scholarly journals Extracellular Vesicles Carry lncRNA SNHG16 to Promote Metastasis of Breast Cancer Cells via the miR-892b/PPAPDC1A Axis

2021 ◽  
Vol 9 ◽  
Author(s):  
Wenfei Xia ◽  
Yun Liu ◽  
Teng Cheng ◽  
Tao Xu ◽  
Menglu Dong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Extracellular Vesicles ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Gene Reporter Assay ◽  
Metastasis Model ◽  
Rna Immunoprecipitation

Breast cancer (BC) represents the most commonly diagnosed malignancy among women. Long non-coding RNAs (lncRNAs) can be transferred by extracellular vesicles (EVs) to participate in BC progression. This study demonstrated that SNHG16 expression was significantly increased in BC tissues and cells. Overexpression of SNHG16 promoted the migration, invasion, and epithelial–mesenchymal transition (EMT) of BC cells. SNHG16 was carried by EVs. Bioinformatics analysis predicted that SNHG16 regulated PPAPDC1A expression by sponging miR-892b, which was confirmed by RNA-fluorescence in situ hybridization (FISH), RT-qPCR, dual-luciferase gene reporter assay, and RNA immunoprecipitation (RIP). MDA-MB-157 and HS578T cells were transfected with pcDNA3.1-SNHG16, miR-892b-mimic, or si-PPAPDC1A for functional rescue experiments in vitro, and the cells were treated with MDA-MB-231 cell-derived EVs. The results confirmed that enhanced miR-892b expression partially eliminated the increase of migration, invasion, and EMT of BC cells mediated by SNHG16 or EVs. The lung metastasis model in nude mice was established by injecting HS578T cells via tail vein. The results showed that si-SNHG16 reduced the metastatic nodules and decreased the vimentin expression. In conclusion, EVs derived from BC cells transferred SNHG16 via the miR-892b/PPAPDC1A axis, thus promoting EMT, migration, and invasion of BC.

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.

Development of improved SRC-3 inhibitors as breast cancer therapeutic agents

2021 ◽  
Author(s):  
Li Qin ◽  
Jianwei Chen ◽  
Dong Lu ◽  
Prashi Jain ◽  
Yang Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
High Throughput Screening ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Agents ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Steroid Receptor Coactivators ◽  
Plasma Half Life

Steroid receptor coactivators (SRCs) possess specific and distinct oncogenic roles in the initiation of cancer and in cancer progression to a more aggressive disease. These coactivators interact with nuclear receptors and other transcription factors to boost transcription of multiple genes which potentiate cancer cell proliferation, migration, invasion, tumor angiogenesis and epithelial mesenchymal transition (EMT). Targeting SRCs using small molecule inhibitors (SMIs) is a promising approach to control cancer progression and metastasis. By high throughput screening analysis, we recently identified SI-2 as a potent SRC SMI. To develop therapeutic agents, SI-10 and SI-12, the SI-2 analogs, are synthesized that incorporate the addition of fluorine atoms to the SI-2 chemical structure. As a result, these analogs exhibit a significantly prolonged plasma half-life, minimal toxicity and improved hERG activity. Biological functional analysis showed that SI-10 and SI-12 treatment (5-50 nM) can significantly inhibit viability, migration and invasion of breast cancer cells in vitro and repress the growth of breast cancer PDX organoids. Treatment of mice with 10 mg/kg/day of either SI-10 or SI-12 was sufficient to repress growth of xenograft tumors derived from MDA-MB-231 and LM2 cells. Furthermore, in spontaneous and experimental metastasis mouse models developed from MDA-MB-231 and LM2 cells respectively, SI-10 and SI-12 effectively inhibited progression of breast cancer lung metastasis. These results demonstrate that SI-10/SI-12 are promising therapeutic agents and are specifically effective in blocking tumor metastasis, a key point in tumor progression to a more lethal state that results in patient mortality in the majority of cases.

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 Actinomycin V Inhibits Migration and Invasion via Suppressing Snail/Slug-Mediated Epithelial-Mesenchymal Transition Progression in Human Breast Cancer MDA-MB-231 Cells In Vitro

Marine Drugs ◽  
2019 ◽  
Vol 17 (5) ◽  
pp. 305 ◽  
Author(s):  
Shiqi Lin ◽  
Caiyun Zhang ◽  
Fangyuan Liu ◽  
Jiahui Ma ◽  
Fujuan Jia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Actinomycin D ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Human Breast ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
E Cadherin

