scholarly journals Phosphorylation of Serine 11 and Serine 92 as New Positive Regulators of Human Snail1 Function: Potential Involvement of Casein Kinase-2 and the cAMP-activated Kinase Protein Kinase A

2010 ◽  
Vol 21 (2) ◽  
pp. 244-253 ◽  
Author(s):  
Matthew Reid MacPherson ◽  
Patricia Molina ◽  
Serhiy Souchelnytskyi ◽  
Christer Wernstedt ◽  
Jorge Martin-Pérez ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Tumor Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Cop9 Signalosome ◽  
Mesenchymal Transition ◽  
Depth Analysis ◽  
Positive Regulators

Snail1 is a major factor for epithelial-mesenchymal transition (EMT), an important event in tumor metastasis and in other pathologies. Snail1 is tightly regulated at transcriptional and posttranscriptional levels. Control of Snail1 protein stability and nuclear export by GSK3β phosphorylation is important for Snail1 functionality. Stabilization mechanisms independent of GSK3β have also been reported, including interaction with LOXL2 or regulation of the COP9 signalosome by inflammatory signals. To get further insights into the role of Snail1 phosphorylation, we have performed an in-depth analysis of in vivo human Snail1 phosphorylation combined with mutational studies. We identify new phosphorylation sites at serines 11, 82, and 92 and confirmed previously suggested phosphorylations at serine 104 and 107. Serines 11 and 92 participate in the control of Snail1 stability and positively regulate Snail1 repressive function and its interaction with mSin3A corepressor. Furthermore, serines 11 and 92 are required for Snail1-mediated EMT and cell viability, respectively. PKA and CK2 have been characterized as the main kinases responsible for in vitro Snail1 phosphorylation at serine 11 and 92, respectively. These results highlight serines 11 and 92 as new players in Snail1 regulation and suggest the participation of CK2 and PKA in the modulation of Snail1 functionality.

scholarly journals Investigations on the Role of the MicroRNA-338-5p/Wnt Family Member 2B (WNT2B) Axis in Regulating the Pathogenesis of Nasopharyngeal Carcinoma (NPC)

2021 ◽  
Vol 11 ◽  
Author(s):  
Suzhen Wang ◽  
Tianning Yang ◽  
Zhengxiang He
Keyword(s):  
Family Member ◽  
Colony Formation ◽  
Epithelial Mesenchymal Transition ◽  
Colony Formation Assay ◽  
Transwell Assay ◽  
Mesenchymal Transition ◽  
Downstream Target

BackgroundThe involvement of microRNA-338-5p in modulating NPC pathogenesis is still largely unknown, and this study aimed to investigate this issue.MethodsThe expressions of cancer associated genes were determined by Real-Time qPCR and Western Blot, and cell apoptosis was determined by flow cytometer (FCM). CCK-8 assay and colony formation assay were respectively used to determine cell proliferation and colony formation abilities. Transwell assay was used to evaluate cell migration. The expression levels of Ki67 protein in mice tissues were measured by Immunohistochemistry (IHC) assay.ResultsThe present study found that microRNA-338-5p suppressed NPC progression by degrading its downstream target, Wnt family member 2B (WNT2B). Specifically, microRNA-338-5p tended to be low-expressed in NPC tissues and cell lines, compared to the non-tumor nasopharyngeal mucosa tissues and normal nasopharyngeal cell line (NP69). Upregulation of microRNA-338-5p inhibited proliferation, mobility, and epithelial-mesenchymal transition (EMT) in NPC cells in vitro, while silencing of microRNA-338-5p had opposite effects. Consistently, microRNA-338-5p suppressed tumorigenesis of NPC cells in vivo. In addition, microRNA-338-5p targeted WNT2B for degradation and inhibition, and the inhibiting effects of microRNA-338-5p overexpression on NPC development were reversed by upregulating WNT2B.ConclusionsTaken together, we concluded that microRNA-338-5p targeted WNT2B to hinder NPC development.

scholarly journals Linc00426 accelerates lung adenocarcinoma progression by regulating miR-455-5p as a molecular sponge

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Hongli Li ◽  
Qingjie Mu ◽  
Guoxin Zhang ◽  
Zhixin Shen ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Biological Significance ◽  
Mesenchymal Transition

