scholarly journals TGFβ-induced expression of long noncoding lincRNA Platr18 controls breast cancer axonogenesis

2021 ◽  
Vol 5 (2) ◽  
pp. e202101261
Author(s):  
Simon Grelet ◽  
Cécile Fréreux ◽  
Clémence Obellianne ◽  
Ken Noguchi ◽  
Breege V Howley ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cell ◽  
Tumor Progression ◽  
Primary Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Progression ◽  
Mesenchymal Transition ◽  
Elevated Expression

Metastasis is the leading driver of cancer-related death. Tumor cell plasticity associated with the epithelial–mesenchymal transition (EMT), an embryonic program also observed in carcinomas, has been proposed to explain the colonization of distant organs by the primary tumor cells. Many studies have established correlations between EMT marker expression in the primary tumor and metastasis in vivo. However, the longstanding model of EMT-transitioned cells disseminating to secondary sites is still actively debated and hybrid states are presently considered as more relevant during tumor progression and metastasis. Here, we describe an unexplored role of EMT on the tumor microenvironment by controlling tumor innervation. Using in vitro and in vivo breast tumor progression models, we demonstrate that TGFβ-mediated tumor cell EMT triggers the expression of the embryonic LincRNA Platr18 those elevated expression controls the expression of the axon guidance protein semaphorin-4F and other neuron-related molecules such as IGSF11/VSIG-3. Platr18/Sema4F axis silencing abrogates axonogenesis and attenuates metastasis. Our observations suggest that EMT-transitioned cells are also locally required in the primary tumor to support distant dissemination by promoting axonogenesis, a biological process known for its role in metastatic progression of breast cancer.

scholarly journals CD73 facilitates EMT progression and promotes lung metastases in triple-negative breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nataliia Petruk ◽  
Sanni Tuominen ◽  
Malin Åkerfelt ◽  
Jesse Mattsson ◽  
Jouko Sandholm ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Lung Metastases ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Cell Protrusion

AbstractCD73 is a cell surface ecto-5′-nucleotidase, which converts extracellular adenosine monophosphate to adenosine. High tumor CD73 expression is associated with poor outcome among triple-negative breast cancer (TNBC) patients. Here we investigated the mechanisms by which CD73 might contribute to TNBC progression. This was done by inhibiting CD73 with adenosine 5′-(α, β-methylene) diphosphate (APCP) in MDA-MB-231 or 4T1 TNBC cells or through shRNA-silencing (sh-CD73). Effects of such inhibition on cell behavior was then studied in normoxia and hypoxia in vitro and in an orthotopic mouse model in vivo. CD73 inhibition, through shRNA or APCP significantly decreased cellular viability and migration in normoxia. Inhibition of CD73 also resulted in suppression of hypoxia-induced increase in viability and prevented cell protrusion elongation in both normoxia and hypoxia in cancer cells. Sh-CD73 4T1 cells formed significantly smaller and less invasive 3D organoids in vitro, and significantly smaller orthotopic tumors and less lung metastases than control shRNA cells in vivo. CD73 suppression increased E-cadherin and decreased vimentin expression in vitro and in vivo, proposing maintenance of a more epithelial phenotype. In conclusion, our results suggest that CD73 may promote early steps of tumor progression, possibly through facilitating epithelial–mesenchymal transition.

scholarly journals Verminoside from Pseudolysimachion rotundum var. subintegrum sensitizes cisplatin-resistant cancer cells and suppresses metastatic growth of human breast cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Changhu Lee ◽  
Hyung Won Ryu ◽  
Sahee Kim ◽  
Min Kim ◽  
Sei-Ryang Oh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Breast ◽  
Human Breast ◽  
Mesenchymal Transition ◽  
Bioactive Component ◽  
Metastatic Growth

AbstractBreast cancer is one of the most common cancers in women and is associated with a high mortality rate. The majority of deaths resulting from breast cancer are attributable to metastatic growth; in addition, chemoresistance is a major concern in the treatment of patients with breast cancer. However, limited drugs are available for the treatment of metastatic breast cancer. In this study, the chemoadjuvant effects of a methanolic extract from the leaves of Pseudolysimachion rotundum var. subintegrum (NC13) and an active component isolated from the plant, verminoside (Vms), were evaluated. Furthermore, their potent anti-metastatic activities were validated in vitro and in vivo in animal models. The anti-metastatic and chemosensitizing activities of NC13 and Vms on cisplatin treatment were found to be partly mediated by suppression of the epithelial–mesenchymal transition of cancer cells. Collectively, our results implied that NC13 and its bioactive component Vms could be developed as effective chemoadjuvants in combination with conventional therapeutics.

