Abstract P009: Notch Signaling Regulates Pluripotent Gene Expressions in Cardiac c-Kit+ Cells

We and others have shown that transplantation of explant-derived cells (EDCs) obtained from cardiac biopsies improved cardiac function after myocardial infarction. The current study was designed to examine the molecular mechanisms regulating expression of pluripotent genes in these cells. Toward this end, EDCs were separated based on expression of c-Kit antigen after 21 days in culture. We found that Notch signaling was activated mainly in c-Kit+ cells, but to a lesser degree in c-Kit- cells. In addition, we found that the pluripotency markers Sca-1, Nanog and Sox2 were mainly expressed in c-Kit+ cells. Also, in c-Kit+ cells, forced activation of Notch signaling via over-expression of Notch intracellular domain (NICD) induced cellular and molecular changes typical of epithelial-mesenchymal transition (EMT), evident by a decrease in VE cadherin and increases in N-cadherin, MMP, and ICAM. . Suppression of Notch signaling was associated with c-Kit+ cells exhibition of an epithelial/endothelial morphology. This observation is further supported by the increase in Nanog, Sca1, Sox2, VEGFR2 gene expressions after Notch suppression. In contrast, overexpression of NICD resulted in down-regulation of pluripotency gene expressions. Furthermore, suppression of Notch signaling was coincided with stabilization of β-catenin and accumulation of phosphorylated glycogen synthase kinase 3 beta (pGSK3β) suggestive of a crosstalk between Notch and canonical Wnt pathway. Thus, Notch regulates expression of pluripotency genes and mesenchymal transition of c-Kit+ cardiac EDCs.

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Increased Expressions of Matrix Metalloproteinases (MMPs) in Prostate Cancer Tissues of Men with Type 2 Diabetes

Biomedicines ◽

10.3390/biomedicines8110507 ◽

2020 ◽

Vol 8 (11) ◽

pp. 507

Author(s):

Andras Franko ◽

Lucia Berti ◽

Jörg Hennenlotter ◽

Steffen Rausch ◽

Marcus O. Scharpf ◽

...

Keyword(s):

Prostate Cancer ◽

Type 2 Diabetes ◽

Matrix Metalloproteinases ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Prostate Tissue ◽

Nuclear Antigen ◽

Gene Expressions ◽

Mesenchymal Transition

Type 2 diabetes (T2D) is associated with worse prognosis of prostate cancer (PCa). The molecular mechanisms behind this association are still not fully understood. The aim of this study was to identify key factors, which contribute to the more aggressive PCa phenotype in patients with concurrent T2D. Therefore, we investigated benign and PCa tissue of PCa patients with and without diabetes using real time qPCR. Compared to patients without diabetes, patients with T2D showed a decreased E-cadherin/N-cadherin (CDH1/CDH2) ratio in prostate tissue, indicating a switch of epithelial-mesenchymal transition (EMT), which is a pivotal process in carcinogenesis. In addition, the gene expression levels of matrix metalloproteinases (MMPs) and CC chemokine ligands (CCLs) were higher in prostate samples of T2D patients. Next, prostate adenocarcinoma PC3 cells were treated with increasing glucose concentrations to replicate hyperglycemia in vitro. In these cells, high glucose induced expressions of MMPs and CCLs, which showed significant positive associations with the proliferation marker proliferating cell nuclear antigen (PCNA). These results indicate that in prostate tissue of men with T2D, hyperglycemia may induce EMT, increase MMP and CCL gene expressions, which in turn activate invasion and inflammatory processes accelerating the progression of PCa.

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A “NOTCH” Deeper into the Epithelial-To-Mesenchymal Transition (EMT) Program in Breast Cancer

Genes ◽

10.3390/genes10120961 ◽

2019 ◽

Vol 10 (12) ◽

pp. 961 ◽

Cited By ~ 10

Author(s):

Rohan Kar ◽

Niraj Kumar Jha ◽

Saurabh Kumar Jha ◽

Ankur Sharma ◽

Sunny Dholpuria ◽

...