AbstractIncreasing lines of evidence indicate the role of long non-coding RNAs (LncRNAs) in gene regulation and tumor development. Hence, it is important to elucidate the mechanisms of LncRNAs underlying the proliferation, metastasis, and invasion of lung adenocarcinoma (LUAD). We employed microarrays to screen LncRNAs in LUAD tissues with and without lymph node metastasis and revealed their effects on LUAD. Among them, Linc00426 was selected for further exploration in its expression, the biological significance, and the underlying molecular mechanisms. Linc00426 exhibits ectopic expression in LUAD tissues and cells. The ectopic expression has been clinically linked to tumor size, lymphatic metastasis, and tumor differentiation of patients with LUAD. The deregulation of Linc00426 contributes to a notable impairment in proliferation, invasion, metastasis, and epithelial–mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the deregulation of Linc00426 could reduce cytoskeleton rearrangement and matrix metalloproteinase expression. Meanwhile, decreasing the level of Linc00426 or increasing miR-455-5p could down-regulate the level of UBE2V1. Thus, Linc00426 may act as a competing endogenous RNA (ceRNA) to abate miR-455-5p-dependent UBE2V1 reduction. We conclude that Linc00426 accelerates LUAD progression by acting as a molecular sponge to regulate miR-455-5p, and may be a potential novel tumor marker for LUAD.

scholarly journals New Actors Driving the Epithelial–Mesenchymal Transition in Cancer: The Role of Leptin

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1676
Author(s):  
Monserrat Olea-Flores ◽  
Juan C. Juárez-Cruz ◽  
Miriam D. Zuñiga-Eulogio ◽  
Erika Acosta ◽  
Eduardo García-Rodríguez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Epithelial Cancers ◽  
Patients With Cancer

Leptin is a hormone secreted mainly by adipocytes; physiologically, it participates in the control of appetite and energy expenditure. However, it has also been linked to tumor progression in different epithelial cancers. In this review, we describe the effect of leptin on epithelial–mesenchymal transition (EMT) markers in different study models, including in vitro, in vivo, and patient studies and in various types of cancer, including breast, prostate, lung, and ovarian cancer. The different studies report that leptin promotes the expression of mesenchymal markers and a decrease in epithelial markers, in addition to promoting EMT-related processes such as cell migration and invasion and poor prognosis in patients with cancer. Finally, we report that leptin has the greatest biological relevance in EMT and tumor progression in breast, lung, prostate, esophageal, and ovarian cancer. This relationship could be due to the key role played by the enriched tumor microenvironment in adipose tissue. Together, these findings demonstrate that leptin is a key biomolecule that drives EMT and metastasis in cancer.

Role of Glioma-associated GLI1 Oncogene in Carcinogenesis and Cancertargeted Therapy

2018 ◽  
Vol 18 (6) ◽  
pp. 558-566 ◽  
Author(s):  
Jie Wu ◽  
Dingxin Di ◽  
Chen Zhao ◽  
Yingyi Liu ◽  
Hongxia Chen ◽  
...  
Keyword(s):  
Zinc Finger Protein ◽  
Epithelial Mesenchymal Transition ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
Gli Proteins ◽  
Canonical Pathways ◽  
Cancer Targeted Therapy

Glioma-associated oncogenes (GLIs) are zinc finger protein family members and downstream regulatory factors of the classic Hedgehog (Hh) signaling pathway. GLI proteins influence the growth and development of organisms and aid in tissue repair. However, aberrant expression of the GLI family member GLI1 promotes carcinogenesis by inducing epithelial–mesenchymal transition (EMT), angiogenesis, and other signaling pathways. Overexpression of GLI1 is thought to be an indicator of poor prognosis as well as a potential therapeutic target for cancers. GLI inhibitors such as zerumbone, GANT61, resveratrol, and cyclopamine depress the Hh pathway in vitro and in vivo cancer research, and other non-canonical pathways may also activate expression of GLI1. Here, we summarize GLI function in carcinogenesis and cancer-targeted therapy.

microRNA-382 suppresses the progression of pancreatic cancer through the PI3K/Akt signaling pathway by inhibition of Anxa3

2020 ◽  
Vol 319 (3) ◽  
pp. G309-G322
Author(s):  
Xiaohui Wan ◽  
Dongrui Guo ◽  
Qi Zhu ◽  
Rongfeng Qu
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Mesenchymal Transition ◽  
Node Metastasis

This study focused on the mechanism of miR-382 in epithelial mesenchymal transition and lymph node metastasis in PC in relation to Anxa3 and the PI3K/Akt signaling pathway. We found the inhibitory role of miR-382 in PC in vitro and in vivo.

