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.

scholarly journals Knockdown of ARK5 Expression Suppresses Invasion and Metastasis of Gastric Cancer

2017 ◽  
Vol 42 (3) ◽  
pp. 1025-1036 ◽  
Author(s):  
Dehu Chen ◽  
Guiyuan Liu ◽  
Ning Xu ◽  
Xiaolan You ◽  
Haihua Zhou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Western Blot ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Invasion And Metastasis ◽  
Ags Cells ◽  
Mesenchymal Transition

Background/Aims: Gastric cancer (GC) is a common and lethal malignancy, and AMP-activated protein kinase-related kinase 5 (ARK5) has been discovered to promote cancer metastasis in certain types of cancer. In this study, we explored the role of ARK5 in GC invasion and metastasis. Methods: ARK5 and epithelial-mesenchymal transition (EMT)-related markers were determined by immunohistochemistry and western blot in GC specimens. Other methods including stably transfected against ARK5 into SGC7901 and AGS cells, western blot, migration and invasion assays in vitro and nude mice tumorigenicity in vivo were also employed. Results: The results demonstrated that ARK5 expression was increased and positively correlated with metastasis, EMT-related markers and poor prognosis in patients with GC. Knockdown of ARK5 expression remarkably suppressed GC cells invasion and metastasis via regulating EMT, rather than proliferation in vitro and in vivo. And knockdown of ARK5 expression in GC cells resulted in the down-regulation of the mTOR/p70S6k signals, Slug and SIP1. Conclusion: The elevated ARK5 expression was closely associated with cancer metastasis and patient survival, and it seemed to function in GC cells migration and invasion via EMT alteration, together with the alteration of the mTOR/p70S6k signals, Slug and SIP1, thus providing a potential therapeutic target for GC.

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 Knockdown of microRNA-214-3p Promotes Tumor Growth and Epithelial-Mesenchymal Transition in Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5875
Author(s):  
Patrice Cagle ◽  
Nikia Smith ◽  
Timothy O. Adekoya ◽  
Yahui Li ◽  
Susy Kim ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Protein Tyrosine Kinase ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Oncogenic Signaling ◽  
Mesenchymal Transition

Abnormal expression of microRNA miR-214-3p (miR-214) is associated with multiple cancers. In this study, we assessed the effects of CRISPR/Cas9 mediated miR-214 depletion in prostate cancer (PCa) cells and the underlying mechanisms. Knockdown of miR-214 promoted PCa cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), and increased resistance to anoikis, a key feature of PCa cells that undergo metastasis. The reintroduction of miR-214 in miR-214 knockdown cells reversed these effects and significantly suppressed cell proliferation, migration, and invasion. These in vitro studies are consistent with the role of miR-214 as a tumor suppressor. Moreover, miR-214 knockout increased tumor growth in PCa xenografts in nude mice supporting its anti-oncogenic role in PCa. Knockdown of miR-214 increased the expression of its target protein, Protein Tyrosine Kinase 6 (PTK6), a kinase shown to promote oncogenic signaling and tumorigenesis in PCa. In addition, miR-214 modulated EMT as exhibited by differential regulation of E-Cadherin, N-Cadherin, and Vimentin both in vitro and in vivo. RNA-seq analysis of miR-214 knockdown cells revealed altered gene expression related to PCa tumor growth pathways, including EMT and metastasis. Collectively, our findings reveal that miR-214 is a key regulator of PCa oncogenesis and is a potential novel therapeutic target for the treatment of the disease.

Cripto-1 promotes tumor invasion and predicts poor outcomes in hepatocellular carcinoma

2019 ◽  
Vol 41 (5) ◽  
pp. 571-581
Author(s):  
Tao Huang ◽  
Yi-Zhan Guo ◽  
Xiao Yue ◽  
Guo-Pei Zhang ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Migration And Invasion ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Poor Outcomes

Abstract Cripto-1 (CR1), an oncofetal protein, had been implied to reactivate in some cancers. However, the relationship between CR1 expression and patient outcomes and the tumor biological function of CR1 contributing to invasion and metastasis in hepatocellular carcinoma (HCC) is poorly defined. In this study, we demonstrated that CR1 was expressed in over 80% of HCCs in a training cohort (n = 242) and a validation cohort (n = 159). High CR1 expression was significantly correlated with aggressive HCC phenotypes (i.e. portal vein tumor thrombus, microscopic vascular invasion, multiple tumors and poor tumor differentiation). In both the training and validation cohorts, patients with high CR1 expression had remarkably shorter disease-free survival and overall survival rates than those with low CR1 expression. A series in vitro and in vivo assays showed that CR1 substantially promoted HCC cell migration, invasion and metastasis. Mechanistically, we demonstrated that CR1 induced HCC cells to undergo epithelial–mesenchymal transition through activating the Akt/NFκB/p65 signaling. Chromatin immunoprecipitation assay showed that NFκB/p65 enhanced CR1 expression by binding its promoter. Thus, CR1 and NFκB/p65 form a positive feedback loop that sustained the process of migration and invasion of HCC. Therefore, CR1 plays an important role in HCC invasion and metastasis and may be an effective and reliable prognostic biomarker for HCC recurrence after resection. Targeting CR1 may be a promising treatment for HCC.