Actinomycin V, an analog of actinomycin D produced by the marine-derived actinomycete Streptomyces sp., possessing a 4-ketoproline instead of a 4-proline in actinomycin D. In this study, the involvement of snail/slug-mediated epithelial-mesenchymal transition (EMT) in the anti-migration and -invasion actions of actinomycin V was investigated in human breast cancer MDA-MB-231 cells in vitro. Cell proliferation effect was evaluated by 3-(4,5-Dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay. Wound-healing and Transwell assay were performed to investigate the anti-migration and -invasion effects of actinomycin V. Western blotting was used to detect the expression levels of E-cadherin, N-cadherin, vimentin, snail, slug, zinc finger E-box binding homeobox 1 (ZEB1), and twist proteins and the mRNA levels were detected by rt-PCR. Actinomycin V showed stronger cytotoxic activity than that of actinomycin D. Actinomycin V up-regulated both of the protein and mRNA expression levels of E-cadherin and down-regulated that of N-cadherin and vimentin in the same cells. In this connection, actinomycin V decreased the snail and slug protein expression, and consequently inhibited cells EMT procession. Our results suggest that actinomycin V inhibits EMT-mediated migration and invasion via decreasing snail and slug expression, which exhibits therapeutic potential for the treatment of breast cancer and further toxicity investigation in vivo is needed.

scholarly journals Activation of Vimentin Is Critical to Promote a Metastatic Potential of Cholangiocarcinoma Cells

2018 ◽  
Vol 26 (4) ◽  
pp. 605-616 ◽  
Author(s):  
Waraporn Saentaweesuk ◽  
Norie Araki ◽  
Kulthida Vaeteewoottacharn ◽  
Atit Silsirivanit ◽  
Wunchana Seubwai ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Cancer ◽  
Metastatic Tumor ◽  
Migration And Invasion ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Tail Vein

Cholangiocarcinoma (CCA) is a highly metastatic tumor, and the majority of patients with CCA have a short survival time because there are no available effective treatments. Hence, a better understanding regarding CCA metastasis may provide an opportunity to improve the strategies for treatment. A comparison study between the highly metastatic cells and their parental cells is an approach to uncover the molecular mechanisms underlying the metastatic process. In the present study, a lung metastatic CCA cell line, KKU-214L5, was established by the in vivo selection of the tail vein-injected mouse model. KKU-214L5 cells possessed mesenchymal spindle-like morphology with higher migration and invasion abilities in vitro than the parental cells (KKU-214). KKU-214L5 also exhibited extremely aggressive lung colonization in the tail vein-injected metastatic model. Epithelial‐mesenchymal transition (EMT) was clearly observed in KKU-214L5 cells. Significant downregulation of epithelial markers (ZO-1 and claudin-1), with unique upregulation of E-cadherin and mesenchymal markers (vimentin, β-catenin, and slug), was observed in KKU-214L5. Increasing MMP-2 and MMP-9 activities and CD147 expression reflected the high invasion activity in KKU-214L5 cells. Suppression of vimentin using siRNA significantly decreased the migration and invasion capabilities of KKU-214L5 to almost the basal levels of the parental cells without any change on the expression levels of other EMT markers and the activities of MMPs. These results suggest that vimentin activation is essential to potentiate the metastatic characters of CCA cells, and suppression of vimentin expression could be a potential strategy to improve the treatment of CCA, a highly metastatic cancer.

scholarly journals Long non-coding RNA SPRY4-IT1 promotes epithelial–mesenchymal transition of cervical cancer by regulating the miR-101-3p/ZEB1 axis

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Ming-Jun Fan ◽  
Yong-Hui Zou ◽  
Peng-Juan He ◽  
Shuai Zhang ◽  
Xiao-Mei Sun ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
E Cadherin

AbstractBackground: Emerging evidences have indicated that long non-coding RNAs (LncRNAs) play vital roles in cancer development and progression. Previous studies have suggested that overexpression of SPRY4 intronic transcript 1 (SPRY4-IT1) predicates poor prognosis and promotes tumor progress in cervical cancer (CC). However, the underlying mechanism of SPRY4-IT1 in CC remains unknown. The aim of the present study is to evaluate the function and mechanism of SPRY4-IT1 in CC.Methods: SPRY4-IT1 was detected by quantitative PCR. Wound-healing assay and Transwell assay were performed to detect cell migration and invasion, respectively. Western blotting assays were used to analyze the protein expression of E-cadherin, N-cadherin and vimentin. Tumor xenografts experiments were performed to detect the effect of SPRY4-IT1 in vivo. Dual luciferase reporter assay was used to investigate potential molecular mechanism of SPRY4-IT1 in CC cells.Results: SPRY4-IT1 was up-regulated in CC cell lines. Knockdown of SPRY4-IT1 significantly inhibited CC cells migration and invasion in vitro and in vivo. Moreover, knockdown of SPRY4-IT1 significantly suppressed the epithelial–mesenchymal transition (EMT) of CC by increased E-cadherin expression and decreased the N-cadherin and vimentin expression. Mechanically, SPRY4-IT1 could directly bind to miR-101-3p and effectively act as a competing endogenous RNA (ceRNA) for miR-101-3p to regulate the expression of the target gene ZEB1.Conclusions: Our findings indicate that the SPYR4-IT1/miR-101-3p/ZEB1 axis contributes to CC migration and invasion, which may provide novel insights into the function of lncRNA-driven tumorigenesis of CC.

