MicroRNA-30a increases tight junction protein expression to suppress the epithelial-mesenchymal transition and metastasis by targeting Slug in breast cancer

Chang, Chia Wei; Yu, Jyh Cherng; Hsieh, Yi‐Hsien; Yao, Chung Chin; Ji, Chao; Chen, Po Ming; Hsieh, He-Yen; Hsiung, Chia Ni; Chu, Hou Wei; Shen, Chen; Cheng, Chun‐Chia

doi:10.18632/oncotarget.7656

Cited by 48 publications

(43 citation statements)

References 40 publications

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“…Growing evidence demonstrates that miR-30a-5p can suppress tumor cell growth in breast cancer and colorectal cancer [28, 29]. The decreased expression of miR-30a-5p was correlated with the higher clinical grading of cancer tissues (Fig.…”

Section: Resultsmentioning

confidence: 94%

MicroRNA-30a-5p Inhibits the Growth of Renal Cell Carcinoma by Modulating GRP78 Expression

Wang

Cai

Liu

et al. 2017

Cell Physiol Biochem

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Background/Aims: MiR-30a-5p, a member of the microRNA-30 family (miR-30), is known to function as a tumor suppressor in several different cancers. However, the expression levels, biological function, and underlying mechanisms of miR-30a-5p in renal cell carcinoma (RCC) remain unclear. Glucose-regulated protein78 (GRP78) is a common cancer biomarker and promotes the growth and survival of cancer cells. The expression of GRP78 has been reported to be modulated by miR-30a in neurons. In this study, the expression profile of miR-30a-5p in clear cell renal cell carcinoma (ccRCC) and its effect on ccRCC through regulating GRP78 expression was investigated. Methods: MiR-30a-5p expression was analyzed using bioinformatic software on open microarray datasets from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and confirmed by quantitative RT-PCR (qRT-PCR) in ccRCC cell lines. Cell proliferation was investigated using CCK-8 and cell count assays. Western blotting, immunohistochemistry, luciferase reporter assays, and flow cytometry were employed to investigate the mechanisms of the effect of miR-30a-5p on ccRCC Results: MiR-30a-5p was down-regulated in ccRCC and related to the clinicopathological factors and prognosis of ccRCC. MiR-30a-5p was found to both suppress the growth of ccRCC cells and promote apoptosis of ccRCC cells in vitro. GRP78 was the direct target gene of miR-30a-5p, and the GRP78 expression was inversely correlated with the expression of miR-30a-5p in vivo and in vitro. The functional studies of GRP78 overexpression or knockdown demonstrated that GRP78 promoted proliferation and anti-apoptosis of ccRCC cells, and the oncogenic activity of GRP78 resulting in by miR-30a-5p overexpression. Conclusion: MiR-30a-5p is a bona fide negative regulator of GRP78 expression, and the anti-tumor activity of miR-30a-5p in ccRCC is due at least in part to down-regulating GRP78 expression and modulating the unfolded protein response (UPR) pathway. Thus, miR-30-GRP78 interaction provides a novel therapeutic candidate target in ccRCC treatment.

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Section: Resultsmentioning

confidence: 94%

MicroRNA-30a-5p Inhibits the Growth of Renal Cell Carcinoma by Modulating GRP78 Expression

Wang

Cai

Liu

et al. 2017

Cell Physiol Biochem

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“…It has been demonstrated that miR-30a can ameliorate hepatic fibrosis through suppressing Beclin-mediated autophagy [22]. Increasing evidence shows that miR-30a contributes to the suppression of EMT process in various cancers [23-25]. In this study, we aimed to explore whether miR-30a-mediated EMT process is involved in HSC activation.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-30a Suppresses the Activation of Hepatic Stellate Cells by Inhibiting Epithelial-to-Mesenchymal Transition

Zheng¹,

Wang²,

Yu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The activation of hepatic stellate cells (HSCs) is considered as a pivotal event in liver fibrosis and epithelial-mesenchymal transition (EMT) process has been reported to be involved in HSC activation. It is known that microRNAs (miRNAs) play a pro-fibrotic or anti-fibrotic role in HSC activation. Recently, emerging studies show that miR-30a is down-regulated in human cancers and over-expression of miR-30a inhibits tumor growth and invasion via suppressing EMT process. However, whether miR-30a could regulate EMT process in HSC activation is still unclear. Methods: miR-30a expression was quantified using real-time PCR in carbon tetrachloride (CCl₄)-induced rat liver fibrosis, activated HSCs and patients with cirrhosis. Roles of miR-30a in liver fibrosis in vivo and in vitro were also analyzed. Luciferase activity assays were performed to examine the binding of miR-30a to the 3′-untranslated region of snail family transcriptional repressor 1 (Snai1). Results: miR-30a was down-regulated in human cirrhotic tissues. In CCl₄ rats, reduced miR-30a was found in fibrotic liver tissues as well as isolated HSCs. There was a significant reduction in miR-30a in primary HSCs during culture days. miR-30a over-expression resulted in the suppression of CCl₄-induced liver fibrosis. Restoration of miR-30a led to the inhibition of HSC activation including cell proliferation, α-SMA and collagen expression. Notably, miR-30a inhibited EMT process, with a reduction in TGF-β1 and Vimentin as well as an increase in GFAP and E-cadherin. miR-30a induced a significant reduction in Snai1 protein expression when compared with the control. Interestingly, Snail protein expression was increased during liver fibrosis, indicating that there may be a negative correlation between miR-30a level and Snai1 protein expression. Further studies demonstrated that Snai1 was a target of miR-30a. Conclusion: Our results suggest that miR-30a inhibits EMT process, at least in part, via reduction of Snai1, leading to the suppression of HSC activation in liver fibrosis.

