scholarly journals Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1488 ◽  
Author(s):  
Sayon Basu ◽  
Sanith Cheriyamundath ◽  
Avri Ben-Ze’ev
Keyword(s):  
Cell Adhesion ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Circulating Tumor Cell ◽  
Adhesion Properties ◽  
Mesenchymal Transition ◽  
Tumor Tissues

Changes in cell adhesion and motility are considered key elements in determining the development of invasive and metastatic tumors. Co-opting the epithelial-to-mesenchymal transition (EMT) process, which is known to occur during embryonic development, and the associated changes in cell adhesion properties in cancer cells are considered major routes for tumor progression. More recent in vivo studies in tumor tissues and circulating tumor cell clusters suggest a stepwise EMT process rather than an “all-or-none” transition during tumor progression. In this commentary, we addressed the molecular mechanisms underlying the changes in cell adhesion and motility and adhesion-mediated signaling and their relationships to the partial EMT states and the acquisition of stemness traits by cancer cells.

scholarly journals Role of E2Fs and mitotic regulators controlled by E2Fs in the epithelial to mesenchymal transition

2019 ◽  
Vol 244 (16) ◽  
pp. 1419-1429
Author(s):  
Shirley Jusino ◽  
Harold I Saavedra
Keyword(s):  
Epithelial Cells ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Centrosome Amplification ◽  
Mesenchymal Transition

The epithelial-to-mesenchymal transition (EMT) is a complex cellular process in which epithelial cells acquire mesenchymal properties. EMT occurs in three biological settings: development, wound healing and fibrosis, and tumor progression. Despite occurring in three independent biological settings, EMT signaling shares some molecular mechanisms that allow epithelial cells to de-differentiate and acquire mesenchymal characteristics that confer cells invasive and migratory capacity to distant sites. Here we summarize the molecular mechanism that delineates EMT and we will focus on the role of E2 promoter binding factors (E2Fs) in EMT during tumor progression. Since the E2Fs are presently undruggable due to their control in numerous pivotal cellular functions and due to the lack of selectivity against individual E2Fs, we will also discuss the role of three mitotic regulators and/or mitotic kinases controlled by the E2Fs (NEK2, Mps1/TTK, and SGO1) in EMT that can be useful as drug targets. Impact statement The study of the epithelial to mesenchymal transition (EMT) is an active area of research since it is one of the early intermediates to invasion and metastasis—a state of the cancer cells that ultimately kills many cancer patients. We will present in this review that besides their canonical roles as regulators of proliferation, unregulated expression of the E2F transcription factors may contribute to cancer initiation and progression to metastasis by signaling centrosome amplification, chromosome instability, and EMT. Since our discovery that the E2F activators control centrosome amplification and mitosis in cancer cells, we have identified centrosome and mitotic regulators that may represent actionable targets against EMT and metastasis in cancer cells. This is impactful to all of the cancer patients in which the Cdk/Rb/E2F pathway is deregulated, which has been estimated to be most cancer patients with solid tumors.

scholarly journals Operative ubiquitin-specific protease 22 deubiquitination confers a more invasive phenotype to cholangiocarcinoma

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Yu Tian ◽  
Bo Tang ◽  
Chengye Wang ◽  
Yan Wang ◽  
Jiakai Mao ◽  
...  
Keyword(s):  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Sirtuin 1 ◽  
Mesenchymal Transition ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Paired Tumour

AbstractOncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-β-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

scholarly journals Roles of microRNAs in Regulating Cancer Stemness in Head and Neck Cancers

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1742
Author(s):  
Melysa Fitriana ◽  
Wei-Lun Hwang ◽  
Pak-Yue Chan ◽  
Tai-Yuan Hsueh ◽  
Tsai-Tsen Liao
Keyword(s):  
Growth Factor ◽  
Head And Neck ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Epithelial To Mesenchymal Transition ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Cancer Stemness ◽  
Mesenchymal Transition

Head and neck squamous cell carcinomas (HNSCCs) are epithelial malignancies with 5-year overall survival rates of approximately 40–50%. Emerging evidence indicates that a small population of cells in HNSCC patients, named cancer stem cells (CSCs), play vital roles in the processes of tumor initiation, progression, metastasis, immune evasion, chemo-/radioresistance, and recurrence. The acquisition of stem-like properties of cancer cells further provides cellular plasticity for stress adaptation and contributes to therapeutic resistance, resulting in a worse clinical outcome. Thus, targeting cancer stemness is fundamental for cancer treatment. MicroRNAs (miRNAs) are known to regulate stem cell features in the development and tissue regeneration through a miRNA–target interactive network. In HNSCCs, miRNAs act as tumor suppressors and/or oncogenes to modulate cancer stemness and therapeutic efficacy by regulating the CSC-specific tumor microenvironment (TME) and signaling pathways, such as epithelial-to-mesenchymal transition (EMT), Wnt/β-catenin signaling, and epidermal growth factor receptor (EGFR) or insulin-like growth factor 1 receptor (IGF1R) signaling pathways. Owing to a deeper understanding of disease-relevant miRNAs and advances in in vivo delivery systems, the administration of miRNA-based therapeutics is feasible and safe in humans, with encouraging efficacy results in early-phase clinical trials. In this review, we summarize the present findings to better understand the mechanical actions of miRNAs in maintaining CSCs and acquiring the stem-like features of cancer cells during HNSCC pathogenesis.

