Valproic acid (VPA) inhibits the epithelial–mesenchymal transition in prostate carcinoma via the dual suppression of SMAD4

Lan, Xiaopeng; Yuan, Chuanwei; Mao, Shaowei; Jiang, Wei; Chen, Yougen; Jin, Xunbo; Xia, Qinghua

doi:10.1007/s00432-015-2020-4

Cited by 37 publications

(33 citation statements)

References 42 publications

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“…The data presented here demonstrated that miR-130a-3p-regulated EMT and cell invasion through inhibition of Smad4 in HCC GR cells. Recent studies have identified critical roles of Smad4 in tumorigenesis and EMT processes [ 50 , 51 ]. Some studies have demonstrated that Smad4 plays tumor suppressive functions in most types of human cancers [ 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, overexpression of Smad4 was observed in HCC patient tumors compared with adjacent tissues [ 54 ]. Furthermore, knockdown of Smad4 significantly increased E-cadherin expression in prostate cancer cells [ 50 ]. Qiao et al reported that miR-34a inhibited EMT in human cholangiocarcinoma by targeting Smad4 via TGF-beta/Smad signaling pathway [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

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MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells

Liu

Wang

et al. 2016

J Exp Clin Cancer Res

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BackgroundEmerging evidence demonstrates that microRNAs (miRNAs) play an important role in regulation of cell growth, invasion and metastasis through inhibiting the expression of their targets. It has been reported that miR-130a-3p controls cell growth, migration and invasion in a variety of cancer cells. However, it is unclear whether miR-130a-3p regulates epithelial-mesenchymal transition (EMT) in drug resistant cancer cells. Therefore, in the current study, we explore the role and molecular mechanisms of miR-130a-3p in gemcitabine resistant (GR) hepatocellular carcinoma (HCC) cells.MethodsThe real-time RT-PCR was used to measure the miR-130a-3p expression in GR HCC cells compared with their parental cells. The wound healing assay was conducted to determine the cell migratory activity in GR HCC cells treated with miR-130a-3p mimics. The migration and invasion assays were also performed to explore the role of miR-130a-3p in GR HCC cells. Western blotting analysis was used to measure the expression of Smad4, E-cadherin, Vimentin, and MMP-2 in GR HCC cells after depletion of Smad4. The luciferase assay was conducted to validate whether Smad4 is a target of miR-130a-3p. The student t-test was used to analyze our data.ResultsWe found the down-regulation of miR-130a-3p in GR HCC cells. Moreover, we validate the Smad4 as a potential target of miR-130a-3p. Furthermore, overexpression of miR-130a-3p suppressed Smad4 expression, whereas inhibition of miR-130a-3p increased Smad4 expression. Consistently, overexpression of miR-130a-3p or down-regulation of Smad4 suppressed the cell detachment, attachment, migration, and invasion in GR HCC cells.ConclusionsOur findings provide a molecular insight on understanding drug resistance in HCC cells. Therefore, activation of miR-130a-3p or inactivation of Smad4 could be a novel approach for the treatment of HCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells

Liu

Wang

et al. 2016

J Exp Clin Cancer Res

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“…inhibited the metastatic capacity of lung and breast cancer cells (26). The authors previously demonstrated that VPA inhibited metastasis in prostate cancer (27). The expression of E-cadherin increased following treatment with VPA in ovarian cancer (28) and this effect was further demonstrated in thyroid cancer cells (29).…”

Section: Smad4 Expression Tif1-γ Expression -------------------------mentioning

confidence: 91%

Valproic acid inhibits epithelial-mesenchymal transition in renal cell carcinoma by decreasing SMAD4 expression