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“…Therefore, other mechanisms potentially lead to the down-regulation of miR-30a by AR activating signal. Some studies have shown that AR and miR-30a are involved in the epithelial-mesenchymal transition in breast cancer (25)(26)(27)(28), and vimentin is a specific bridge between AR and miR-30a (26,27). Feng et al reported that AR activated by DHT potentiates the promoter activity of vimentin and upregulates vimentin expression (27), whereas Cheng et al showed that vimentin is the target of miR-30a (26).…”

Section: Discussionmentioning

confidence: 99%

Interrelation of androgen receptor and miR-30a and miR-30a function in ER−, PR−, AR+ MDA-MB-453 breast cancer cells

Lyu¹,

Liu²,

Liu³

et al. 2017

Oncology Letters

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Abstract.The association between androgen-induced androgen receptor (AR) activating signal and microRNA (miR)-30a was investigated, as well as the function of miR-30a in estrogen receptor-negative (ER -), progesterone receptor-negative (PR -), and AR-positive (AR + ) MDA-MB-453 breast cancer cells. Androgen-induced AR activating signal upregulated the expression of AR, and downregulated the expression of miR-30a, b and c. Bioinformatics analysis indicated a putative miR-30a, b and c binding site in the 3'-untranslated region of AR mRNA. It was confirmed that the AR gene is a direct target of miR-30a, whereas AR does not target the miR-30a promoter, and AR activating signal may indirectly downregulate miR-30a through other cell signaling pathways. In this positive feedback mechanism AR is then upregulated through miR-30a. Overexpression of miR-30a inhibited cell proliferation, whereas inhibition of miR-30a expression by specific antisense oligonucleotides, increased cell growth. Previously, androgen-induced AR activating signal was demonstrated to inhibit cell proliferation in ER -, PR -and AR + MDA-MB-453 breast cancer cells, but AR activating signal downregulated the expression of miR-30a, relieving the inhibition of MDA-MB-453 cell growth. Therefore, in MDA-MB-453 breast cancer cells, miR-30a has two different functions regarding cell growth: Inhibition of cell proliferation through a positive feedback signaling pathway; and the relative promotion of cell proliferation through downregulation of miR-30a. Thus, the association between AR activating signal and microRNAs is complex, and microRNAs may possess different functions due to different signaling pathways. Although the results of the present study were obtained in one cell line, they contribute to subsequent studies on ER -, PR -and AR + breast cancer. IntroductionSex steroid hormones and sex steroid hormone receptors play a critical role in breast cancer development and progression. + breast cancer obtain little benefit from anti-estrogen therapy (1), more and more studies are focusing on AR as a useful therapeutic target, with some encouraging results (2).AR is an androgen-dependent transcription factor activated by binding androgens. Activated AR recognizes androgen response elements (AREs) located in or near the promoter and enhancer regions of androgen-dependent genes, thereby activating the transcriptional machinery, including microRNA transcription (3-5).MicroRNAs are evolutionarily conserved ~22-nucleotide-long short non-coding RNA molecules. These molecules repress target gene expression by binding to complementary sequences in the 3'-untranslated regions (UTRs) of target mRNAs. MicroRNAs participate in diverse biological functions, including development, cell proliferation, differentiation, and apoptosis (6-9). As microRNAs play a central role in the regulation of gene expression, aberrant expression is found in almost all types of human cancer (10).As both AR and microRNA have the ability to regulate genes, their interaction within a cancer cell...

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MicroRNA-30a increases tight junction protein expression to suppress the epithelial-mesenchymal transition and metastasis by targeting Slug in breast cancer

Cited by 48 publications

References 40 publications

MicroRNA-30a-5p Inhibits the Growth of Renal Cell Carcinoma by Modulating GRP78 Expression

MicroRNA-30a-5p Inhibits the Growth of Renal Cell Carcinoma by Modulating GRP78 Expression

MicroRNA-30a Suppresses the Activation of Hepatic Stellate Cells by Inhibiting Epithelial-to-Mesenchymal Transition

Interrelation of androgen receptor and miR-30a and miR-30a function in ER−, PR−, AR+ MDA-MB-453 breast cancer cells

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