The Role of LIN28-let-7-ARID3B Pathway in Placental Development

Placental disorders are a major cause of pregnancy loss in humans, and 40–60% of embryos are lost between fertilization and birth. Successful embryo implantation and placental development requires rapid proliferation, invasion, and migration of trophoblast cells. In recent years, microRNAs (miRNAs) have emerged as key regulators of molecular pathways involved in trophoblast function. A miRNA binds its target mRNA in the 3ʹ-untranslated region (3ʹ-UTR), causing its degradation or translational repression. Lethal-7 (let-7) miRNAs induce cell differentiation and reduce cell proliferation by targeting proliferation-associated genes. The oncoprotein LIN28 represses the biogenesis of mature let-7 miRNAs. Proliferating cells have high LIN28 and low let-7 miRNAs, whereas differentiating cells have low LIN28 and high let-7 miRNAs. In placenta, low LIN28 and high let-7 miRNAs can lead to reduced proliferation of trophoblast cells, resulting in abnormal placental development. In trophoblast cells, let-7 miRNAs reduce the expression of proliferation factors either directly by binding their mRNA in 3ʹ-UTR or indirectly by targeting the AT-rich interaction domain (ARID)3B complex, a transcription-activating complex comprised of ARID3A, ARID3B, and histone demethylase 4C (KDM4C). In this review, we discuss regulation of trophoblast function by miRNAs, focusing on the role of LIN28-let-7-ARID3B pathway in placental development.

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LncRNA CEACAMP8 Regulates the Proliferation, Invasion and Migration of Trophoblast Cells

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2019.2118 ◽

2019 ◽

Vol 9 (9) ◽

pp. 1215-1221

Author(s):

Li Jie ◽

Zhangcai Zheng ◽

Liping Liu ◽

Yali Liu ◽

Zhaoyan Meng ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Flow Cytometry Analysis ◽

Trophoblast Cells ◽

Vimentin Expression ◽

Mesenchymal Transition ◽

Invasion And Migration ◽

Qpcr Analysis ◽

And Migration ◽

E Cadherin

Preeclampsia (PE) is an idiopathic hypertension syndrome occurring after 20 weeks of gestation. Reports showed that lncRNAs expression was abnormal in preeclampsia. We aimed to investigate the role of lncRNA CEACAMP8 in the proliferation, invasion and migration of trophoblast cells to improve the preeclampsia. The cell transfection effects were determined by RT-qPCR analysis. The proliferation, invasion and migration of HTR-8/SVneo cells were detected by CCK-8 assay, transwell assay and wound healing assay. The flow cytometry analysis analyzed the cell cycle. Moreover, the expression of CDK2, cyclinD1, P21, MMP2, MMP9, E-cadherin, b-catenin and vimentin was determined by the western blot analysis. Consequently, CEACAMP8 inhibition promoted the proliferation, invasion and migration of HTR-8/SVneo cells and kept most of the cells in the S phase. The expression of proteins related to the proliferation, invasion and migration of HTR-8/SVneo cells were also changed in accordance with the increase of proliferation, invasion and migration of HTR-8/SVneo cells. In addition, lncRNA CEACAMP8 inhibition decreased the expression of E-cadherin and b-catenin, and increased the vimentin expression to promote the epithelial-mesenchymal transition. And, CEACAMP8 overexpression could reverse the above changes. This study indicated that CEACAMP8 inhibition promoted the proliferation, invasion and migration of HTR-8/SVneo cells and lncRNA CEACAMP8 overexpression reversed.

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Interleukin 11: similar or opposite roles in female reproduction and reproductive cancer?