SOX10 induces epithelial–mesenchymal transition and contributes to nasopharyngeal carcinoma progression

2018 ◽  
Vol 96 (3) ◽  
pp. 326-331 ◽  
Author(s):  
Ping He ◽  
Xiaojie Jin
Keyword(s):  
Cell Proliferation ◽  
Nasopharyngeal Carcinoma ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Objective: The aim of this study was to investigate the role of SOX10 in nasopharyngeal carcinoma (NPC) and the underlying molecular mechanisms. Methods: The expression of SOX10 was initially assessed in human NPC tissues and a series of NPC cell lines through quantitative real-time PCR (qRT-PCR) and Western blot. Then, cell proliferation, cycle, migration, and the invasiveness of NPC cells with knockdown of SOX10 were examined by MTT, flow cytometry, and Transwell migration and invasion assays, respectively. Finally, nude mice tumorigenicity experiments were performed to evaluate the effects of SOX10 on NPC growth and metastasis in vivo. Results: SOX10 was significantly increased in NPC tissues and cell lines. In-vitro experiments revealed that loss of SOX10 obviously inhibited cell proliferation, migration, and invasiveness, as well as the epithelial–mesenchymal transition (EMT) process in NPC cells. In-vivo experiments further demonstrated that disrupted SOX10 expression restrained NPC growth and metastasis, especially in lung and liver. Conclusion: Taken together, our data confirmed the role of SOX10 as an oncogene in NPC progression, and revealed that SOX10 may serve as a novel biomarker for diagnosis of NPC, as well as a potential therapeutic target against this disease.

scholarly journals METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Ben Yue ◽  
Chenlong Song ◽  
Linxi Yang ◽  
Ran Cui ◽  
Xingwang Cheng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Qrt Pcr ◽  
Rna Immunoprecipitation ◽  
E Cadherin

Abstract Background As one of the most frequent chemical modifications in eukaryotic mRNAs, N6-methyladenosine (m6A) modification exerts important effects on mRNA stability, splicing, and translation. Recently, the regulatory role of m6A in tumorigenesis has been increasingly recognized. However, dysregulation of m6A and its functions in tumor epithelial-mesenchymal transition (EMT) and metastasis remain obscure. Methods qRT-PCR and immunohistochemistry were used to evaluate the expression of methyltransferase-like 3 (METTL3) in gastric cancer (GC). The effects of METTL3 on GC metastasis were investigated through in vitro and in vivo assays. The mechanism of METTL3 action was explored through transcriptome-sequencing, m6A-sequencing, m6A methylated RNA immunoprecipitation quantitative reverse transcription polymerase chain reaction (MeRIP qRT-PCR), confocal immunofluorescent assay, luciferase reporter assay, co-immunoprecipitation, RNA immunoprecipitation and chromatin immunoprecipitation assay. Results Here, we show that METTL3, a major RNA N6-adenosine methyltransferase, was upregulated in GC. Clinically, elevated METTL3 level was predictive of poor prognosis. Functionally, we found that METTL3 was required for the EMT process in vitro and for metastasis in vivo. Mechanistically, we unveiled the METTL3-mediated m6A modification profile in GC cells for the first time and identified zinc finger MYM-type containing 1 (ZMYM1) as a bona fide m6A target of METTL3. The m6A modification of ZMYM1 mRNA by METTL3 enhanced its stability relying on the “reader” protein HuR (also known as ELAVL1) dependent pathway. In addition, ZMYM1 bound to and mediated the repression of E-cadherin promoter by recruiting the CtBP/LSD1/CoREST complex, thus facilitating the EMT program and metastasis. Conclusions Collectively, our findings indicate the critical role of m6A modification in GC and uncover METTL3/ZMYM1/E-cadherin signaling as a potential therapeutic target in anti-metastatic strategy against GC.

scholarly journals DCBLD2 Mediates Epithelial-Mesenchymal Transition-Induced Metastasis by Cisplatin in Lung Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1403
Author(s):  
Xiaosu Chen ◽  
Yajing Lv ◽  
Kejia Xu ◽  
Xiaoshuang Wang ◽  
Yujia Zhao ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Tumor Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Bioinformatic Analysis ◽  
Critical Issue ◽  
Chemotherapeutic Agents ◽  
Clinical Practices ◽  
Mesenchymal Transition

Growing evidence suggests that cisplatin and other chemotherapeutic agents promote tumor metastasis while inhibiting tumor growth, which is a critical issue for certain patients in clinical practices. However, the role of chemotherapeutics in promoting tumor metastasis and the molecular mechanism involved are unclear. Here, we investigated the roles of cisplatin in promoting tumor metastasis in lung adenocarcinoma (LUAD). We demonstrated that cisplatin promoted epithelial-mesenchymal transition (EMT), cell motility, and metastasis in vitro and in vivo. The bioinformatic analysis and molecular biology approaches also indicated that DCBLD2 (Discoidin, CUB and LCCL domain containing 2) is a key gene that mediates cisplatin-induced metastasis. DCBLD2 stabilizes β-catenin by phosphorylating GSK3β and transporting accumulated β-catenin to the nucleus to promote the expression of EMT-related transcriptional factors (TFs), ultimately resulting in tumor metastasis. We also identified that cisplatin enhanced DCBLD2 expression by phosphorylating ERK and hence the AP-1-driven transcription of DCBLD2. Furthermore, DCBLD2-specific siRNAs encapsulated by nanocarriers prominently inhibit cisplatin-induced metastasis in vivo. Therefore, DCBLD2 plays a key role in cisplatin-induced metastasis in LUAD and is a potential target for preventing chemotherapy-induced metastasis in vivo.