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.

scholarly journals Architectural Transcription Factor HMGI(Y) Promotes Tumor Progression and Mesenchymal Transition of Human Epithelial Cells

2001 ◽  
Vol 21 (2) ◽  
pp. 575-594 ◽  
Author(s):  
Raymond Reeves ◽  
Dale D. Edberg ◽  
Ying Li
Keyword(s):  
Epithelial Cells ◽  
Tumor Progression ◽  
Nude Mice ◽  
Epithelial Mesenchymal Transition ◽  
Neoplastic Transformation ◽  
Dominant Negative ◽  
Metastatic Progression ◽  
Aberrant Expression ◽  
Mesenchymal Transition

ABSTRACT Numerous studies have demonstrated that overexpression or aberrant expression of the HMGI(Y) family of architectural transcription factors is frequently associated with both neoplastic transformation of cells and metastatic tumor progression. Little is known, however, about the molecular roles played by the HMGI(Y) proteins in these events. Here we report that human breast epithelial cells harboring tetracycline-regulated HMGI(Y) transgenes acquire the ability to form both primary and metastatic tumors in nude mice only when the transgenes are actively expressed. Unexpectedly, the HMG-Y, rather than the HMG-I, isoform of these proteins is the most effective elicitor of both neoplastic transformation and metastatic progression in vivo. Furthermore, expression of either antisense or dominant-negative HMGI(Y) constructs inhibits both the rate of proliferation of tumor cells and their ability to grow anchorage independently in soft agar. Array analysis of transcription profiles demonstrates that the HMG-I and HMG-Y isoform proteins each modulate the expression of distinctive constellations of genes known to be involved in signal transduction, cell proliferation, tumor initiation, invasion, migration, induction of angiogenesis, and colonization. Immunohistochemical analyses of tumors formed in nude mice indicate that many have undergone an epithelial-mesenchymal transition in vivo. Together, these findings demonstrate that overexpression of the HMGI(Y) proteins, more specifically, the HMG-Y isoform protein, is causally associated with both neoplastic transformation and metastatic progression and suggest that induction of integrins and their signaling pathways may play significant molecular roles in these biological events.

scholarly journals The SF3B1R625H Mutation Promotes Prolactinoma Tumor Progression Through Aberrant Splicing Of DLG1

2021 ◽  
Author(s):  
Jing Guo ◽  
Qiuyue Fang ◽  
Yulou Liu ◽  
Dawei Wang ◽  
Chuzhong Li ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Human Tumor ◽  
Gh3 Cells ◽  
Aberrant Splicing ◽  
Mesenchymal Transition ◽  
Molecular Therapeutic ◽  
Mutant Cells

Abstract Background Recently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 (SF3B1R625H), but its functional effects and mechanisms are poorly understood. Methods Using the CRISPR/Cas9 genome editing system and rat pituitary GH3 cells, we generated heterozygous Sf3b1R625H mutant cells. Sanger and whole-genome sequencing were conducted to verify the introduction of this mutation. Transcriptome analysis was performed in SF3B1-wild-type versus mutant human prolactinoma samples and GH3 cells. Quantitative PCR and minigene reporter assays were conducted to verify aberrant splicing. The functional consequences of SF3B1R625H were evaluated in vitro and in vivo. Critical makers of epithelial-mesenchymal transition and key components of relevant signaling pathways were detected by western blot, immunohistochemistry, and immunofluorescence, and were knocked down by siRNA-mediated silencing. Results Transcriptomic analysis of prolactinomas and heterozygous mutant cells revealed that the SF3B1R625H allele led to different alterations in splicing properties, affecting different genes in different species. Consistently between rat cells and human tumor samples, mutant SF3B1 promoted aberrant splicing and the suppression of DLG1. Additionally, mutant SF3B1 with knockdown of DLG1 expression promoted cell migration, invasion, and epithelial-mesenchymal transition by activating the PI3K/Akt pathway. Conclusions Our findings elucidate a mechanism through which mutant SF3B1 promotes tumor progression and may provide a potent molecular therapeutic target for prolactinomas with the SF3B1R625H mutation.

