Metastatic Heterogeneity of Breast Cancer Cells Is Associated with Expression of a Heterogeneous TGFβ-Activating miR424–503 Gene Cluster

Li, Yun; Li, Wei; Ying, Zhe; Tian, Han; Zhu, Xun; Li, Jun; Li, Mengfeng

doi:10.1158/0008-5472.can-14-0389

Cited by 38 publications

(25 citation statements)

References 48 publications

(55 reference statements)

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“…We focused on miR-503 , which was strongly upregulated in the T/E VI only (∼7-fold), but not in the T/E III only microarray dataset (Supplementary Table 1). A search for potential miR-503 targets using in silico prediction algorithms showed that miR-503 could target SMAD7 [28], which was downregulated in T/E VI, but upregulated in T/E III cells. We therefore hypothesized that miR-503 might be a candidate modulating the biological activity of the T/E VI fusion variants.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, the miR-503 -mediated downregulation of SMAD7 in T/E VI, but not in T/E III cells, explains T/E VI variant-specific transcription. Recently, Li et al could show that miR-503 downregulates SMAD7 expression and thereby enhances TGF-β signaling and the metastatic capability of breast cancer cells [28]. SMAD7-mediated stabilization of β-catenin binding to E-cadherin turned out to increase cell-cell adhesion and formation of adherens junctions [53], thereby potentially blocking metastasis.…”

Section: Discussionmentioning

confidence: 99%

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TMPRSS2:ERGgene fusion variants induce TGF-β signaling and epithelial to mesenchymal transition in human prostate cancer cells

et al. 2017

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TMPRSS2:ERG (T/E) gene fusions are present in approximately 50% of all prostate cancer (PCa) cases. The expression of fusion mRNAs from distinct T/E variants is associated with clinicopathological parameters, while the underlying molecular processes remain unclear. We characterized the molecular mechanisms and functional implications caused by doxycycline (Dox)-inducible overexpression of the frequent T/E III and VI fusion variants in LNCaP cells. Induction of T/E expression resulted in increased cellular migratory and invasive potential, and reduced proliferation and accumulation in G1 phase. T/E overexpressing cells showed epithelial-to-mesenchymal transition (EMT), as demonstrated by upregulation of TGF-β and WNT pathway genes, mesenchymal markers, and increased phosphorylation of the p38 MAPK. Augmented secretion of TGF-β1 and –β2, and T/E-mediated regulation of ALK1, a member of the TGF-β receptor family, was detected. ALK1 inhibition in T/E overexpressing cells blocked p38 phosphorylation and reduced the expression of the TGF-β target genes VIM, MMP1, CDH2, and SNAI2. We found a T/E variant VI-specific induction of miR-503 associated with reduced expression of SMAD7 and CDH1. Overexpression of miR-503 led to increased levels of VIM and MMP1. Our findings indicate that TGF-β signaling is a major determinant of EMT in T/E overexpressing LNCaP cells. We provide evidence that T/E VI-specific transcriptional modulation by miR-503 accounts for differences in the activation of EMT pathway genes, promoting the aggressive phenotype of tumors expressing T/E variant VI. We suggest that ALK1-mediated TGF-β signaling is a novel oncogenic mechanism in T/E positive PCa.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TMPRSS2:ERGgene fusion variants induce TGF-β signaling and epithelial to mesenchymal transition in human prostate cancer cells

et al. 2017

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“…Although we have achieved a better understanding of the genetic alterations in CRC in recent years, the prognosis of CRC patients remains poor because of cancer cell invasion and distant metastasis [24], which result from the inherent heterogeneity and complex gene interactions of CRC [25]. Accordingly, discovering new biological mechanisms and novel regulators of CRC will provide a better approach for controlling CRC development [4].…”