Mao

Lan

Yuan

et al. 2017

Molecular Medicine Reports

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Renal cell carcinoma (RCC) is the most common malignancy in urogenital neoplasms worldwide. According to previous studies, valproic acid (VPA), an anticonvulsant drug, can suppress tumor metastasis and decrease the expression level of Mothers against decapentaplegic homolog 4 (SMAD4) and therefore may inhibit epithelial‑mesenchymal transition (EMT), which is responsible for cancer metastasis. However, the association between VPA, EMT and SMAD4 in RCC metastasis remains obscure. In the present study, it was demonstrated that in the RCC cell lines 786‑O and Caki‑1 treated with VPA, the neural (N)‑cadherin, vimentin and SMAD4 protein and mRNA levels were decreased, accompanied with an increase in expression of epithelial (E)‑cadherin. Silencing SMAD4 expression decreased the expression of EMT markers, including N‑cadherin and simultaneously upregulated E‑cadherin in RCC cell lines. SMAD4 overexpression counteracted the VPA‑mediated EMT‑inhibitory effect (P<0.05). The present study demonstrates that VPA inhibited EMT in RCC cells via altering SMAD4 expression. In addition, immunohistochemical staining demonstrated that transforming growth factor‑β (TGF‑β) and low expression of SMAD4 was associated with a lower Fuhrman grade and low expression of transcription intermediary factor 1‑γ was associated with a higher tumor Fuhrman grade (P<0.05), Therefore, based on the regulatory effect of SMAD4 on EMT‑associated transcription factors, SMAD4 which can form a SMAD3/SMAD4 complex induced by TGF‑β, could be a potential anticancer drug target inhibiting tumor invasion and metastasis in RCC.

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“…VPA is a histone deacetylase inhibitor that can induce cell apoptosis, differentiation, and cell-cycle arrest. Previous studies have found that VPA promotes the EMT of colorectal cancer cells [ 31 ], although another research group indicated that VPA inhibited EMT in prostate carcinoma [ 32 ]. Our results demonstrated that VPA sodium salt promoted expression of the EMT marker vimentin protein in lung cancer cells (Figure 6B, 6D ).…”

Section: Discussionmentioning

confidence: 99%

A combination of valproic acid sodium salt, CHIR99021, E-616452, tranylcypromine, and 3-Deazaneplanocin A causes stem cell-like characteristics in cancer cells

et al. 2017

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Many studies are based on the hypothesis that recurrence and drug resistance in lung carcinoma are due to a subpopulation of cancer stem-like cells (CSLCs) in solid tumors. Therefore it is crucial to screen for and recognize lung CSLCs. In this study, we stimulated non-small cell lung cancer (NSCLC) A549 cells to display stem cell-like characteristics using a combination of five small molecule compounds. The putative A549 stem cells activated an important CSLC marker, CD133 protein, as well multiple CSLC-related genes including ATP-binding cassette transporter G2 (ABCG2), C-X-C chemokine receptor type 4 (CXCR4), NESTIN, and BMI1. The A549 stem-like cells displayed resistance to the chemotherapeutic drugs etoposide and cisplatin, epithelial-to-mesenchymal transition properties, and increased protein expression levels of NOTCH1 and Hes Family bHLH Transcription Factor 1 (HES1). When A549 cells were pretreated with a NOTCH signaling pathway inhibitor before compound induction, expression of the NOTCH1 target gene HES1 was reduced. This demonstrated that the NOTCH signaling pathway in the putative A549 stem-like cells had been activated. Together, the results of our study showed that a combination of five small molecule agents could transform A549 cells into putative stem-like cells, and that these compounds could also elevate CD133 and ABCG2 protein expression levels in H460 cells. This study provides a convenient method for obtaining lung CSLCs, which may be an effective strategy for developing lung carcinoma treatments.

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Valproic acid (VPA) inhibits the epithelial–mesenchymal transition in prostate carcinoma via the dual suppression of SMAD4

Abstract: VPA inhibits the EMT in PCa cells via the inhibition of SMAD4 expression and the mono-ubiquitination of SMAD4. VPA could serve as a promising agent in PCa treatment, with new strategies based on its diverse effects on posttranscriptional regulation.

Cited by 37 publications

References 42 publications

MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells

MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells

Valproic acid inhibits epithelial-mesenchymal transition in renal cell carcinoma by decreasing SMAD4 expression

A combination of valproic acid sodium salt, CHIR99021, E-616452, tranylcypromine, and 3-Deazaneplanocin A causes stem cell-like characteristics in cancer cells

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