell proliferation, increasing apoptosis, and reducing activation of p-AKT and p-mTOR. R18 can significantly decrease cell proliferation and increase apoptosis. R18 and 14-3-3ζ siRNA can rescue the effects of down-regulation of ERα by knocking down miR-451a. Over-expression of miR-451a inhibits autophagy, knocking-down miR-451a stimulates autophagy.

Significance

MiR-451a functions as a suppressor of resistance to TAM through regulating autophagy, the expression of 14-3-3ζ and ERα. This suggests miR-451a to be a potential target for reversing resistance to TAM.