scholarly journals LTBP4 Inhibits the Proliferation and Metastasis in Melanoma by Activating Hippo-YAP Signaling

2020 ◽  
Author(s):  
Li na Wang ◽  
Dong run Tang ◽  
Tong Wu ◽  
Feng yuan Sun
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Western Blotting ◽  
Nuclear Translocation ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
Hippo Signaling ◽  
Ppi Network ◽  
Hippo Signaling Pathway ◽  
Proliferation And Metastasis

Abstract Background: Malignant melanoma is the deadliest of skin cancer. The present study aimed to elucidate potential key candidate genes in melanoma and its molecular mechanism. Methods: Three gene expression profile data sets (GSE46517, GSE52882 and GSE54493) were downloaded from the GEO database, which included data from melanoma tissue samples and cell lines. DEGs were subsequently investigated by GO analysis via using DAVID website. PPI network was constructed using the STRING database and visualized by Cytoscape software and MCODE were utilized to PPI network to pick out meaningful DEGs. Cell proliferation, apoptosis, migration and invasion were measured using CCK-8, colony formation, flow cytometry, transwell and wound healing assays. RT-PCR, western blotting and immunohistochemistry assays were used to detect mRNA and protein expressions. TCGAportal and GEPIA databases were used to perform the bioinformatics analysis of LTBP4 in melanoma. Results: LTBP4 both is the DEG and a key gene from the most significant module of the PPI network. LTBP4 expression was down-regulation in melanoma tissues and cells relative to controls, which showed positive correlation with invasion, TNM stage, distal metastasis and lymph node metastasis, and predicted the poor prognosis for patients with melanoma. Cox analysis identified LTBP4 low-expression as an independent prognostic variable for overall survival (OS) in patients with melanoma. The results revealed that LTBP4 inhibition reduced cell apoptosis, promoted cell proliferation and metastasis. These changes were correlated caspase-3, ki67 and E-cadherin expressions by western blotting assay. Further in vivo tumor formation study in nude mice indicated that LTBP4 inhibition promoted the progress of tumor formation. LTBP4 gene knockout reduced the phosphorylation level of YAP, MST1 and MOB1 and promoted the nuclear translocation of YAP to inhibit the activation of Hippo signaling pathway. The functions of LTBP4 overexpression (OE) inhibiting the expressions of CTGF, Cyr61 and Birc5, promoting the apoptosis, and inhibiting the metastasis and proliferation of melanoma cells were reversed by YAP/or MST1 OE.Conclusions: LTBP4 OE suppressed the proliferation and metastasis in melanoma via inhibiting the nuclear translocation of YAP to activating Hippo signaling pathway, thereby inhibiting the development and progression of melanoma.

scholarly journals miR-24-3p Promotes Cell Proliferation, Migration, and Invasion of Human Cervical Cancer Cells through/via Targeting AMOTL2 and Attenuating the YAP/Hippo Pathway

2021 ◽  
Author(s):  
Yiyun Huang ◽  
Lijun Hu ◽  
Lu Lin ◽  
Yan Liu ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Target Genes ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Cervical Cancer Cells

Abstract BackgroundmiR-24-3p promotes the development of the majority of malignancies.However, its function in cervical cancer is not clearly elucidated so far.MethodsIn this study, cell proliferation, migration, and invasion were measured by the CCK8 and transwell assays. Bioinformatic methods were used to predict the target genes of miR-24-3p, verifying by luciferase reporter assay and western blotting. The target genes set was also used for KEGG pathway enrichment analysis. ResultsThen we obsrved higher miR-24-3p level in cervical cancer cells and faster growth of tumor in a xenograft model. The function assays demonstrated that miR-24-3p promoted proliferation, migration, and invasion of cervical cancer cells in vitro. It was confirmed that miR-24-3p directly targeted AMOTL2 and the recovery of AMOTL2 reversed the function of miR-24-3p in cervical cancer cell line CaSki. Besides, miR-24-3p suppressed the Hippo signaling pathway in CaSki and SiHa cells. ConclusionsIn conclusion, our results reminded that miR-24-3p could boost the migration and proliferation of cervical cancer cells via down-regulating AMOTL2 and attenuating YAP/Hippo signaling pathway activity.