Keyword(s):

Breast Cancer ◽

Notch Signaling ◽

Human Breast Cancer ◽

Large Scale ◽

Molecular Mechanisms ◽

Target Genes ◽

Epithelial Mesenchymal Transition ◽

Human Breast ◽

Breast Tumorigenesis ◽

Mesenchymal Transition

Notch signaling is a primitive signaling pathway having various roles in the normal origin and development of each multicellular organisms. Therefore, any aberration in the pathway will inevitably lead to deadly outcomes such as cancer. It has now been more than two decades since Notch was acknowledged as an oncogene in mouse mammary tumor virus-infected mice. Since that discovery, activated Notch signaling and consequent up-regulation of tumor-promoting Notch target genes have been observed in human breast cancer. Moreover, consistent over-expression of Notch ligands and receptors has been shown to correlate with poor prognosis in human breast cancer. Notch regulates a number of key processes during breast carcinogenesis, of which, one key phenomenon is epithelial–mesenchymal transition (EMT). EMT is a key process for large-scale cell movement during morphogenesis at the time of embryonic development. Cancer cells aided by transcription factors usurp this developmental program to execute the multi-step process of tumorigenesis and metastasis. In this review, we recapitulate recent progress in breast cancer research that has provided new perceptions into the molecular mechanisms behind Notch-mediated EMT regulation during breast tumorigenesis.

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Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives

Cancers ◽

10.3390/cancers13205106 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5106

Author(s):

Nadezda Zhdanovskaya ◽

Mariarosaria Firrincieli ◽

Sara Lazzari ◽

Eleonora Pace ◽

Pietro Scribani Rossi ◽

...

Keyword(s):

Stem Cell ◽

Notch Signaling ◽

Cell Fate ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Clinical Success ◽

Tumor Stroma ◽

Chemotherapeutic Drugs ◽

Mesenchymal Transition ◽

Cell Fate Decisions

Notch signaling guides cell fate decisions by affecting proliferation, apoptosis, stem cell self-renewal, and differentiation depending on cell and tissue context. Given its multifaceted function during tissue development, both overactivation and loss of Notch signaling have been linked to tumorigenesis in ways that are either oncogenic or oncosuppressive, but always context-dependent. Notch signaling is critical for several mechanisms of chemoresistance including cancer stem cell maintenance, epithelial-mesenchymal transition, tumor-stroma interaction, and malignant neovascularization that makes its targeting an appealing strategy against tumor growth and recurrence. During the last decades, numerous Notch-interfering agents have been developed, and the abundant preclinical evidence has been transformed in orphan drug approval for few rare diseases. However, the majority of Notch-dependent malignancies remain untargeted, even if the application of Notch inhibitors alone or in combination with common chemotherapeutic drugs is being evaluated in clinical trials. The modest clinical success of current Notch-targeting strategies is mostly due to their limited efficacy and severe on-target toxicity in Notch-controlled healthy tissues. Here, we review the available preclinical and clinical evidence on combinatorial treatment between different Notch signaling inhibitors and existent chemotherapeutic drugs, providing a comprehensive picture of molecular mechanisms explaining the potential or lacking success of these combinations.

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MiR-597 Targeting 14-3-3σ Enhances Cellular Invasion and EMT in Nasopharyngeal Carcinoma Cells

Current Molecular Pharmacology ◽

10.2174/1874467212666181218113930 ◽

2019 ◽

Vol 12 (2) ◽

pp. 105-114 ◽

Cited By ~ 1

Author(s):

Lisha Xie ◽

Tao Jiang ◽

Ailan Cheng ◽

Ting Zhang ◽

Pin Huang ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Cell Lines ◽

Western Blotting ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Suppressor Gene ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Downstream Target ◽

Before And After

Background: Alterations in microRNAs (miRNAs) are related to the occurrence of nasopharyngeal carcinoma (NPC) and play an important role in the molecular mechanism of NPC. Our previous studies show low expression of 14-3-3σ (SFN) is related to the metastasis and differentiation of NPC, but the underlying molecular mechanisms remain unclear. Methods: Through bioinformatics analysis, we find miR-597 is the preferred target miRNA of 14-3-3σ. The expression level of 14-3-3σ in NPC cell lines was detected by Western blotting. The expression of miR-597 in NPC cell lines was detected by qRT-PCR. We transfected miR-597 mimic, miR-597 inhibitor and 14-3-3σ siRNA into 6-10B cells and then verified the expression of 14-3-3σ and EMT related proteins, including E-cadherin, N-cadherin and Vimentin by western blotting. The changes of migration and invasion ability of NPC cell lines before and after transfected were determined by wound healing assay and Transwell assay. Results: miR-597 expression was upregulated in NPC cell lines and repaired in related NPC cell lines, which exhibit a potent tumor-forming effect. After inhibiting the miR-597 expression, its effect on NPC cell line was obviously decreased. Moreover, 14-3-3σ acts as a tumor suppressor gene and its expression in NPC cell lines is negatively correlated with miR-597. Here 14-3-3σ was identified as a downstream target gene of miR-597, and its downregulation by miR-597 drives epithelial-mesenchymal transition (EMT) and promotes the migration and invasion of NPC. Conclusion: Based on these findings, our study will provide theoretical and experimental evidences for molecular targeted therapy of NPC.

