LEFTY2 Controls Migration of Human Endometrial Cancer Cells via Focal Adhesion Kinase Activity (FAK) and miRNA-200a

Alowayed, Nour; Salker, Madhuri S.; Zeng, Ni; Singh, Yogesh; Läng, Florian

doi:10.1159/000447792

Cited by 27 publications

(23 citation statements)

References 83 publications

(38 reference statements)

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“…A previous study also clarifies that miR-29b plays a significant role in the mouse early embryonic development through modulating the expressions of DNMT3A and DNMT3B [25]. Base on the study of Alowayed et al, LEFTY2 can negatively regulate the endometrial cell proliferation and migration through inhibiting FAK activity and MKi67 expression, as well as elevating miR-200a and E-cadherin [26]. Additionally, Qiang et al have provided evidence that the down-regulation of miR-29b is one of the mechanisms underlying the excessive accumulation of the extracellular matrix, which is the most notable pathophysiological characteristic of uterine leiomyoma [27].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-29b Inhibits Angiogenesis by Targeting VEGFA through the MAPK/ERK and PI3K/Akt Signaling Pathways in Endometrial Carcinoma

Chen

Tan

et al. 2017

Cell Physiol Biochem

103

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Objective: The purpose of this study is to explore the effects of microRNA-29b (miR-29b) regulating MAPK/ERK and PI3K/Akt signaling pathways on angiogenesis in endometrial carcinoma (EC) by targeting VEGFA. Methods: Between February 2013 and April 2015, 126 EC patients admitted to the Second Affiliated Hospital of Nanchang University were randomly selected, with 126 EC tissues and the corresponding adjacent normal tissues collected after surgery. The human EC cell lines RL-95-2 and HEC-1-B and human endometrial cells were assigned to the normal group (human endometrial cells), the blank group (untransfected RL-95-2 or HEC-1-B cells), the pMIR-control group (RL-95-2 or HEC-1-B cells transfected with an empty vector), the pMIR-miR-29b group (RL-95-2 or HEC-1-B cells transfected with the miR-29b plasmid), LNA-control group (RL-95-2 or HEC-1-B cells transfected with an oligonucleotide inhibitors control), the LNA-miR-29b inhibitors group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNA^{^TM} miR-29b inhibitors), the LNA-miR-29b inhibitors + PD98059 group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNA^{^TM} miR-29b inhibitors and PD98059, an inhibitor of the MAPK/ERK signaling pathway) and the LNA-miR-29b inhibitors + wortmannin group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNA^{^TM} miR-29b inhibitors and wortmannin, an inhibitor of the PI3K/Akt signaling pathway). qRT-PCR and Western blotting were conducted to detect the miR-29b expression and the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2. Immunohistochemistry (IHC) was performed to determine the microvessel density (MVD) expression in the EC tissues, adjacent normal tissues and nude-mice. Results: Compared with the adjacent normal tissues, miR-29b expression was down-regulated, the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 were up-regulated, and MVD expression was increased in the EC tissues. Compared with the normal group, miR-29b expression was down-regulated, while the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 were up-regulated in the other groups. Compared with the blank, pMIR-control and LNA-control groups, miR-29b expression was increased, while mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 were decreased in the pMIR-miR-29b group. The LNA-miR-29b inhibitors group exhibited elevated miR-29b expression and decreased mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 (All P < 0.05). Additionally, miR-29b expression was reduced in the LNA-miR-29b inhibitors + PD98059 and LNA-miR-29b inhibitors + wortmannin groups. In comparison to the normal group, MVD expression was elevated in the other groups. Compared with the blank, pMIR-control, LNA-control, LNA-miR-29b inhibitors + PD98059 and LNA-miR-29b inhibitors + wortmannin groups, MVD expression was decreased in the pMIR-miR-29b group but increased in the LNA-miR-29b inhibitors group. Conclusion: Our results indicate that miR-29b negatively mo...

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Section: Discussionmentioning

confidence: 99%

MicroRNA-29b Inhibits Angiogenesis by Targeting VEGFA through the MAPK/ERK and PI3K/Akt Signaling Pathways in Endometrial Carcinoma

Chen

Tan

et al. 2017

Cell Physiol Biochem

103

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“…Regulators of actin polymerization include the focal adhesion kinase (FAK)], which activates several signaling molecules including Rac1 . Particularly, the signaling cascade activated by FAK or Rac1 further influences NHE1 activity.…”

Section: Discussionmentioning

confidence: 99%

Gut Bacterial Metabolite Urolithin A Decreases Actin Polymerization and Migration in Cancer Cells