ZBTB7A promotes migration, invasion and metastasis of human breast cancer cells through NF-κB-induced epithelial–mesenchymal transition in vitro and in vivo

2019 ◽  
Vol 166 (6) ◽  
pp. 485-493 ◽  
Author(s):  
Anyun Mao ◽  
Maojian Chen ◽  
Qinghong Qin ◽  
Zhijie Liang ◽  
Wei Jiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Cancer Tissue ◽  
Mesenchymal Transition ◽  
Mcf 7

Abstract It has been generally confirmed that zinc finger and BTB domain containing 7A (ZBTB7A) plays an important role in the occurrence and progression of malignant tumours, but the promotion or inhibition effect is related to tumour type. The mechanism between ZBTB7A and breast cancer is not well understood, so further research is needed. In this study, we first investigated the expression of ZBTB7A in tissue samples of clinical breast cancer patients, MDA-MB-231, MCF-7 and MCF-10A cells. Second, we overexpressed the ZBTB7A in MCF-7 cells and silenced the ZBTB7A in MDA-MB-231 cells using lentivirus transfection technology, respectively, and verified the effect of ZBTB7A on migration and invasion of breast cancer cell lines through in vitro cell function experiments, such as wound-healing assay, migration and invasion assay, quantitative real time reverse transcriptase (qRT-PCR) and western blot. Then, the correlation between the above influences, epithelial–mesenchymal transition (EMT) and NF-κB was analysed. Finally, in vivo tumour transplantation model in nude mice was established to verified the effect of ZBTB7A on metastasis of breast cancer MDA-MB-231 cells. In conclusion, ZBTB7A is highly expressed in cancer tissue, breast cancer cell line MDA-MB-231 and MCF-7. Meanwhile, the high expression of ZBTB7A may promote cell migration, invasion and tumour metastasis, which may be related to EMT events by regulating NF-κB.

scholarly journals Breast tumor cells promotes the horizontal propagation of EMT, stemness, and metastasis by transferring the MAP17 protein between subsets of neoplastic cells

Oncogenesis ◽  
2020 ◽  
Vol 9 (10) ◽  
Author(s):  
José Manuel García-Heredia ◽  
Daniel Otero-Albiol ◽  
Marco Pérez ◽  
Elena Pérez-Castejón ◽  
Sandra Muñoz-Galván ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Notch Pathway ◽  
Metastatic Potential ◽  
Tumor Evolution ◽  
Neoplastic Cells ◽  
Mesenchymal Transition

Abstract MAP17 (PDZK1IP1) is a small protein regulating inflammation and tumor progression, upregulated in a broad range of carcinomas. MAP17 levels increase during tumor progression in a large percentage of advanced tumors. In the present work, we explored the role of this protein shaping tumor evolution. Here we show that in breast cancer, cells increased MAP17 levels in tumors by demethylation induced multiple changes in gene expression through specific miRNAs downregulation. These miRNA changes are dependent on Notch pathway activation. As a consequence, epithelial mesenchymal transition (EMT) and stemness are induced promoting the metastatic potential of these cells both in vitro and in vivo. Furthermore, MAP17 increased the exosomes in tumor cells, where MAP17 was released as cargo, and this horizontal propagation also increased the EMT in the recipient cells. Importantly, an antibody against MAP17 in the media reduces the EMT and stemness alterations promoted by the conditioned media from MAP17-expressing cells. Therefore, MAP17 expression promotes the horizontal propagation of EMT and metastasis by transferring the MAP17 protein between subsets of neoplastic cells. Thus, MAP17 can be used to describe a new mechanism for cell malignity at distance, without the involvement of genetic or epigenetic modifications. MAP17 can also be taken in consideration as new target for metastatic high-grade breast tumors.

scholarly journals Dark Sweet Cherry (Prunus avium) Anthocyanins Inhibited the Growth and Biomarkers for Breast Cancer Growth and Invasion in Highly Metastatic 4T1 Tumor Cells