scholarly journals NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

2011 ◽  
Vol 193 (4) ◽  
pp. 633-642 ◽  
Author(s):  
Sandra Habbig ◽  
Malte P. Bartram ◽  
Roman U. Müller ◽  
Ricarda Schwarz ◽  
Nikolaos Andriopoulos ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Negative Regulator ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway ◽  
Potent Negative Regulator

The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.

scholarly journals The Long Non-Coding RNA CRNDE Promotes Colorectal Carcinoma Progression by Competitively Binding miR-217 with TCF7L2 and Enhancing the Wnt/β-Catenin Signaling Pathway

2017 ◽  
Vol 41 (6) ◽  
pp. 2489-2502 ◽  
Author(s):  
Bo Yu ◽  
Xuan Ye ◽  
Qiong Du ◽  
Bin Zhu ◽  
Qing Zhai
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Western Blotting ◽  
Migration And Invasion ◽  
Down Regulation ◽  
Over Expression ◽  
Non Coding Rna ◽  
Colorectal Cancer Cells ◽  
Long Non Coding Rna

Background/Aims: The long non-coding RNA colorectal neoplasia differentially expressed (CRNDE) contributes to the proliferation and migration of tumors. However, its molecular mechanism underlying gastric cancer remains unknown. In the present study, we investigated whether CRNDE was involved in the development of colorectal cancer via the binding of microRNA (miR)-217 with transcription factor 7-like 2 (TCF7L2) to enhance the Wnt signaling pathway. Methods: Quantitative polymerase chain reaction was used to detect CRNDE, miR-217 and TCF7L2 in colorectal cancer tissues and cells. The CCK-8 assay, wound healing assay, and Transwell assay were used to detect cell proliferation, migration and invasion, respectively. Western blotting and luciferase activity assays were used to identify CRNDE and TCF7L2 as one of the direct targets of miR-217. The activity of the Wnt/β-catenin signaling pathway was analyzed by the TOPflash assay, and the subcellular localization of β-catenin and TCF7L2 was analyzed by western blotting and confocal microscopy. Results: In this study, we found that high expression of CRNDE is negatively correlated with low expression of miR-217 in colorectal cancer tissue and colorectal cancer cells. The dual luciferase reporter analysis showed that miR-217 is bound to CRNDE and TCF7L2 and negatively regulate their expression. CRNDE down-regulation inhibited the cell proliferation, migration and invasion in vitro and in vivo and the inhibitions were both completely blocked after miR-217 inhibition or TCF7L2 overexpression. Finally, TOPflash analysis showed that the activity of Wnt/β-catenin signaling is inhibited by CRNDE down-regulation and rescued by TCF7L2 over-expression. Consistently immunostaining and western blotting analysis showed that the expression of b-catenin and TCF7L2 in the nucleus was significantly decreased by CRNDE down-regulation and was rescued by TCF7L2 over-expression. Conclusions: The present study suggest that CRNDE involves in the cell proliferation, migration and invasion of colorectal cancer cells via increasing the expression of TCF7L2 and activity of Wnt/β-catenin signaling through binding miR-217 competitively.

scholarly journals The long noncoding RNA AATBC promotes breast cancer migration and invasion by interacting with YBX1 and activating the YAP1/Hippo signaling pathway

2021 ◽  
Author(s):  
Maonan Wang ◽  
Manli Dai ◽  
Dan Wang ◽  
Ting Tang ◽  
Fang Xiong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
Differentially Expressed ◽  
Migration And Invasion ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway

Abstract BackgroundLong noncoding RNAs (lncRNAs) play an important role in the regulation of gene expression and are involved in several pathological responses. However, many important lncRNAs in breast cancer have not been identified and their expression levels and functions in breast cancer remain unknown.MethodsWe used the microarray data to identify differentially expressed lncRNAs between breast cancer and adjacent breast epithelial tissues. In vitro and in vivo assays were used to explore the biological effects of the differentially expressed lncRNA Apoptosis-Associated Transcript in Bladder Cancer (AATBC) in breast cancer cells. The mass spectrometry and RNA pulldown were used to screen AATBC interacting proteins. Using the Kaplan-Meier method, survival analysis was performed.ResultsThe expression of AATBC was significantly high in breast cancer samples, and this high AATBC level was tightly correlated with poor prognosis in breast cancer patients. In vitro and in vivo experiments indicated that AATBC promoted breast cancer cells migration and invasion. AATBC specifically interacted with Y-box binding protein 1 (YBX1), which activated the YAP1/Hippo signaling pathway by binding to macrophage stimulating 1 (MST1) and promoting the nuclear translocation of Yes associated protein 1 (YAP1), allowing its function as a nuclear transcriptional regulator. ConclusionsAATBC is highly expressed in breast cancer and contributes to patients’ progression, indicating that it could serve as a novel prognostic marker for the disease. Mechanistically, AATBC affects migration and invasion of breast cancer cells through an AATBC-YBX1-MST1 axis, resulting in activating the YAP1/Hippo signaling pathway. This is also an important supplement to the composition of the YAP1/Hippo signaling pathway. The model of “AATBC-YAP1” may bring a new dawn to the treatment of breast cancer.