scholarly journals FBXL10 promotes EMT and metastasis of breast cancer cells via regulating the acetylation and transcriptional activity of SNAI1

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yangyang Yang ◽  
Binggong Zhao ◽  
Linlin Lv ◽  
Yuxi Yang ◽  
Shujing Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Bioinformatics Analyses ◽  
Positive Role ◽  
Mesenchymal Transition ◽  
E Cadherin

AbstractF-box and leucine-rich repeat protein 10 (FBXL10) has been reported to play a regulatory role in the initiation and development of breast cancer. Bioinformatics analyses revealed that FBXL10 may involve in the process of cytoskeleton organization. This research aimed to investigate the function of FBXL10 in epithelial-mesenchymal transition (EMT) and metastasis of breast cancer, and tried to reveal the molecular mechanism involved in this issue. Functional experiments in vitro revealed that FBXL10 promoted the migration and invasion of breast cancer cells through inhibiting E-cadherin expression and inducing EMT. Mechanical studies revealed that FBXL10 could specifically interact with SNAI1, but not Slug or ZEB1. And it promoted the transcriptional repression activity of SNAI1 on CDH1 in breast cancer cells. Furthermore, FBXL10 had a positive role for the deacetylation of SNAI1 by facilitating the interaction between SNAI1 and HDAC1, a dominating deacetylase of SNAI1. And the deacetylated SNAI1 showed a more suppressive ability to inhibit the transcription of E-cadherin. Moreover, mouse models were also conducted to confirm the effect of FBXL10 on the lung metastasis of breast cancer in vivo. Totally, our data revealed that FBXL10 served as a pro-metastatic factor in breast cancer via repressing the expression of E-cadherin and inducing EMT. It may provide a novel regulatory axis in the EMT of breast cancer.

scholarly journals XJP Inhibits Apoptosis, Invasion, EMT, and Wnt/Β-Catenin Pathway in Triple-Negative Breast Cancer

2021 ◽  
Author(s):  
Dandan Feng ◽  
Hongzhi Chen ◽  
Guangxi Shi ◽  
Mengdi Zhang ◽  
Hongyi Liang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Abstract Background: Triple-negative breast cancer (TNBC) progresses at a rapid pace. Chemotherapy is a major clinical application. However, resistance and metastases are key barriers to chemotherapy. Xiaojin pills (XJP) have been used clinically for treating TNBC for decades. However, the potential molecular mechanisms of the effect of XJP on breast cancer is still not understood.Methods: The cell viability was analyzed using Cell Counting Kit-8 (CCK-8). Flow cytometry was used to detect apoptosis, and the migration and invasion abilities of TNBC were assessed using Transwell assay. For molecular mechanisms, the protein expression levels were determined by Western blot analysis. The expression of β-catenin in the Wnt/β-serial protein (β-catenin) pathway was detected with immunofluorescence (IF).Results: XJP inhibited the viability and proliferation of the TNBC cell line in vitro. Flow cytometry analysis showed that apoptosis increased in both MDA-MB-231 and MDA-MB-468 cells induced by XJP. The expression of the proteins associated with invasion, for example, matrix metalloproteinase (MMP) and MMP9, was reduced. Among epithelial–mesenchymal transition markers, E-cadherin was upregulated and N-cadherin was downregulated. The apoptosis-related proteins caspase-8, caspase-3, caspase-9, and Parp were all upregulated. Additionally, XJP effectively suppressed the expression of β-catenin, which belonged to the Wnt/β-catenin pathway.Conclusions: These results suggested that XJP suppressed the progression of TNBC cells by suppressing apoptosis, invasion, EMT, and Wnt/β-catenin pathway.

scholarly journals The m6A methyltransferase METTL3 controls epithelial-mesenchymal transition, migration and invasion of breast cancer through the MALAT1/miR-26b/HMGA2 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chengpeng Zhao ◽  
Xiaoling Ling ◽  
Yunxia Xia ◽  
Bingxue Yan ◽  
Quanlin Guan
Keyword(s):  
Breast Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Invasion And Migration ◽  
Protein Levels ◽  
Rna Immunoprecipitation ◽  
Functional Relevance ◽  
And Migration