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 279-279
Author(s):  
Ana Carolina Silveira Rabelo ◽  
Shirley Arbizu ◽  
Maria Angelica Miglino ◽  
Susanne Talcott ◽  
Giuliana Noratto
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Viability ◽  
Prunus Avium ◽  
Epithelial Mesenchymal Transition ◽  
Dose Range ◽  
Mesenchymal Transition ◽  
4T1 Cells

Abstract Objectives To investigate the mechanisms underlying the breast cancer anti-invasive activity of DSC phenolics enriched in anthocyanins (ACN) in vitro and their potential in vivo. Methods 4T1 cells were treated with ACN extracted from DSC concentrate juice (FruitSmart, Grandview, WA) within dose range 20–80 µg cyanidin 3-glucoside equivalent (C3G)/mL to assess reactive oxygen species (ROS) levels using carboxy-H2DFFDA probe and cell viability using the resazurin kit (Sigma-Aldrich, St Louis, MO). Protein and mRNA expression were investigated using standard procedures and cell migration by wound healing assay. The pilot in vivo study was performed with 4T1 cells orthotopically injected into mammary fat pads of BALB/c mice (Envigo, Houston, TX, USA) (n = 4). After tumor growth, animals were gavaged with ACN (150 mg C3G/kg body weight/day, n = 2) or saline solution (control, n = 2) for one week followed by euthanasia and collection of tumors, lungs, and liver tissues for analyses. Results ACN induced ROS production (up to 5.13-fold of control) and inhibited cell viability by 50% (IC50) at 58.6 µg C3G/mL. The ACN (IC50 dose) treatment downregulated phospho-ERK1/2 and upregulated phospho-p38 proteins, linked to cell growth inhibition and caspase-dependent apoptosis mediated by the increase in cleaved/total caspase-3 protein ratio (∼3-fold of control) and suppression of total PARP (∼0.4-fold of control). ACN also suppressed the Akt/mTOR/CREB pathway that promotes proliferation and invasion. 4T1 cell migration was inhibited by 22%, consistent with the phospho-Src downregulation (down to ∼ 0.25-fold of control), that regulate epithelial-mesenchymal transition. Phospho-ERK1/2 and phospho-CREB were downregulated in mice tumors. This was accompanied by the downregulation of Cenpf mRNA in liver and lungs, which correlates with poor prognosis and metastasis, thus supporting the in vitro findings. Conclusions ACN provides a dietary alternative to fight human breast cancer invasion by incorporating DSC into the diet. More studies are guarantee to help improve the quality of life of breast cancer patients. Funding Sources This work was supported by the Northwest Cherry Growers. The authors thank the support of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Brazil for providing Ana Carolina Silveira Rabelo the scholarship.

scholarly journals Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial–Mesenchymal Transition in Cancer

2019 ◽  
Vol 20 (12) ◽  
pp. 2885 ◽  
Author(s):  
Monserrat Olea-Flores ◽  
Miriam Daniela Zuñiga-Eulogio ◽  
Miguel Angel Mendoza-Catalán ◽  
Hugo Alberto Rodríguez-Ruiz ◽  
Eduardo Castañeda-Saucedo ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Mapk Pathway ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Cellular Processes ◽  
Extracellular Signal ◽  
Epithelial Phenotype

Epithelial–mesenchymal transition (EMT) is a reversible cellular process, characterized by changes in gene expression and activation of proteins, favoring the trans-differentiation of the epithelial phenotype to a mesenchymal phenotype. This process increases cell migration and invasion of tumor cells, progression of the cell cycle, and resistance to apoptosis and chemotherapy, all of which support tumor progression. One of the signaling pathways involved in tumor progression is the MAPK pathway. Within this family, the ERK subfamily of proteins is known for its contributions to EMT. The ERK subfamily is divided into typical (ERK 1/2/5), and atypical (ERK 3/4/7/8) members. These kinases are overexpressed and hyperactive in various types of cancer. They regulate diverse cellular processes such as proliferation, migration, metastasis, resistance to chemotherapy, and EMT. In this context, in vitro and in vivo assays, as well as studies in human patients, have shown that ERK favors the expression, function, and subcellular relocalization of various proteins that regulate EMT, thus promoting tumor progression. In this review, we discuss the mechanistic roles of the ERK subfamily members in EMT and tumor progression in diverse biological systems.

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