scholarly journals TIPE1 Suppresses Growth and Metastasis of Ovarian Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Zhenyu Zhang ◽  
Minghui Chang ◽  
Xingguo Song ◽  
Kangyu Wang ◽  
Wenjuan Sun ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Cervix Uteri ◽  
Human Tissues ◽  
Mesenchymal Transition ◽  
Normal Human ◽  
Cancer Tissues

TIPE1, a newly identified member in TIPE (TNFAIP8) family, plays an important role in tumorigenesis and immune regulation, but its role in ovarian cancer, especially in tumor metastasis, remains unknown. In the current study, we aimed to reveal the protein expression spectrum of TIPE1 in normal human tissues and explored its relationship with metastasis in ovarian cancer. The results of IHC staining showed that TIPE1 protein was not only detected in cytoplasm in most human tissues but also expressed in both cytoplasm and nucleus in squamous epithelium and some epithelial-derived cells with secretory functions, such as esophagus, cervix uteri and ovary, and thyroid gland. Moreover, TIPE1 protein was downregulated in ovarian cancer tissues compared with that in the paracancerous. More importantly, TIPE1 suppressed tumorigenesis and metastasis of ovarian cancer in vitro and in vivo, as evidence shows its ability to suppress growth, colony formation, migration, and epithelial-mesenchymal transition (EMT) of ovarian cancer. Taken together, our results demonstrate the suppressor role of TIPE1 in ovarian cancer metastasis, indicating TIPE1 might be a metastasis predictor and a novel therapeutic target for ovarian cancer.

scholarly journals Exosomes in ovarian cancer ascites promote epithelial–mesenchymal transition of ovarian cancer cells by delivery of miR-6780b-5p

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Jing Cai ◽  
Lanqing Gong ◽  
Guodong Li ◽  
Jing Guo ◽  
Xiaoqing Yi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Tumor Metastasis ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Ovarian Cancer Cells ◽  
Specific Mechanism ◽  
Mesenchymal Transition

AbstractThe poor prognosis of ovarian cancer is mainly due to metastasis, and the specific mechanism underlying ovarian cancer metastasis is not clear. Ascites-derived exosomes (ADEs) play an important role in the progression of ovarian cancer, but the mechanism is unknown. Here, we found that ADEs promoted ovarian cancer metastasis not only in vitro but also in vivo. This promotive function was based on epithelial–mesenchymal transition (EMT) of ovarian cancer cells. Bioinformatics analysis of RNA sequencing microarray data indicated that miR-6780b-5p may be the key microRNA (miRNA) in ADEs that facilitates cancer metastasis. Moreover, the expression of exosomal miR-6780b-5p correlated with tumor metastasis in ovarian cancer patients. miR-6780b-5p overexpression promoted and miR-6780b-5p downregulation suppressed EMT of ovarian cancer cells. These results suggest that ADEs transfer miR-6780b-5p to ovarian cancer cells, promoting EMT and finally facilitating ovarian cancer metastasis.

scholarly journals Snail Driving Alternative Splicing of CD44 by ESRP1 Enhances Invasion and Migration in Epithelial Ovarian Cancer