scholarly journals MiR-205 suppresses epithelial–mesenchymal transition and inhibits tumor growth of human glioma through down-regulation of HOXD9

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Bin Dai ◽  
Guanghua Zhou ◽  
Zhiqiang Hu ◽  
Guangtong Zhu ◽  
Beibei Mao ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Pcr Analysis ◽  
Human Glioma ◽  
Mesenchymal Transition

AbstractEpithelial–mesenchymal transition (EMT) plays a pivotal role in cancer progression. Hsa-miR-205 is considered one of the fundamental regulators of EMT. In the present study, we found that miR-205 was down-regulated in glioma tissues and human glioma cells U87 and U251. Meanwhile, miR-205 overexpression enhanced E-cadherin, reduced mesenchymal markers, and decreased cell proliferation, migration, and invasion in vitro. In vivo, miR-205 suppressed tumor growth. Additionally, HOXD9 was confirmed as a direct target of miR-205. Suppression of HOXD9 by miR-205 was demonstrated by luciferase reporter assay, quantitative real time-PCR analysis, and western blot. Moreover, we observed a negative correlation between miR-205 and HOXD9 in human glioma tissues. In summary, our findings demonstrated that miR-205 suppresses glioma tumor growth, invasion, and reverses EMT through down-regulating its target HOXD9.

A Study on the Effect and Mechanism of Xiaoaiping (XAP) Injection and S-1 Combination Therapy in Inhibiting the Invasion and Metastasis of Human GC Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Peiyu Wen ◽  
Haibo Wang ◽  
Tengyang Ni ◽  
Xiaojun Dai ◽  
Zewen Chu ◽  
...  
Keyword(s):  
Western Blotting ◽  
Epithelial Mesenchymal Transition ◽  
Inhibitory Effect ◽  
Migration And Invasion ◽  
Combination Group ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Single Drug

Background: This study aimed to determine the effect and mechanism of Xiaoaiping (XAP) injection combined with S-1 in inhibiting the invasion and metastasis of human GC cells. Methods: BGC-823 and MGC-803 cells were incubated in vitro, and the effects of treatment on the cytotoxicity and proliferation of BGC-823 and MGC-803 cells were evaluated by MTT assay. Cell adhesion tests and Transwell assays were used to detect the effects of Xiaoaiping injection combined with S-1 on the metastatic ability of BGC-823 and MGC803 cells. The expression of VEGF, metalloproteinases (MMPs) and proteins related to the epithelial-mesenchymal transition (EMT) were detected by Western blotting. Meanwhile, a tumour model was established in nude mice, and the effect of XAP combined with S-1 on BGC-823 cells in vivo was studied. Results: Compared with the single drug group, the combination of XAP with S-1 increased the inhibition rate (P<0.05). The adhesion test showed that the combination group significantly inhibited the adhesion of BGC-823 and MGC-803 cells (P<0.05). Combination of XAP with S-1 reduced the migration and invasion potential of human GC BGC-823 and MGC803 cells. Western blotting showed that the expression of VEGF, MMP-9, N-cadherin and vimentin was decreased and Ecadherin expression was increased in the combination group compared with these expression values in either the XAP or S-1 alone group (P<0.05). In vivo, we found that XAP combined with S-1 had a significant inhibitory effect on the growth of tumours compared with XAP or S-1 alone. Immunohistochemistry showed that XAP combined with S-1 was able to enhance the levels of E-cadherin and downregulate N-cadherin and vimentin. Conclusion: The combination of XAP with S-1 can enhance the inhibitory effect of a single drug on proliferation, invasion and metastasis. The mechanism may be related to the decrease in the expression of VEGF and MMP-9 proteins and the effect on EMT.

scholarly journals HDAC4 promotes nasopharyngeal carcinoma progression and serves as a therapeutic target

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Chun Cheng ◽  
Jun Yang ◽  
Si-Wei Li ◽  
Guofu Huang ◽  
Chenxi Li ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Tumor Growth ◽  
Therapeutic Target ◽  
Histone Deacetylases ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
E Cadherin