Reproduction Fertility and Development ◽

10.1071/rd14128 ◽

2016 ◽

Vol 28 (4) ◽

pp. 395 ◽

Cited By ~ 6

Author(s):

Amy Winship ◽

Ellen Menkhorst ◽

Michelle Van Sinderen ◽

Evdokia Dimitriadis

Keyword(s):

Embryo Implantation ◽

Cell Types ◽

Malignant Cell ◽

Vascular Supply ◽

Female Reproduction ◽

Placental Development ◽

Invasion And Migration ◽

Gynaecological Malignancy ◽

Uterine Environment ◽

And Migration

During placental development and carcinogenesis, cell invasion and migration are critical events in establishing a self-supporting vascular supply. Interleukin (IL)-11 is a pleiotropic cytokine that affects the invasive and migratory capabilities of trophoblast cells that form the placenta during pregnancy, as well as various malignant cell types. The endometrium is the site of embryo implantation during pregnancy; conversely, endometrial carcinoma is the most common gynaecological malignancy. Here, we review what is known about the role of IL-11 in trophoblast function and in gynaecological malignancies, focusing primarily on the context of the uterine environment.

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New insights into the function of Cullin 3 in trophoblast invasion and migration

Reproduction ◽

10.1530/rep-15-0126 ◽

2015 ◽

Vol 150 (2) ◽

pp. 139-149 ◽

Cited By ~ 9

Author(s):

Qian Zhang ◽

Song Yu ◽

Xing Huang ◽

Yi Tan ◽

Cheng Zhu ◽

...

Keyword(s):

Ex Vivo ◽

Trophoblast Invasion ◽

Trophoblast Cells ◽

Human Trophoblast ◽

Invasion And Migration ◽

Cullin 3 ◽

And Migration ◽

F Box Protein ◽

Extravillous Trophoblasts

Cullin 3 (CUL3), a scaffold protein, assembles a large number of ubiquitin ligase complexes, similar to Skp1-Cullin 1-F-box protein complex. Several genetic models have shown that CUL3 is crucial for early embryonic development. Nevertheless, the role of CUL3 in human trophoblast function remains unclear. In this study, immunostaining revealed that CUL3 was strongly expressed in the villous cytotrophoblasts, the trophoblast column, and the invasive extravillous trophoblasts. Silencing CUL3 significantly inhibited the outgrowth of villous explant ex vivo and decreased invasion and migration of trophoblast HTR8/SVneo cells. Furthermore, CUL3 siRNA decreased pro-MMP9 activity and increased the levels of TIMP1 and 2. We also found that the level of CUL3 in the placental villi from pre-eclamptic patients was significantly lower as compared to that from their gestational age-matched controls. Moreover, in the lentiviral-mediated placenta-specific CUL3 knockdown mice, lack of CUL3 resulted in less invasive trophoblast cells in the maternal decidua. Taken together, these results suggest an essential role for CUL3 in the invasion and migration of trophoblast cells, and dysregulation of its expression may be associated with the onset of pre-eclampsia.

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Glioblastoma invasion and NMDA receptors: A novel prospect

Physiology International ◽

10.1556/2060.106.2019.22 ◽

2019 ◽

Vol 106 (3) ◽

pp. 250-260 ◽

Cited By ~ 3

Author(s):

DN Nandakumar ◽

P Ramaswamy ◽

C Prasad ◽

D Srinivas ◽

K Goswami

Keyword(s):

Glutamate Receptors ◽

Cell Lines ◽

Intracellular Signaling ◽

Transcript Level ◽

Glioblastoma Cells ◽

Invasion And Migration ◽

Matrigel Invasion ◽

Nmdar Activation ◽

And Migration

Purpose Glioblastoma cells create glutamate-rich tumor microenvironment, which initiates activation of ion channels and modulates downstream intracellular signaling. N-methyl-D-aspartate receptors (NMDARs; a type of glutamate receptors) have a high affinity for glutamate. The role of NMDAR activation on invasion of glioblastoma cells and the crosstalk with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is yet to be explored. Main methods LN18, U251MG, and patient-derived glioblastoma cells were stimulated with NMDA to activate NMDAR glutamate receptors. The role of NMDAR activation on invasion and migration and its crosstalk with AMPAR were evaluated. Invasion and migration of glioblastoma cells were investigated by in vitro trans-well Matrigel invasion and trans-well migration assays, respectively. Expression of NMDARs and AMPARs at transcript level was evaluated by quantitative real-time polymerase chain reaction. Results We determined that NMDA stimulation leads to enhanced invasion in LN18, U251MG, and patient-derived glioblastoma cells, whereas inhibition of NMDAR using MK-801, a non-competitive antagonist of the NMDAR, significantly decreased the invasive capacity. Concordant with these findings, migration was significantly augmented by NMDAR in both cell lines. Furthermore, NMDA stimulation upregulated the expression of GluN2 and GluA1 subunits at the transcript level. Conclusions This study demonstrated the previously unexplored role of NMDAR in invasion of glioblastoma cells. Furthermore, the expression of the GluN2 subunit of NMDAR and the differential overexpression of the GluA1 subunit of AMPAR in both cell lines provide a plausible rationale of crosstalk between these calcium-permeable subunits in the glutamate-rich microenvironment of glioblastoma.

