The role of small GTPases of the Rho/Rac family in TGF‐β‐induced EMT and cell motility in cancer

Ungefroren, Hendrik; Witte, David P.; Lehnert, Hendrik

doi:10.1002/dvdy.24505

Cited by 110 publications

(94 citation statements)

References 120 publications

(131 reference statements)

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“…This observation implies a significant role of KDM2B in tumorigenesis and suggests the implication of actin cytoskeleton and small GTPases signaling in this phenomenon. Indeed, this assumption was postulated previously in various tumor cell models by analyzing the correlation of EMT with actin signaling and migration [13, 19-27]. Moreover, previous studies showed that the Serum glucocorticoid kinase 1 (Sgk1) plays a key role in EMT in colon carcinoma [28].…”

Section: Discussionmentioning

confidence: 98%

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The Epigenetic Factor KDM2B Regulates EMT and Small GTPases in Colon Tumor Cells

Zacharopoulou

Tsapara

Kallergi

et al. 2018

Cell Physiol Biochem

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Background/Aims: The epigenetic factor KDM2B is a histone demethylase expressed in various tumors. Recently, we have shown that KDM2B regulates actin cytoskeleton organization, small Rho GTPases signaling, cell-cell adhesion and migration of prostate tumor cells. In the present study, we addressed its role in regulating EMT and small GTPases expression in colon tumor cells. Methods: We used RT-PCR for the transcriptional analysis of various genes, Western blotting for the assessment of protein expression and immunofluorescence microscopy for visualization of fluorescently labeled proteins. Results: We report here that KDM2B regulates EZH2 and BMI1 in HCT116 colon tumor cells. Knockdown of this epigenetic factor induced potent up-regulation of the protein levels of the epithelial markers E-cadherin and ZO-1, while the mesenchymal marker N-cadherin was downregulated. On the other hand, KDM2B overexpression downregulated the levels of both epithelial markers and upregulated the mesenchymal marker, suggesting control of EMT by KDM2B. In addition, RhoA, RhoB and RhoC protein levels diminished upon KDM2B-knockdown, while all three small GTPases became upregulated in KDM2B-overexpressing HCT116 cell clones. Interestingly, Rac1 GTPase level increased upon KDM2B-knockdown and diminished in KDM2B-overexpressing HCT116 colon tumor- and DU-145 prostate cancer cells. Conclusions: These results establish a clear functional role of the epigenetic factor KDM2B in the regulation of EMT and small-GTPases expression in colon tumor cells and further support the recently postulated oncogenic role of this histone demethylase in various tumors.

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Section: Discussionmentioning

confidence: 98%

“…Moreover, previous reports established a functional link between EMT, actin cytoskeleton reorganization and small GTPases signaling [20-27]. Accordingly, we further analyzed the functional link of the KDM2B gene with various small GTPase family proteins, namely RhoA/B/C and Rac1 in colon tumor cells.…”

Section: Resultsmentioning

confidence: 99%

The Epigenetic Factor KDM2B Regulates EMT and Small GTPases in Colon Tumor Cells

Zacharopoulou

Tsapara

Kallergi

et al. 2018

Cell Physiol Biochem

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“…37 Many investigations aim at the markers of EMT from thirty-two cancer types 38,39 and the roles of TGF-b pathway. 38,40 A number of elements are important factors in regulation of gene expression and EMT, while referred to development of TNBC. [41][42][43][44] Moreover, the transcriptional regulation mechanism of EMT and how miRNA modulated EMT or development of TNBC was unclear yet.…”

Section: Discussionmentioning

confidence: 99%

miR-425 suppresses EMT and the development of TNBC (triple-negative breast cancer) by targeting the TGF-β 1/SMAD 3 signaling pathway

Liu

Chen

2019

RSC Adv.