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A Comprehensive Bioinformatics Analysis of Notch Pathways in Bladder Cancer

Cancers ◽

10.3390/cancers13123089 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3089

Author(s):

Chuan Zhang ◽

Mandy Berndt-Paetz ◽

Jochen Neuhaus

Keyword(s):

Cell Cycle ◽

Bladder Cancer ◽

Notch Signaling ◽

Epithelial Mesenchymal Transition ◽

Tumor Biology ◽

Disease Free Survival ◽

Mesenchymal Transition ◽

Expression Levels ◽

Notch Receptors ◽

Notch Pathways

Background: A hallmark of Notch signaling is its variable role in tumor biology, ranging from tumor-suppressive to oncogenic effects. Until now, the mechanisms and functions of Notch pathways in bladder cancer (BCa) are still unclear. Methods: We used publicly available data from the GTEx and TCGA-BLCA databases to explore the role of the canonical Notch pathways in BCa on the basis of the RNA expression levels of Notch receptors, ligands, and downstream genes. For statistical analyses of cancer and non-cancerous samples, we used R software packages and public databases/webservers. Results: We found differential expression between control and BCa samples for all Notch receptors (NOTCH1, 2, 3, 4), the delta-like Notch ligands (DLL1, 3, 4), and the typical downstream gene hairy and enhancer of split 1 (HES1). NOTCH2/3 and DLL4 can significantly differentiate non-cancerous samples from cancers and were broadly altered in subgroups. High expression levels of NOTCH2/3 receptors correlated with worse overall survival (OS) and shorter disease-free survival (DFS). However, at long-term (>8 years) follow-up, NOTCH2 expression was associated with a better OS and DFS. Furthermore, the cases with the high levels of DLL4 were associated with worse OS but improved DFS. Pathway network analysis revealed that NOTCH2/3 in particular correlated with cell cycle, epithelial–mesenchymal transition (EMT), numbers of lymphocyte subtypes, and modulation of the immune system. Conclusions: NOTCH2/3 and DLL4 are potential drivers of Notch signaling in BCa, indicating that Notch and associated pathways play an essential role in the progression and prognosis of BCa through directly modulating immune cells or through interaction with cell cycle and EMT.

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Galectin-3: A factotum in carcinogenesis bestowing an archery for prevention

Tumor Biology ◽

10.3233/tub-200051 ◽

2021 ◽

Vol 43 (1) ◽

pp. 77-96

Author(s):

T. Jeethy Ram ◽

Asha Lekshmi ◽

Thara Somanathan ◽

K. Sujathan

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Therapy Resistance ◽

Cellular Level ◽

Clinical Samples ◽

Innovative Strategy ◽

Mesenchymal Transition ◽

Galectin 3

Cancer metastasis and therapy resistance are the foremost hurdles in oncology at the moment. This review aims to pinpoint the functional aspects of a unique multifaceted glycosylated molecule in both intracellular and extracellular compartments of a cell namely galectin-3 along with its metastatic potential in different types of cancer. All materials reviewed here were collected through the search engines PubMed, Scopus, and Google scholar. Among the 15 galectins identified, the chimeric gal-3 plays an indispensable role in the differentiation, transformation, and multi-step process of tumor metastasis. It has been implicated in the molecular mechanisms that allow the cancer cells to survive in the intravascular milieu and promote tumor cell extravasation, ultimately leading to metastasis. Gal-3 has also been found to have a pivotal role in immune surveillance and pro-angiogenesis and several studies have pointed out the importance of gal-3 in establishing a resistant phenotype, particularly through the epithelial-mesenchymal transition process. Additionally, some recent findings suggest the use of gal-3 inhibitors in overcoming therapeutic resistance. All these reports suggest that the deregulation of these specific lectins at the cellular level could inhibit cancer progression and metastasis. A more systematic study of glycosylation in clinical samples along with the development of selective gal-3 antagonists inhibiting the activity of these molecules at the cellular level offers an innovative strategy for primary cancer prevention.