scholarly journals Molecular mechanisms underpinning sarcomas and implications for current and future therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Victoria Damerell ◽  
Michael S. Pepper ◽  
Sharon Prince
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Cells Of Origin ◽  
Novel Treatment Strategies ◽  
Future Therapy

AbstractSarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

scholarly journals The epithelial-mesenchymal transcription factor SNAI1 represses transcription of the tumor suppressor miRNA let-7 in cancer

2020 ◽  
Author(s):  
H Wang ◽  
E Chirshev ◽  
N Hojo ◽  
T Suzuki ◽  
A Bertucci ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Transcription Factor ◽  
Stem Cell ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Burden ◽  
Cell Phenotype ◽  
Mesenchymal Transition

AbstractWe aimed to determine the mechanism of epithelial-mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.Novelty and ImpactThis study provides new insight into molecular mechanisms by which EMT transcription factor SNAI1 exerts its pro-stemness effects in cancer cells, demonstrating its potential as a stem cell-directed target for therapy. In vitro and in vivo, mesoporous silica nanoparticle-mediated SNAI1 knockdown resulted in restoration of let-7 miRNA, inhibiting stemness and reducing tumor burden. Our studies validate in vivo nanoparticle-delivered RNAi targeting the SNAI1/let-7 axis as a clinically relevant approach.

scholarly journals P4HA2 Promotes Epithelial-to-Mesenchymal Transition and Glioma Malignancy through the Collagen-Dependent PI3K/AKT Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Jing Lin ◽  
Lei Jiang ◽  
Xiaogang Wang ◽  
Wenxin Wei ◽  
Chaoli Song ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Enzyme Inhibitor ◽  
Tumor Xenograft ◽  
Mesenchymal Transition ◽  
Akt Activation ◽  
Collagen Genes ◽  
First Time

Prolyl-4-hydroxylase subunit 2 (P4HA2) is a member of collagen modification enzymes involved in the remodeling of the extracellular matrix (ECM). Mounting evidence has suggested that deregulation of P4HA2 is common in cancer. However, the role of P4HA2 in glioma remains unknown. The present study aimed to elucidate the expression pattern, oncogenic functions, and molecular mechanisms of P4HA2 in glioblastoma cells. The TCGA datasets and paraffin samples were used for examining the expressions of P4HA2. P4HA2-specific lentivirus was generated to assess its oncogenic functions. A P4HA2 enzyme inhibitor (DHB) and an AKT agonist (SC79) were utilized to study the mechanisms. As a result, we demonstrated that P4HA2 is overexpressed in glioma and inversely correlates with patient survival. Knockdown of P4HA2 inhibited proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) like phenotype of glioma cells in vitro and suppressed tumor xenograft growth in vivo. Mechanistically, expressions of a series of collagen genes and of phosphorylated PI3K/AKT were downregulated by either P4HA2 silencing or inhibition of its prolyl hydroxylase. Finally, the inhibitory effects on the migration, invasion, and EMT-related molecules by P4HA2 knockdown were reversed by AKT activation with SC79. Our findings for the first time reveal that P4HA2 acts as an oncogenic molecule in glioma malignancy by regulating the expressions of collagens and the downstream PI3K/AKT signaling pathway.

scholarly journals CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling

2020 ◽  
Author(s):  
Qian Zhong ◽  
Yuxin Fang ◽  
Qiuhua Lai ◽  
Shanci Wang ◽  
Chengcheng He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Macrophage Polarization ◽  
Tumor Associated Macrophages ◽  
Antibody Treatment ◽  
Mesenchymal Transition ◽  
Stat3 Signaling