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YB-1 Is Altered in Pregnancy-Associated Disorders and Affects Trophoblast in Vitro Properties via Alternation of Multiple Molecular Traits

International Journal of Molecular Sciences ◽

10.3390/ijms22137226 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7226

Author(s):

Violeta Stojanovska ◽

Aneri Shah ◽

Katja Woidacki ◽

Florence Fischer ◽

Mario Bauer ◽

...

Keyword(s):

Cell Lines ◽

Cancer Progression ◽

Cell Function ◽

Trophoblast Cell ◽

Mrna Levels ◽

Trophoblast Cells ◽

Invasion And Migration ◽

And Migration ◽

Apoptosis And Inflammation

Cold shock Y-box binding protein-1 (YB-1) coordinates several molecular processes between the nucleus and the cytoplasm and plays a crucial role in cell function. Moreover, it is involved in cancer progression, invasion, and metastasis. As trophoblast cells share similar characteristics with cancer cells, we hypothesized that YB-1 might also be necessary for trophoblast functionality. In samples of patients with intrauterine growth restriction, YB-1 mRNA levels were decreased, while they were increased in preeclampsia and unchanged in spontaneous abortions when compared to normal pregnant controls. Studies with overexpression and downregulation of YB-1 were performed to assess the key trophoblast processes in two trophoblast cell lines HTR8/SVneo and JEG3. Overexpression of YB-1 or exposure of trophoblast cells to recombinant YB-1 caused enhanced proliferation, while knockdown of YB-1 lead to proliferative disadvantage in JEG3 or HTR8/SVneo cells. The invasion and migration properties were affected at different degrees among the trophoblast cell lines. Trophoblast expression of genes mediating migration, invasion, apoptosis, and inflammation was altered upon YB-1 downregulation. Moreover, IL-6 secretion was excessively increased in HTR8/SVneo. Ultimately, YB-1 directly binds to NF-κB enhancer mark in HTR8/SVneo cells. Our data show that YB-1 protein is important for trophoblast cell functioning and, when downregulated, leads to trophoblast disadvantage that at least in part is mediated by NF-κB.

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miR-373-3p Regulates Invasion and Migration Abilities of Trophoblast Cells via Targeted CD44 and Radixin

International Journal of Molecular Sciences ◽

10.3390/ijms22126260 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6260

Author(s):

Hyun-Jung Lee ◽

Seung Mook Lim ◽

Hee Yeon Jang ◽

Young Ran Kim ◽

Joon-Seok Hong ◽

...

Keyword(s):