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MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development

Biomolecules ◽

10.3390/biom11081074 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1074

Author(s):

Giuseppina Divisato ◽

Silvia Piscitelli ◽

Mariantonietta Elia ◽

Emanuela Cascone ◽

Silvia Parisi

Keyword(s):

Stem Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Embryonic Stem ◽

Cell Types ◽

Cancer Development ◽

Special Focus ◽

Self Renewal ◽

Mesenchymal Transition ◽

Different Cell Types

Embryonic stem cells (ESCs) have the extraordinary properties to indefinitely proliferate and self-renew in culture to produce different cell progeny through differentiation. This latter process recapitulates embryonic development and requires rounds of the epithelial–mesenchymal transition (EMT). EMT is characterized by the loss of the epithelial features and the acquisition of the typical phenotype of the mesenchymal cells. In pathological conditions, EMT can confer stemness or stem-like phenotypes, playing a role in the tumorigenic process. Cancer stem cells (CSCs) represent a subpopulation, found in the tumor tissues, with stem-like properties such as uncontrolled proliferation, self-renewal, and ability to differentiate into different cell types. ESCs and CSCs share numerous features (pluripotency, self-renewal, expression of stemness genes, and acquisition of epithelial–mesenchymal features), and most of them are under the control of microRNAs (miRNAs). These small molecules have relevant roles during both embryogenesis and cancer development. The aim of this review was to recapitulate molecular mechanisms shared by ESCs and CSCs, with a special focus on the recently identified classes of microRNAs (noncanonical miRNAs, mirtrons, isomiRs, and competitive endogenous miRNAs) and their complex functions during embryogenesis and cancer development.

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Circulating miRNAs Related to Epithelial–Mesenchymal Transitions (EMT) as the New Molecular Markers in Endometriosis

Current Issues in Molecular Biology ◽

10.3390/cimb43020064 ◽

2021 ◽

Vol 43 (2) ◽

pp. 900-916

Author(s):

Anna Zubrzycka ◽

Monika Migdalska-Sęk ◽

Sławomir Jędrzejczyk ◽

Ewa Brzeziańska-Lasota

Keyword(s):

Molecular Mechanisms ◽

Immune Cell ◽

Epithelial Mesenchymal Transition ◽

Clinical Symptoms ◽

Diagnostic Tools ◽

Endometrial Stromal Cells ◽

Disease Etiology ◽

Diagnostic Biomarkers ◽

Mesenchymal Transition ◽

Non Invasive

Endometriosis is a chronic gynecological disease defined by the presence of endometrial-like tissue found outside the uterus, most commonly in the peritoneal cavity. Endometriosis lesions are heterogenous but usually contain endometrial stromal cells and epithelial glands, immune cell infiltrates and are vascularized and innervated by nerves. The complex etiopathogenesis and heterogenity of the clinical symptoms, as well as the lack of a specific non-invasive diagnostic biomarkers, underline the need for more advanced diagnostic tools. Unfortunately, the contribution of environmental, hormonal and immunological factors in the disease etiology is insufficient, and the contribution of genetic/epigenetic factors is still fragmentary. Therefore, there is a need for more focused study on the molecular mechanisms of endometriosis and non-invasive diagnostic monitoring systems. MicroRNAs (miRNAs) demonstrate high stability and tissue specificity and play a significant role in modulating a range of molecular pathways, and hence may be suitable diagnostic biomarkers for the origin and development of endometriosis. Of these, the most frequently studied are those related to endometriosis, including those involved in epithelial–mesenchymal transition (EMT), whose expression is altered in plasma or endometriotic lesion biopsies; however, the results are ambiguous. Specific miRNAs expressed in endometriosis may serve as diagnostics markers with prognostic value, and they have been proposed as molecular targets for treatment. The aim of this review is to present selected miRNAs associated with EMT known to have experimentally confirmed significance, and discuss their utility as biomarkers in endometriosis.