Abstract Background: Crosstalk between cancer cells and tumor-associated macrophages (TAMs) mediates tumor progression in colorectal cancer (CRC). Cytoplasmic polyadenylation element binding protein 3 (CPEB3) has been shown to exhibit tumor-suppressive role in CRC. Methods: The expression of CPEB3, CD68, CD86 and CD163 was determined in CRC tissues. SW480 or HCT116 cells overexpressing CPEB3 and LoVo or RKO cells with CPEB3 knockdown were constructed. Stably transfected CRC cells were co-cultured with THP-1 macrophages to determine the malignant phenotype of CRC cells, macrophage polarization, and secretory signals. The inhibition of CPEB3 on tumor progression and M2-like TAM polarization was confirmed in nude mice. Results: Decreased CPEB3 expression in CRC was associated with fewer CD86+ TAMs and more CD163+ TAMs. CPEB3 knockdown in CRC cells increased the number of CD163+ TAMs and the expression of IL1RA, IL-6, IL-4 and IL-10 in TAM supernatants. TAMs enhanced CRC cell proliferation and invasion via IL-6, and then activated the IL-6R/STAT3 pathway in CRC cells. However, CPEB3 reduced the IL-6R protein levels by directly binding to IL-6R mRNA, leading to decreased phosphorylated-STAT3 expression in CRC cells. CCL2 was significantly increased in CPEB3 knockdown cells, while CCL2 antibody treatment rescued the effect of CPEB3 knockdown in promoting CD163+ TAM polarization. Eventually, we confirmed that CPEB3 inhibits tumor progression and M2-like TAM polarization in vivo. Conclusions: CPEB3 is involved in the crosstalk between CRC cells and TAMs by targeting IL-6R/STAT3 signaling.

scholarly journals Control of the Epithelial-to-Mesenchymal Transition and Cancer Metastasis by Autophagy-Dependent SNAI1 Degradation

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 129 ◽  
Author(s):  
Sahib Zada ◽  
Jin Hwang ◽  
Mahmoud Ahmed ◽  
Trang Lai ◽  
Trang Pham ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Nuclear Translocation ◽  
Degradation Process ◽  
Mesenchymal Transition ◽  
Invasion And Migration

Autophagy, an intracellular degradation process, is essential for maintaining cell homeostasis by removing damaged organelles and proteins under various conditions of stress. In cancer, autophagy has conflicting functions. It plays a key role in protecting against cancerous transformation by maintaining genomic stability against genotoxic components, leading to cancerous transformation. It can also promote cancer cell survival by supplying minimal amounts of nutrients during cancer progression. However, the molecular mechanisms underlying how autophagy regulates the epithelial-to-mesenchymal transition (EMT) and cancer metastasis are unknown. Here, we show that starvation-induced autophagy promotes Snail (SNAI1) degradation and inhibits EMT and metastasis in cancer cells. Interestingly, SNAI1 proteins were physically associated and colocalized with LC3 and SQSTM1 in cancer cells. We also found a significant decrease in the levels of EMT and metastatic proteins under starvation conditions. Furthermore, ATG7 knockdown inhibited autophagy-induced SNAI1 degradation in the cytoplasm, which was associated with a decrease in SNAI1 nuclear translocation. Moreover, cancer cell invasion and migration were significantly inhibited by starvation-induced autophagy. These findings suggest that autophagy-dependent SNAI1 degradation could specifically regulate EMT and cancer metastasis during tumorigenesis.

scholarly journals HPV E7-mediated NCAPH ectopic expression regulates the carcinogenesis of cervical carcinoma via PI3K/AKT/SGK pathway

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Meng Wang ◽  
Xiaowen Qiao ◽  
Tamara Cooper ◽  
Wei Pan ◽  
Liang Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Depth Of Invasion ◽  
Mesenchymal Transition ◽  
Hpv E7

AbstractCervical cancer is one of the most common gynecological tumors in the world, and human papillomavirus (HPV) infection is its causative agent. However, the molecular mechanisms involved in the carcinogenesis of cervical cancer still require clarification. Here we found that knockdown of Non-SMC (Structural Maintenance of Chromosomes) condensin I complex subunit H (NCAPH) gene expression significantly inhibited the proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) of cervical cancer cells in vitro, and restrained xenograft tumor formation in vivo. Intriguingly, HPV E7 could form a positive feedback loop with NCAPH. E7 upregulated NCAPH gene expression via E2F1 which initiated NCAPH transcription by binding to its promoter directly. Silencing of NCAPH reduced E7 transcription via promoting the transition of AP-1 heterodimer from c-Fos/c-Jun to Fra-1/c-Jun. Moreover, the E7-mediated NCAPH overexpression was involved in the activation of the PI3K/AKT/SGK signaling pathway. In vivo, NCAPH expression in cervical cancer tissues was significantly higher than which in normal cervix and high-grade squamous intraepithelial lesion (HSIL) tissues, and its expression was significantly correlated with tumor size, depth of invasion and lymph node metastasis. Patients with high NCAPH expression had a significantly better survival outcomes than those with low-expression, suggesting that NCAPH-induced cell proliferation might sensitize cancer cells to adjuvant therapy. In conclusion, our results revealed the role of NCAPH in the carcinogenesis of cervical cancer in vitro and in vivo. The interaction between E7 and NCAPH expands the mechanism of HPV induced tumorigenesis and that of host genes regulating HPV E7.

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