scholarly journals SP1 Initiates Epithelial-Mesenchymal Transition of CTCs and Inhibits Metastasis in Prostate Cancer

2021 ◽  
Author(s):  
Mei Yang ◽  
Hui Liu ◽  
Guo Ping Qiu ◽  
Fei Gao
Keyword(s):  
Prostate Cancer ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Clinical Trial Registry ◽  
Mesenchymal Transition ◽  
Bioinformatics Software ◽  
Local Pca

Abstract Background: Circulating tumor cells （CTCs）are the basis of cancer metastasis. Till now, the role of different subtypes of CTCs in metastasis is unclear. Methods: We used the CanpatrolTM technique to isolate CTCs from 102 prostate cancer (PCa) patients. The EMT markers of CTCs were detected by FISH and classified CTCs into Epethial (E-CTCs), Mesenchymal (M-CTCs) and Mesenchymal/Epethial-CTCs (M/E-CTCs). Further, the potential EMT related molecules regulators were predicted by bioinformatics software, and SP1 was identified as the key EMT regulator. Then overexpress SP1 of PCa cells to verify the effect of SP1 on the EMT regulation and PCa metastasis. Results: The count of Total-CTCs, E-CTCs, and M/E-CTCs in metastatic PCa was significantly higher than that in local PCa. Although M-CTCs was not significantly different between local and metastatic PCa, the ratio of M-CTCs/Total-CTCs in metastatic PCa was markedly lower than that in local PCa. We found that Total-CTCs is an independent risk factor for PCa metastasis. Overexpression of SP1 initiated EMT of PCa cells and enhanced the invasion in vitro. Injecting overexpression SP1 PCa cells via tail vein, generating M-CTCs in vivo, we found the ability of M-CTCs to form lung metastasis was significantly inhibited compared with that of the control PCa-CTCs. Conclusion: Our study suggested Total-CTCs >14 predict PCa metastasis. M/E-CTCs might facilitate to PCa metastasis; however, M-CTCs might not. SP1 is an EMT regulator, which has the potential role of regulating the EMT of CTCs, thus changing the proportion of subtypes of CTCs. It is a potential therapeutic target.（Trial registration: Chinese Clinical Trial Registry. Registered 30 JUNE 2020, http://www.chictr.org.cn/registry.aspx）

scholarly journals CDX2 inhibits epithelial–mesenchymal transition in colorectal cancer by modulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression

2020 ◽  
Vol 124 (1) ◽  
pp. 270-280
Author(s):  
Junhui Yu ◽  
Shan Li ◽  
Zhengshui Xu ◽  
Jing Guo ◽  
Xiaopeng Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Pten Expression ◽  
Invasion And Metastasis ◽  
Snail Expression ◽  
Mesenchymal Transition

Abstract Background Emerging evidence suggests the involvement of caudal-related homoeobox transcription factor 2 (CDX2) in tumorigenesis of various cancers. Although CDX2 functions in cancer invasion and metastasis, fewer studies focus on the role of CDX2 during the induction of epithelial–mesenchymal transition (EMT) in colorectal cancer (CRC). Methods Immunohistochemical analysis of CDX2 was performed. A series of in vitro and in vivo experiments were conducted to reveal the role of CDX2 in the invasion and metastasis of CRC. Results CDX2 was downregulated in CRC tissues and reduced CDX2 correlated with poor prognosis. Knockdown of CDX2 promoted colon cancer cell invasion in vitro and facilitated liver metastasis in vivo with inducing EMT phenotypes. Further investigation indicated that CDX2 retarded Akt and GSK-3β phosphorylation, and thereby diminished Snail expression, β-catenin stabilisation and nuclear translocation. The depletion of β-catenin neutralised the regulation of Slug and ZEB1 by CDX2 knockdown. Mechanistically, CDX2 antagonised PI3K/Akt activity in CRC by modulating PTEN expression. CDX2 directly bound to the promoter of PTEN and transactivated its expression. Conclusions Our study first uncovered that CDX2 inhibits EMT and metastasis of CRC by regulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression.

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