Preterm Labor ◽

Target Genes ◽

Gene Array ◽

Migration And Invasion ◽

Trophoblast Cells ◽

Invasion And Migration ◽

Mirna Array ◽

Qrt Pcr ◽

Putative Target ◽

And Migration

Preterm labor (PTL) is one of the obstetric complications, and is known to be associated with abnormal maternal inflammatory response and intrauterine inflammation and/or infection. However, the expression of specific miRNAs associated with PTL is not clear. In this study, we performed combination analysis of miRNA array and gene array, and then selected one miRNA (miR-373-3p) and its putative target genes (CD44 and RDX) that exhibited large expression differences in term and PTL placentas with or without inflammation. Using qRT-PCR and luciferase assays, we confirmed that miR-373-3p directly targeted CD44 and RDX. Overexpression of miR-373-3p reduced the migration and invasion of trophoblast cells, while inhibition of miR-373-3p restored the migration and invasion abilities of trophoblast cells. Finally, we validated the expression of miR-373-3p and its target genes in clinical patients’ blood. miR-373-3p was increased in PTL patients’ blood, and was the most expressed in PTL patients’ blood with inflammation. In addition, by targeting the miR-373-3p, CD44 and RDX was decreased in PTL patients’ blood, and their expression were the lowest in PTL patients’ blood with inflammation. Taken together, these findings suggest that miR-373-3p and its target genes can be potential biomarkers for diagnosis of PTL.

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ERK5 and its role in tumour development

Biochemical Society Transactions ◽

10.1042/bst20110663 ◽

2012 ◽

Vol 40 (1) ◽

pp. 251-256 ◽

Cited By ~ 50

Author(s):

Pamela A. Lochhead ◽

Rebecca Gilley ◽

Simon J. Cook

Keyword(s):

Mitogen Activated Protein Kinase ◽

Invasion And Migration ◽

Extracellular Signal Regulated Kinase ◽

Protein Levels ◽

Extracellular Signal ◽

Mapk Signalling ◽

Mitogen Activated Protein ◽

Tumour Cell Invasion ◽

And Migration

The MEK5 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 5]/ERK5 pathway is the least well studied MAPK signalling module. It has been proposed to play a role in the pathology of cancer. In the present paper, we review the role of the MEK5/ERK5 pathway using the ‘hallmarks of cancer’ as a framework and consider how this pathway is deregulated. As well as playing a key role in endothelial cell survival and tubular morphogenesis during tumour neovascularization, ERK5 is also emerging as a regulator of tumour cell invasion and migration. Several oncogenes can stimulate ERK5 activity, and protein levels are increased by a novel amplification at chromosome locus 17p11 and by down-regulation of the microRNAs miR-143 and miR-145. Together, these finding underscore the case for further investigation into understanding the role of ERK5 in cancer.

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FGFR3 promotes the growth and malignancy of melanoma by influencing EMT and the phosphorylation of ERK, AKT, and EGFR

BMC Cancer ◽

10.1186/s12885-019-6161-8 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 6

Author(s):

Lei Li ◽

Shuai Zhang ◽

Hao Li ◽

Haiyan Chou

Keyword(s):

Cell Proliferation ◽

Lymph Node ◽

Lymph Node Metastasis ◽

Colony Formation ◽

Caspase 3 ◽

Growth Factor Receptor ◽

Invasion And Migration ◽

Node Metastasis ◽

And Migration

Abstract Background Overexpression of fibroblast growth factor receptor 3 (FGFR3) has been linked to tumor progression in many types of cancer. The role of FGFR3 in melanoma remains unclear. In this study, we aimed to uncover the role of FGFR3 in the growth and metastasis of melanoma. Methods FGFR3 knockdown and overexpression strategies were employed to investigate the effects of FGFR3 on colony formation, cell apoptosis, proliferation, migration, and in vitro invasion, along with the growth and metastasis of melanoma in a xenografts mouse model. The protein expression levels of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), epidermal growth factor receptor (EGFR), and epithelial-mesenchymal transition (EMT) markers were determined by Western blot analysis. Results The mRNA expression of FGFR3 was higher in melanoma tissues than normal healthy tissues. FGFR3 expression in cutaneous malignant melanoma (CMM) tissues was positively correlated with the Breslow thickness and lymph node metastasis. In A357 cells, knockdown of the FGFR3 gene decreased the colony formation ability, cell proliferation, invasion, and migration, but increased the caspase 3 activity and the apoptosis rate; overexpression of FGFR3 increased the colony formation ability, cell proliferation, invasion, and migration, but decreased the caspase 3 activity and apoptosis rates. FGFR3 knockdown also upregulated E-cadherin, downregulated N-cadherin and vimentin, and decreased the phosphorylation levels of ERK, AKT, and EGFR. In the MCC xenografts mice, knockdown of FGFR3 decreased tumor growth and metastasis. Conclusions FGFR3, which is highly expressed in CMM tissues, is correlated with increased Breslow thickness and lymph node metastasis. FGFR3 promotes melanoma growth, metastasis, and EMT behaviors, likely by affecting the phosphorylation levels of ERK, AKT, and EGFR.