Abstract Background Previous studies have revealed the key functions of N6-methyladenosine (m6A) modification in breast cancer (BC). MALAT1 as a highly m6A modified lncRNA associated with cancer development and metastasis, but the functional relevance of m6A methyltransferase and MALAT1 in BC is still unknown. Here, our study investigated the effects of the novel m6A methyltransferase METTL3 on epithelial-mesenchymal transition (EMT) in BC via the MALAT1/miR-26b/HMGA2 axis. Methods Firstly, we collected clinical BC samples and cultured BC cells, and detected mRNA and protein levels in the human samples and human cell lines by RT-qPCR and Western blot, respectively. Then, the binding of MALAT1 and miR-26b and the targeting relationship between miR-26b and HMGA2 were examined by dual-luciferase assay. Moreover, the binding of MALAT1 and miR-26b was tested by RNA pull down and RNA immunoprecipitation (RIP) assays. Methylated-RNA immunoprecipitation (Me-RIP) was used to detect the m6A modification level of MALAT1. The interaction of METTL3 and MALAT1 was detected by photoactivatable ribonucleoside-crosslinking immunoprecipitation (PAR-CLIP). Finally, effects on invasion and migration were detected by Transwell. Results In BC, the level of miR-26b was consistently low, while the levels of METTL3, MALAT1 and HMGA2 were high. Further experiments showed that METTL3 up-regulated MALAT1 expression by modulating the m6A modification of MALAT1, and that MALAT1 could promote the expression of HMGA2 by sponging miR-26b. In BC cells, we found that silencing METTL3 could inhibit EMT and tumor cell invasion by suppressing MALAT1. Furthermore, MALAT1 mediated miR-26b to target HMGA2 and promote EMT, migration, and invasion. In summary, METTL3 promoted tumorigenesis of BC via the MALAT1/miR-26b/HMGA2 axis. Conclusions Silencing METTL3 down-regulate MALAT1 and HMGA2 by sponging miR-26b, and finally inhibit EMT, migration and invasion in BC, providing a theoretical basis for clinical treatment of BC.

scholarly journals Heat treatment-induced autophagy promotes invasion and metastasis via TGF-β2 mediated epithelial-mesenchymal transition in breast cancer cells

2021 ◽  
Author(s):  
Zhen-Nan Li ◽  
Cheng Lu ◽  
Feng-Liang Wang ◽  
Hao-Wei Guo ◽  
Zhi-Peng Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Heat Treatment ◽  
Tumor Growth ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Autophagy Inhibitor

Abstract Background Insufficient thermal ablation can cause accelerated malignant behaviors and increased metastasis in hepatocellular carcinoma (HCC), and epithelial-mesenchymal transition (EMT) and autophagy are implicated in tumor metastasis. However, whether interactions between autophagy and TGF-β2 induce EMT in breast cancer (BC) after insufficient microwave ablation (MWA) remains unclear. Methods In this study, we treated BC cells with sublethal heat treatment for simulating insufficient MWA, and then the effect of heat treatment on the BC cell phenotypes were explored. CCK-8, colony formation, flow cytometry, transwell and wound healing assays were performed to evaluate the influence of sublethal heat treatment on the proliferation, apoptosis, invasion and migration of BC cells treated with/without autophagy inhibitors. Western blotting, real-time quantitative PCR, immunofluorescence and transmission electron microscopy were carried out to determine the changes of markers associated with autophagy and EMT after sublethal heat treatment. Xenograft models in mice were established by using sublethal heat treated BC cells to investigate the effect of autophagy inhibitor on BC tumor growth in vivo. Results Results showed that heat treatment promoted the proliferation of survived BC cells, which was accompanied by autophagy induction. Heat treatment-induced autophagy up-regulated TGF-β2/Smad2 signaling and promoted phenotype of EMT, thereby enhancing abilities of migration and invasion in BC cells. Increase or decrease of TGF-β2 expression resulted in potentiation and suppression of autophagy as well as enhancement and abatement of EMT. Autophagy inhibitor facilitated apoptosis and repressed proliferation of BC cells in vitro, and thwarted BC cell tumor growth and pulmonary metastasis in vivo. Conclusions This study indicate that heat treatment-induced autophagy promotes invasion and metastasis via TGF-β2/Smad2-mediated EMT. Suppressing autophagy might be a new strategy for overcoming sufficient MWA caused progression and metastasis of residual BC cells.

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