Section: Discussionmentioning

confidence: 99%

miR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGFβ-mediated epithelial to mesenchymal transition

et al. 2017

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BackgroundDespite advancements in the diagnosis and treatment of colorectal cancer (CRC), many patients die because of tumor metastasis or recurrence. Therefore, identifying new prognostic markers and elucidating the mechanisms of CRC metastasis and recurrence will help to improve the prognosis of the disease. As dysregulation of microRNAs is strongly related to cancer progression, the aim of this study was to identify the role of miR-4775 in the prognosis of CRC patients and the underling mechanisms involved in CRC progression.MethodsqPCR and in situ hybridization were used to evaluate the expression of miR-4775 in 544 pairs of paraffin-embedded normal and CRC tissues. Kaplan–Meier analysis with the log-rank test was used for survival analyses. Immunohistochemical staining was applied to investigate the expression of miR-4775-regulated Smad7/TGFβ pathway-associated markers. In vitro and in vivo invasion and metastasis assays were used to explore the function of miR-4775 in the progression of CRC.ResultsmiR-4775 was identified as a high-risk factor for CRC metastasis and recurrence, with high levels predicting poor survival among the 544 studied CRC patients. Furthermore, high miR-4775 expression promoted the invasion of CRC cells as well as metastasis and the epithelial to mesenchymal transition (EMT) via Smad7-mediated activation of TGFβ signaling both in vitro and in vivo. Downregulating miR-4775 or overexpressing Smad7 reversed the tumor-promoting roles of miR-4775/Smad7/TGFβ in vitro and in vivo.ConclusionmiR-4775 promotes CRC metastasis and recurrence in a Smad7/TGFβ signaling-dependent manner, providing a new therapeutic target for inhibiting the metastasis or recurrence of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0585-z) contains supplementary material, which is available to authorized users.

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“…As an oncogenic miRNA, miR‐106b‐25 can down‐regulate SMAD7 protein, which is well recognized that mediates destruction of the TGF‐β receptor 1(TGF‐βR1), resulting in elevated levels of the TGF‐βR1 and triggers TGF‐β pathway in breast tumor cells (Gong et al, ; Smith et al, ). Y. Li et al () reported the expression of miR‐424/503 cluster is elevated in metastatic breast tumor. Both miR‐424 and miR‐503 restrain SMAD7 and Smad ubiquitination regulatory factors (Smurf—two negative regulators of TGF‐β signaling—then resulted in the hyperactivation of this signaling pathway and enhance breast tumor metastasis (Y. Li et al, ).…”

Section: Crosstalk Between Various Signaling Pathways and Mirnas In Bmentioning

confidence: 99%

“…Y. Li et al () reported the expression of miR‐424/503 cluster is elevated in metastatic breast tumor. Both miR‐424 and miR‐503 restrain SMAD7 and Smad ubiquitination regulatory factors (Smurf—two negative regulators of TGF‐β signaling—then resulted in the hyperactivation of this signaling pathway and enhance breast tumor metastasis (Y. Li et al, ). MiR‐21 boosts migration and invasion of breast tumor cell induced by TGF‐β and epidermal growth factor (EGF).…”

Section: Crosstalk Between Various Signaling Pathways and Mirnas In Bmentioning

confidence: 99%

MicroRNAs in breast cancer: Roles, functions, and mechanism of actions

Abolghasemi

Tehrani

Yousefi

et al. 2019

Journal Cellular Physiology

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Breast cancer is one of the most lethal malignancies in women in the world. Various factors are involved in the development and promotion of the malignancy; most of them involve changes in the expression of certain genes, such as microRNAs (miRNAs). MiRNAs can regulate signaling pathways negatively or positively, thereby affecting tumorigenesis and various aspects of cancer progression, particularly breast cancer. Besides, accumulating data demonstrated that miRNAs are a novel tool for prognosis and diagnosis of breast cancer patients. Herein, we will review the roles of these RNA molecules in several important signaling pathways, such as transforming growth factor, Wnt, Notch, nuclear factor‐κ B, phosphoinositide‐3‐kinase/Akt, and extracellular‐signal‐regulated kinase/mitogen activated protein kinase signaling pathways in breast cancer.

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Metastatic Heterogeneity of Breast Cancer Cells Is Associated with Expression of a Heterogeneous TGFβ-Activating miR424–503 Gene Cluster

Cited by 38 publications

References 48 publications

TMPRSS2:ERGgene fusion variants induce TGF-β signaling and epithelial to mesenchymal transition in human prostate cancer cells

TMPRSS2:ERGgene fusion variants induce TGF-β signaling and epithelial to mesenchymal transition in human prostate cancer cells

miR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGFβ-mediated epithelial to mesenchymal transition

MicroRNAs in breast cancer: Roles, functions, and mechanism of actions

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