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A novel homeostatic loop of sorcin drives paclitaxel-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human ovarian cancer

Oncogene ◽

10.1038/s41388-021-01891-6 ◽

2021 ◽

Author(s):

Jinguo Zhang ◽

Wencai Guan ◽

Xiaolin Xu ◽

Fanchen Wang ◽

Xin Li ◽

...

Keyword(s):

Ovarian Cancer ◽

Calcium Binding ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Malignant Progression ◽

Bioinformatics Analyses ◽

Aberrant Expression ◽

Mesenchymal Transition ◽

E Box

AbstractThe primary chemotherapy of ovarian cancer (OC) often acquires chemoresistance. Sorcin (SRI), a soluble resistance-related calcium-binding protein, has been reported to be an oncogenic protein in cancer. However, the molecular mechanisms of SRI regulation and the role and aberrant expression of SRI in chemoresistant OC remain unclear. Here, we identified SRI as a key driver of paclitaxel (PTX)-resistance and explored its regulatory mechanism. Using transcriptome profiles, qRT-PCR, proteomics, Western blot, immunohistochemistry, and bioinformatics analyses, we found that SRI was overexpressed in PTX-resistant OC cells and the overexpression of SRI was related to the poor prognosis of patients. SRI was a key molecule required for growth, migration, and PTX-resistance in vitro and in vivo and was involved in epithelial–mesenchymal transition (EMT) and stemness. Mechanistic studies showed that miR-142-5p directly bound to the 3ʹ-UTR of SRI to suppress its expression, whereas a transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) inhibited the transcription of miR-142-5p by directly binding to the E-box fragment in the miR-142 promoter region. Furthermore, ZEB1 was negatively regulated by SRI which physically interacted with Smad4 to block its translocation from the cytosol to the nucleus. Taken together, our findings unveil a novel homeostatic loop of SRI that drives the PTX-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human OC. Targeting this SRI/Smad4/ZEB1/miR-142-5p loop may reverse the PTX-resistance.

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Circular RNA hsa_circ_0000277 sequesters miR-4766-5p to upregulate LAMA1 and promote esophageal carcinoma progression

Cell Death and Disease ◽

10.1038/s41419-021-03911-5 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Peng Li Zhou ◽

Zhengyang Wu ◽

Wenguang Zhang ◽

Miao Xu ◽

Jianzhuang Ren ◽

...

Keyword(s):

Molecular Mechanisms ◽

Bioinformatics Analysis ◽

Epithelial Mesenchymal Transition ◽

Expression Profiles ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Circular Rnas ◽

Mesenchymal Transition ◽

Dismal Prognosis ◽

Advanced Tumor

AbstractGrowing evidence has indicated that circular RNAs (circRNAs) play a pivotal role as functional RNAs in diverse cancers. However, most circRNAs involved in esophageal squamous cell carcinoma (ESCC) remain undefined, and the underlying molecular mechanisms mediated by circRNAs are largely unclear. Here, we screened human circRNA expression profiles in ESCC tissues and found significantly increased expression of hsa_circ_0000277 (termed circPDE3B) in ESCC tissues and cell lines compared to the normal controls. Moreover, higher circPDE3B expression in patients with ESCC was correlated with advanced tumor-node-metastasis (TNM) stage and dismal prognosis. Functional experiments demonstrated that circPDE3B promoted the tumorigenesis and metastasis of ESCC cells in vitro and in vivo. Mechanistically, bioinformatics analysis, a dual-luciferase reporter assay, and anti-AGO2 RNA immunoprecipitation showed that circPDE3B could act as a competing endogenous RNA (ceRNA) by harboring miR-4766-5p to eliminate the inhibitory effect on the target gene laminin α1 (LAMA1). In addition, LAMA1 was significantly upregulated in ESCC tissues and was positively associated with the aggressive oncogenic phenotype. More importantly, rescue experiments revealed that the oncogenic role of circPDE3B in ESCC is partly dependent on the miR-4766-5p/LAMA1 axis. Furthermore, bioinformatics analysis combined with validation experiments showed that epithelial-mesenchymal transition (EMT) activation was involved in the oncogenic functions of the circPDE3B–miR-4766-5p/LAMA1 axis in ESCC. Taken together, we demonstrate for the first time that the circPDE3B/miR-4766-5p/LAMA1 axis functions as an oncogenic factor in promoting ESCC cell proliferation, migration, and invasion by inducing EMT, implying its potential prognostic and therapeutic significance in ESCC.

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