scholarly journals ALCAP2 inhibits lung adenocarcinoma cell proliferation, migration and invasion via the ubiquitination of β-catenin by upregulating the E3 ligase NEDD4L

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Weijie Zhang ◽  
Ruochen Zhang ◽  
Yuanyuan Zeng ◽  
Yue Li ◽  
Yikun Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Nuclear Translocation ◽  
E3 Ligase ◽  
Migration And Invasion ◽  
Drug Candidate ◽  
Proliferation And Metastasis

AbstractLung cancer is recognized as the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) being the predominant subtype, accounting for approximately 85% of lung cancer cases. Although great efforts have been made to treat lung cancer, no proven method has been found thus far. Considering β, β-dimethyl-acryl-alkannin (ALCAP2), a natural small-molecule compound isolated from the root of Lithospermum erythrorhizon. We found that lung adenocarcinoma (LUAD) cell proliferation and metastasis can be significantly inhibited after treatment with ALCAP2 in vitro, as it can induce cell apoptosis and arrest the cell cycle. ALCAP2 also significantly suppressed the volume of tumours in mice without inducing obvious toxicity in vivo. Mechanistically, we revealed that ALCAP2-treated cells can suppress the nuclear translocation of β-catenin by upregulating the E3 ligase NEDD4L, facilitating the binding of ubiquitin to β-catenin and eventually affecting the wnt-triggered transcription of genes such as survivin, cyclin D1, and MMP9. As a result, our findings suggest that targeting the oncogene β-catenin with ALCAP2 can inhibit the proliferation and metastasis of LUAD cells, and therefore, ALCAP2 may be a new drug candidate for use in LUAD therapeutics.

scholarly journals WWC Proteins: Important Regulators of Hippo Signaling in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 306
Author(s):  
Verena Höffken ◽  
Anke Hermann ◽  
Hermann Pavenstädt ◽  
Joachim Kremerskothen
Keyword(s):  
Signaling Pathway ◽  
Intracellular Transport ◽  
Human Cancer ◽  
Hippo Pathway ◽  
Tumor Formation ◽  
Transport Processes ◽  
Published Data ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Upstream Regulators

The Hippo signaling pathway is known to regulate cell differentiation, proliferation and apoptosis. Whereas activation of the Hippo signaling pathway leads to phosphorylation and cytoplasmic retention of the transcriptional coactivator YAP, decreased Hippo signaling results in nuclear import of YAP and subsequent transcription of pro-proliferative genes. Hence, a dynamic and precise regulation of the Hippo signaling pathway is crucial for organ size control and the prevention of tumor formation. The transcriptional activity of YAP is controlled by a growing number of upstream regulators including the family of WWC proteins. WWC1, WWC2 and WWC3 represent cytosolic scaffolding proteins involved in intracellular transport processes and different signal transduction pathways. Earlier in vitro experiments demonstrated that WWC proteins positively regulate the Hippo pathway via the activation of large tumor suppressor kinases 1/2 (LATS1/2) kinases and the subsequent cytoplasmic accumulation of phosphorylated YAP. Later, reduced WWC expression and subsequent high YAP activity were shown to correlate with the progression of human cancer in different organs. Although the function of WWC proteins as upstream regulators of Hippo signaling was confirmed in various studies, their important role as tumor modulators is often overlooked. This review has been designed to provide an update on the published data linking WWC1, WWC2 and WWC3 to cancer, with a focus on Hippo pathway-dependent mechanisms.

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