2017 ◽  
Vol 43 (6) ◽  
pp. 2489-2504 ◽  
Author(s):  
Le Chen ◽  
Ying Yao ◽  
Lijuan Sun ◽  
Jiajia Zhou ◽  
Minmin Miao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Alternative Splicing ◽  
Epithelial Ovarian Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Regulatory Protein ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Background/Aims: Our study aims to investigate the role, effect and mechanisms of ESRP1 (epithelial splicing regulatory protein 1) in epithelial-mesenchymal transition (EMT) in epithelial ovarian cancer (EOC). Methods: Microarray and immunohistochemical analysis of ESRP1 expression were performed in EOC cases. The correlations between ESRP1 expression and clinical factors on EOC were assessed. Lentivirus-mediated RNA interference and EGFP vector which contains ESRP1 gene were used to down-regulate and up-regulate ESRP1 expression in human EOC cell lines. Roles of ESRP1 in cell growth, migration and invasion of EOC cells were also measured by Cell Counting Kit-8 and Transwell systems in vitro and by a nude mice intraperitoneal transplantation model in vivo. Results: By the analysis of Gene Expression Omnibus (GEO) (p<0.05) and our own microarray data (p<0.001), ESRP1 expression in EOC was significantly different from normal ovarian tissue. It was abundant in the nuclei of cancer cells and in malignant lesions. However, it was weakly expressed or negative in both normal and benign lesions. High ESRP1 expression in EOC was associated with poor clinical outcomes. Decreased ESRP1 expression significantly increased cell migration and invasion both in vivo and in vitro. Snail strongly repressed ESRP1 transcription through binding to the ESRP1 promoter in EOC cells. Furthermore, ESRP1 regulated the expression of CD44s. Down-regulated ESRP1 resulted in an isoform switching from CD44v to CD44s, which modulated epithelial-mesenchymal transition (EMT) program in EOC. Up-regulatin of ESRP1 was detected in mesenchymal to epithelial transition (MET) in vivo. Conclusions: ESRP1 regulates CD44 alternative splicing during the EMT process which plays an important role in EOC carcinogenesis. In addition, ESRP1 is associated with disease prognosis in EOC.

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.

scholarly journals CD36 promotes the epithelial–mesenchymal transition and metastasis in cervical cancer by interacting with TGF-β

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Min Deng ◽  
Xiaodong Cai ◽  
Ling Long ◽  
Linying Xie ◽  
Hongmei Ma ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Cd36 Expression ◽  
Cervical Cancer Cells

Abstract Background Accumulating evidence indicates that CD36 initiates metastasis and correlates with an unfavorable prognosis in cancers. However, there are few reports regarding the roles of CD36 in initiation and metastasis of cervical cancer. Methods Using immunohistochemistry, we analyzed 133 cervical cancer samples for CD36 protein expression levels, and then investigated the correlation between changes in its expression and clinicopathologic parameters. The effect of CD36 expression on the epithelial–mesenchymal transition (EMT) in cervical cancer cells was evaluated by Western immunoblotting analysis. In vitro invasion and in vivo metastasis assays were also used to evaluate the role of CD36 in cervical cancer metastasis. Results In the present study, we confirmed that CD36 was highly expressed in cervical cancer samples relative to normal cervical tissues. Moreover, overexpression of CD36 promoted invasiveness and metastasis of cervical cancer cells in vitro and in vivo, while CD36 knockdown suppressed proliferation, migration, and invasiveness. We demonstrated that TGF-β treatment attenuated E-cadherin expression and enhanced the expression levels of CD36, vimentin, slug, snail, and twist in si-SiHa, si-HeLa, and C33a–CD36 cells, suggesting that TGF-β synergized with CD36 on EMT via active CD36 expression. We also observed that the expression levels of TGF-β in si-SiHa cells and si-HeLa cells were down-regulated, whereas the expression levels of TGF-β were up-regulated in C33a–CD36 cells. These results imply that CD36 and TGF-β interact with each other to promote the EMT in cervical cancer. Conclusions Our findings suggest that CD36 is likely to be an effective target for guiding individualized clinical therapy of cervical cancer.

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 MicroRNA-26a and -26b inhibit lens fibrosis and cataract by negatively regulating Jagged-1/Notch signaling pathway

2017 ◽  
Vol 24 (8) ◽  
pp. 1431-1442 ◽  
Author(s):  
Xiaoyun Chen ◽  
Wei Xiao ◽  
Weirong Chen ◽  
Xialin Liu ◽  
Mingxing Wu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Notch Signaling ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Notch Pathway ◽  
Lens Epithelial Cells ◽  
Mesenchymal Transition ◽  
Fibrotic Diseases