AbstractHistone deacetylases (HDACs) are involved in tumor progression, and some have been successfully targeted for cancer therapy. The expression of histone deacetylase 4 (HDAC4), a class IIa HDAC, was upregulated in our previous microarray screen. However, the role of HDAC4 dysregulation and mechanisms underlying tumor growth and metastasis in nasopharyngeal carcinoma (NPC) remain elusive. Here, we first confirmed that the HDAC4 levels in primary and metastatic NPC tissues were significantly increased compared with those in normal nasopharyngeal epithelial tissues and found that high HDAC4 expression predicted a poor overall survival (OS) and progression-free survival (PFS). Functionally, HDAC4 accelerated cell cycle G1/S transition and induced the epithelial-to-mesenchymal transition to promote NPC cell proliferation, migration, and invasion in vitro, as well as tumor growth and lung metastasis in vivo. Intriguingly, knockdown of N-CoR abolished the effects of HDAC4 on the invasion and migration abilities of NPC cells. Mechanistically, HDAC3/4 binds to the E-cadherin promoter to repress E-cadherin transcription. We also showed that the HDAC4 inhibitor tasquinimod suppresses tumor growth in NPC. Thus, HDAC4 may be a potential diagnostic marker and therapeutic target in patients with NPC.

scholarly journals Overexpressed P75CUX1 promotes EMT in glioma infiltration by activating β-catenin

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Anqi Xu ◽  
Xizhao Wang ◽  
Jie Luo ◽  
Mingfeng Zhou ◽  
Renhui Yi ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Tumor Grade ◽  
Prognostic Indicator ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
Kaplan Meier ◽  
Homeobox Protein

AbstractThe homeobox protein cut-like 1 (CUX1) comprises three isoforms and has been shown to be involved in the development of various types of malignancies. However, the expression and role of the CUX1 isoforms in glioma remain unclear. Herein, we first identified that P75CUX1 isoform exhibited consistent expression among three isoforms in glioma with specifically designed antibodies to identify all CUX1 isoforms. Moreover, a significantly higher expression of P75CUX1 was found in glioma compared with non-tumor brain (NB) tissues, analyzed with western blot and immunohistochemistry, and the expression level of P75CUX1 was positively associated with tumor grade. In addition, Kaplan–Meier survival analysis indicated that P75CUX1 could serve as an independent prognostic indicator to identify glioma patients with poor overall survival. Furthermore, CUX1 knockdown suppressed migration and invasion of glioma cells both in vitro and in vivo. Mechanistically, this study found that P75CUX1 regulated epithelial–mesenchymal transition (EMT) process mediated via β-catenin, and CUX1/β-catenin/EMT is a novel signaling cascade mediating the infiltration of glioma. Besides, CUX1 was verified to promote the progression of glioma via multiple other signaling pathways, such as Hippo and PI3K/AKT. In conclusion, we suggested that P75CUX1 could serve as a potential prognostic indicator as well as a novel treatment target in malignant glioma.

scholarly journals Resveratrol Enhances Inhibition Effects of Cisplatin on Cell Migration and Invasion and Tumor Growth in Breast Cancer MDA-MB-231 Cell Models In Vivo and In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2204
Author(s):  
Meng-Die Yang ◽  
Yang Sun ◽  
Wen-Jun Zhou ◽  
Xiao-Zheng Xie ◽  
Qian-Mei Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Tumor Growth ◽  
Cell Viability ◽  
Synergistic Effects ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Tgf Β1

Triple-negative breast cancer (TNBC) is a refractory type of breast cancer that does not yet have clinically effective drugs. The aim of this study is to investigate the synergistic effects and mechanisms of resveratrol combined with cisplatin on human breast cancer MDA-MB-231 (MDA231) cell viability, migration, and invasion in vivo and in vitro. In vitro, MTS assays showed that resveratrol combined with cisplatin inhibits cell viability as a concentration-dependent manner, and produced synergistic effects (CI < 1). Transwell assay showed that the combined treatment inhibits TGF-β1-induced cell migration and invasion. Immunofluorescence assays confirmed that resveratrol upregulated E-cadherin expression and downregulated vimentin expression. Western blot assay demonstrated that resveratrol combined with cisplatin significantly reduced the expression of fibronectin, vimentin, P-AKT, P-PI3K, P-JNK, P-ERK, Sma2, and Smad3 induced by TGF-β1 (p < 0.05), and increased the expression of E-cadherin (p < 0.05), respectively. In vivo, resveratrol enhanced tumor growth inhibition and reduced body weight loss and kidney function impairment by cisplatin in MDA231 xenografts, and significantly reduced the expressions of P-AKT, P-PI3K, Smad2, Smad3, P-JNK, P-ERK, and NF-κB in tumor tissues (p < 0.05). These results indicated that resveratrol combined with cisplatin inhibits the viability of breast cancer MDA231 cells synergistically, and inhibits MDA231 cells invasion and migration through Epithelial-mesenchymal transition (EMT) approach, and resveratrol enhanced anti-tumor effect and reduced side of cisplatin in MDA231 xenografts. The mechanism may be involved in the regulations of PI3K/AKT, JNK, ERK and NF-κB expressions.

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.

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