Alauddin

Okumura

Rajaxavier

et al. 2020

Molecular Nutrition Food Res

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Scope: Urolithin A (UA) is a gut-derived bacterial metabolite from ellagic acid found in pomegranates, berries, and nuts can downregulate cell proliferation and migration. Cell proliferation and cell motility require actin reorganization, which is under control of ras-related C3 botulinum toxin substrate 1 (Rac1) and p21 protein-activated kinase 1 (PAK1). The present study explores whether UA can modify actin cytoskeleton in cancer cells. Methods: The effect of UA on globular over filamentous actin ratio is determined utilizing Western blotting, immunofluorescence, and flow cytometry. Rac1 and PAK1 levels are measured by quantitative RT-PCR and immunoblotting. As a result, a 24 h treatment with UA (20 µm) significantly decreased Rac1 and PAK1 transcript levels and activity, depolymerized actin and wound healing. The effect of UA on actin polymerization is mimicked by pharmacological inhibition of Rac1 and PAK1. The effect is also mirrored by knock down using siRNA. Conclusion: UA leads to disruption of Rac1 and Pak1 activity with subsequent actin depolymerization and migration. Thus, use of dietary UA in cancer prevention or as adjuvant therapy is promising.

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“…Additionally, we have shown that LeftyA is involved in the downregulation of Na + /H + exchanger activity, reduces the resting pHi, lactate production and cell volume in Ishikawa cells [48, 49]. Interestingly, LeftyA simultaneously augments the miR-200a expression in Ishikawa cells (endometrial cancer cells) and leads to reduced migration of cells by regulating focal adhesion kinase and E-cadherin expression [50]. miR-200b could be similarly involved in maintenance of resting pHi and cell volume regulation in CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Reactive Oxygen Species Production, Acidic Cytosolic pH and Upregulated Na+/H+ Exchanger (NHE) in Dicer Deficient CD4+ T Cells

Singh

Zhou²,

Zhang³

et al. 2017

Cell Physiol Biochem

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Background: MicroRNAs (miRNAs) negatively regulate gene expression at a post-transcriptional level. Dicer, a cytoplasmic RNase III enzyme, is required for the maturation of miRNAs from precursor miRNAs. Dicer, therefore, is a critical enzyme involved in the biogenesis and processing of miRNAs. Several biological processes are controlled by miRNAs, including the regulation of T cell development and function. T cells generate reactive oxygen species (ROS) with parallel H⁺ extrusion accomplished by the Na⁺/H⁺-exchanger 1 (NHE1). The present study explored whether ROS production, as well as NHE1 expression and function are sensitive to the lack of Dicer (miRNAs deficient) and could be modified by individual miRNAs. Methods: CD4⁺ T cells were isolated from CD4 specific Dicer deficient (Dicer^Δ/Δ) mice and the respective control mice (Dicer^fl/fl). Transcript and protein levels were quantified with RT-PCR and Western blotting, respectively. For determination of intracellular pH (pHi) cells were incubated with the pH sensitive dye bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) and Na⁺/H⁺ exchanger (NHE) activity was calculated from re-alkalinization after an ammonium pulse. Changes in cell volume were measured using the forward scatter in flow cytometry, and ROS production utilizing 2',7' -dichlorofluorescin diacetate (DCFDA) fluorescence. Transfection of miRNA-control and mimics in T cells was performed using DharmaFECT3 reagent. Results: ROS production, cytosolic H⁺ concentration, NHE1 transcript and protein levels, NHE activity, and cell volume were all significantly higher in CD4⁺ T cells from Dicer^Δ/Δ mice than in CD4⁺ T cells from Dicer^fl/fl mice. Furthermore, individual miR-200b and miR-15b modify pHi and NHE activity in Dicer^fl/fl and Dicer^Δ/Δ CD4⁺ T cells, respectively. Conclusions: Lack of Dicer leads to oxidative stress, cytosolic acidification, upregulated NHE1 expression and activity as well as swelling of CD4⁺ T cells, functions all reversed by miR-15b or miR-200b.

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LEFTY2 Controls Migration of Human Endometrial Cancer Cells via Focal Adhesion Kinase Activity (FAK) and miRNA-200a

Cited by 27 publications

References 83 publications

MicroRNA-29b Inhibits Angiogenesis by Targeting VEGFA through the MAPK/ERK and PI3K/Akt Signaling Pathways in Endometrial Carcinoma

MicroRNA-29b Inhibits Angiogenesis by Targeting VEGFA through the MAPK/ERK and PI3K/Akt Signaling Pathways in Endometrial Carcinoma

Gut Bacterial Metabolite Urolithin A Decreases Actin Polymerization and Migration in Cancer Cells

Enhanced Reactive Oxygen Species Production, Acidic Cytosolic pH and Upregulated Na+/H+ Exchanger (NHE) in Dicer Deficient CD4+ T Cells

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