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Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): From Mechanism to Therapy and Prognosis

International Journal of Molecular Sciences ◽

10.3390/ijms22168470 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8470

Author(s):

Hui Wang ◽

Tian Tian ◽

Jinhua Zhang

Keyword(s):

Colorectal Cancer ◽

Clinical Care ◽

Inflammatory Cells ◽

Genetic Alterations ◽

Tumor Associated Macrophages ◽

Invasion And Migration ◽

Complex Process ◽

Incidence And Mortality ◽

And Migration

Colorectal cancer (CRC) is a malignant tumor in the digestive system whose incidence and mortality is high-ranking among tumors worldwide. The initiation and progression of CRC is a complex process involving genetic alterations in cancer cells and multiple factors from the surrounding tumor cell microenvironment. As accumulating evidence has shown, tumor-associated macrophages (TAMs)—as abundant and active infiltrated inflammatory cells in the tumor microenvironment (TME)—play a crucial role in CRC. This review focuses on the different mechanisms of TAM in CRC, including switching of phenotypical subtypes; promoting tumor proliferation, invasion, and migration; facilitating angiogenesis; mediating immunosuppression; regulating metabolism; and interacting with the microbiota. Although controversy remains in clinical evidence regarding the role of TAMs in CRC, clarifying their significance in therapy and the prognosis of CRC may shed new light on the optimization of TAM-centered approaches in clinical care.

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MiR-125b-5p Inhibited The Progression of Hepatoblastoma As A Shared miRNA of The lncRNA NEAT1 and YES1

10.21203/rs.3.rs-49445/v1 ◽

2020 ◽

Author(s):

Zhu Jin ◽

Yutong Chen ◽

Yuchen Mao ◽

Mingjuan Gao ◽

Zebing Zheng ◽

...

Keyword(s):

Clinicopathological Characteristics ◽

Luciferase Reporter ◽

Tumor Growth Inhibition ◽

Invasion And Migration ◽

In Vivo Experiments ◽

Reporter Assays ◽

And Migration ◽

Relationship Of

Abstract Background: microRNAs have been studied widely in hepatoblastoma. However, the role of miR-125b-5p and its relationship with the lncRNA sNEAT1 and YES1 in hepatoblastoma have not been reported previously. We aimed to reveal the role of NEAT1/miR-125b-5p/YES1 in the progression of hepatoblastoma.Methods: We collected tumor tissues and their adjacent tissues from 12 hepatoblastoma patients. qRT-PCR was applied to detect the expression of miR-125b-5p, and the relationship of miR-125b-5p with clinicopathological characteristics was analyzed. Dual luciferase reporter assays and RNA pull down assays were used to identify the relationships among NEAT1, miR-125b-5p and YES1. CCK8, Transwell assays and wound healing assays were used to examine cell viability, invasion and migration. In vivo experiments were also applied to detect the effect of miR-125b-5p on hepatoblastoma.Results: miR-125b-5p was significantly downregulated in hepatoblastoma tissue and cells. The higher the PRETEXT grade, the lower the miR-125b-5p level. NEAT1 could bind to miR-125b-5p and inhibit its expression. miR-125b-5p could target YES1 and inhibit its expression. Overexpression of miR-125b-5p decreased the proliferation, invasion, and migratory ability of hepatoblastoma cells. YES1 could rescue the above effects. At the same time, overexpression of miR-125b-5p resulted in decreased YES1 and tumor growth inhibition in vivo.Conclusion: miR-125b-5p acted as a shared miRNA of NEAT1 and YES1 in hepatoblastoma. Overexpression of miR-125b-5p could target YES1 and inhibit its expression, therefore inhibiting the progression of hepatoblastoma.

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