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Background: EMT has a crucial effect on the progression and metastasis of tumors. This work will elucidate the role of miR-425 in EMT and the development of TNBC. Methods: The differential miRNA expression among non-tumor, para-tumor (adjacent tissue of tumor) and tumor tissues was analyzed. The luciferase activities of TGF-b1 3 0 UTR treated with miR-425 were determined. Then human breast cancer cell lines were treated with mimics or inhibitors of miR-425, and then the cell proliferation and migration, and invasion ability were assessed. The expression of TGF-b1 and markers of epithelial cells and mesenchymal cells were analyzed. The influences of miR-425 on the development of TNBC through inducing EMT by targeting the TGF-b1/SMAD3 signaling pathway in TNBC cell lines were investigated. Furthermore, xenograft mice were used to explore the potential roles of miR-425 on EMT and the development of TNBC in vivo. Results: Compared with non-tumor tissues, 9 miRNAs were upregulated and 3 miRNAs were down-regulated in tumor tissues. The relative expression of miR-425 in tumor tissues was obviously much lower than that in para-tumor and non-tumor tissues. MiR-425 suppressed TGF-b1 expression, and further inhibited expression of mesenchymal cell markers, while it exerted effects on cell proliferation and migration of TNBC cell lines. Moreover, the agomir of miR-425 could protect against the development process in a murine TNBC xenograft model. Conclusions: Our results demonstrated that miR-425 targets TGF-b1, and was a crucial suppressor on EMT and the development of TNBC through inhibiting the TGF-b1/SMAD3 signaling pathway. This suggests that aiming at the TGF-b1/SMAD3 signaling pathway by enhancing relative miR-425 expression, is a feasible therapy strategy for TNBC. RNA extractionTRIzol method was used to extract total RNA from tissues based on the operation manual. Then, smaller RNA (<200 nt) was removed with mirVana RNA isolation kit (Cat. no. AM27828; Invitrogen Thermo Fisher Scientic, Inc., Waltham, MA, USA) according to the instructions for manufacturer. Culture of cellThe cell lines of human TNBC, including MDA-MB-231 (ATCC® HTB-26™) and Hs 578T (ATCC® HTB-126™) were purchased from ATCC (American Type Culture Collection), and then cultured in DMEM with 10% FBS accompanied by Streptomycin and Penicillin (bi-antibiotics) with atmosphere (5% CO 2 ) at 37 C. siRNA for TGF-b1The well known siRNA of TGF-b1 supported by ref. 26 had been used in our study, which had been used as a positive in our study. The siRNA duplexes for TGF-b1 sequences are 5 0 -152 | RSC Adv., 2019,9,[151][152][153][154][155][156][157][158][159][160][161][162][163][164][165] This journal is Fig. 8 MiR-425 suppressed cell invasion of TNBC cell lines. Moreover, the inhibitors of miR-425 promoted invasion ability of TNBC cell lines, but the mimics of miR-425 suppressed the invasion ability of TNBC cell lines.This journal is Fig. 9 MiR-425 agomir suppressed TNBC xenografts. To detect anti-tumor activity induced by miR-425 agomir in vivo, human TNBC ...

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“…The ligands of TGF-β (transforming growth factor β) family often initiate the cellular process, EMT [37]. Many investigations aim at the markers of EMT from thirty-two cancer types [38,39] and the roles of TGF-β pathway [38,40]. A number of elements are important factors in regulation of gene expression and EMT, while referred to development of TNBC [41][42][43][44].…”

Section: Discussionmentioning

confidence: 99%

miR-425 suppresses EMT and inhibits the development of TNBC (triple-negative breast cancer) by targeting TGF-β 1/SMAD 3 signaling pathway

Liu

Qiao

Chen

2018

Preprint

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Background: EMT has the crucial effect on the progression and metastasis of tumor. This work will elucidate the role of miR-425 in EMT and development of TNBC. Methods: The differential miRNA expression among non-tumor, para-tumor (adjacent tissue of tumor) and tumor tissues was analyzed. The luciferase activities of TGF-β1 3' UTR treated with miR-425 were determined. Then human breast cancer cell lines were dealt with mimics or inhibitors of miR-425, and then the cell proliferation and migration, invasion ability were assessed.The expression of TGF-β1 and markers of epithelial cell and mesenchymal cell were analyzed. The influences of miR-425 on development of TNBC through inducing EMT by targeting TGF-β 1 and TGF-β1/SMAD3 signaling pathway in TNBC cell lines were investigated. Furthermore, Xenograft mice were used to explore the potential roles of miR-425 on EMT and development of TNBC in vivo. Results: Compared with non-tumor tissues, 9 miRNAs were upregulated and 3 miRNAs were down-regulated in tumor tissues. The relative expression of miR-425 in tumor tissues was obviously much lower than that in para-tumor and non-tumor tissues. MiR-425 suppressed TGF-β1 expression, additionally inhibited expression of mesenchymal cell markers, while exerted effects on cell proliferation and migration of TNBC cell lines. Moreover, the agomir of miR-425 could protect against development process in murine TNBC xenogarft model. Conclusions: Our results demonstrated that miR-425 targets to TGF-β1, and was a crucial suppressor on EMT and development of TNBC through inhibiting TGF-β1/SMAD3 signaling pathway. It suggested that aim at TGF-β1/SMAD3 signaling pathway by enhancing relative miR-425 expression, was a feasible therapy strategy for TNBC.

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The role of small GTPases of the Rho/Rac family in TGF‐β‐induced EMT and cell motility in cancer

Cited by 110 publications

References 120 publications

The Epigenetic Factor KDM2B Regulates EMT and Small GTPases in Colon Tumor Cells

The Epigenetic Factor KDM2B Regulates EMT and Small GTPases in Colon Tumor Cells

miR-425 suppresses EMT and the development of TNBC (triple-negative breast cancer) by targeting the TGF-β 1/SMAD 3 signaling pathway

miR-425 suppresses EMT and inhibits the development of TNBC (triple-negative breast cancer) by targeting TGF-β 1/SMAD 3 signaling pathway

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