Abstract Fibrosis is a chronic process involving development and progression of multiple diseases in various organs and is responsible for almost half of all known deaths. Epithelial–mesenchymal transition (EMT) is the vital process in organ fibrosis. Lens is an elegant biological tool to investigate the fibrosis process because of its unique biological properties. Using gain- and loss-of-function assays, and different lens fibrosis models, here we demonstrated that microRNA (miR)-26a and miR-26b, members of the miR-26 family have key roles in EMT and fibrosis. They can significantly inhibit proliferation, migration, EMT of lens epithelial cells and lens fibrosis in vitro and in vivo. Interestingly, we revealed that the mechanisms of anti-EMT effects of miR-26a and -26b are via directly targeting Jagged-1 and suppressing Jagged-1/Notch signaling. Furthermore, we provided in vitro and in vivo evidence that Jagged-1/Notch signaling is activated in TGFβ2-stimulated EMT, and blockade of Notch signaling can reverse lens epithelial cells (LECs) EMT and lens fibrosis. Given the general involvement of EMT in most fibrotic diseases, cancer metastasis and recurrence, miR-26 family and Notch pathway may have therapeutic uses in treating fibrotic diseases and cancers.

scholarly journals Comparative study of transcriptomics-based scoring metrics for the epithelial-hybrid-mesenchymal spectrum

2020 ◽  
Author(s):  
Priyanka Chakraborty ◽  
Jason T George ◽  
Shubham Tripathi ◽  
Herbert Levine ◽  
Mohit Kumar Jolly
Keyword(s):  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Multinomial Logistic Regression ◽  
M Cells ◽  
M Cell ◽  
Mesenchymal Transition ◽  
Tumor Types

AbstractThe Epithelial-mesenchymal transition (EMT) is a cellular process implicated in embryonic development, wound healing, and pathological conditions such as cancer metastasis and fibrosis. Cancer cells undergoing EMT exhibit enhanced aggressive behavior characterized by drug resistance, tumor-initiation potential, and the ability to evade immune system. Recent in silico, in vitro, and in vivo evidence indicates that EMT is not an all-or-none process; instead, cells stably acquire one or more hybrid epithelial/mesenchymal (E/M) phenotypes which often can be more aggressive than purely epithelial or mesenchymal cell populations. Thus, the EMT status of cancer cells can prove to be a critical estimate of patient prognosis. Recent attempts have employed different transcriptomics signatures to quantify EMT status in cell lines and patient tumors. However, a comprehensive comparison of these methods, including their accuracy in identifying cells in the hybrid E/M phenotype(s), is lacking. Here, we compare three distinct metrics that score EMT on a continuum, based on the transcriptomics signature of individual samples. Our results demonstrate that these methods exhibit good concordance among themselves in quantifying the extent of EMT in a given sample. Moreover, scoring EMT using any of the three methods discerned that cells undergo varying extents of EMT across tumor types. Separately, our analysis also identified tumor types with maximum variability in terms of EMT and associated an enrichment of hybrid E/M signatures in these samples. Moreover, we also found that the multinomial logistic regression (MLR) based metric was capable of distinguishing between ‘pure’ individual hybrid E/M vs. mixtures of epithelial (E) and mesenchymal (M) cells. Our results, thus, suggest that while any of the three methods can indicate a generic trend in the EMT status of a given cell, the MLR method has two additional advantages: a) it uses a small number of predictors to calculate the EMT score, and b) it can predict from the transcriptomic signature of a population whether it is comprised of ‘pure’ hybrid E/M cells at the single-cell level or is instead an ensemble of E and M cell subpopulations.

scholarly journals Immunosuppressive traits of the hybrid epithelial/mesenchymal phenotype

2021 ◽  
Author(s):  
Sarthak Sahoo ◽  
Sonali Priyadarshini Nayak ◽  
Kishore Hari ◽  
Susmita Mandal ◽  
Akash Kishore ◽  
...  
Keyword(s):  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Causal Link ◽  
M Cells ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Cellular Processes ◽  
Secondary Tumour

Cancer metastasis remains a primary cause of cancer related mortality. Recent in vitro and in vivo data has indicated the high metastatic fitness of hybrid epithelial/mesenchymal (E/M) states, i.e. their enhanced abilities to initiate tumours at secondary tumour site. Mechanistic details about how such hybrid E/M cells survive the metastatic cascade remain unclear. Here, we investigate immune-evasive strategies of hybrid E/M states, an issue that to date has been largely unexplored. We construct a minimalistic regulatory network that captures known associations between regulators of EMT (the epithelial mesenchymal transition) and levels of PD-L1, an established suppressor of immune response, and simulated the network's emergent dynamics. Our model recapitulates observations that cells undergoing EMT have increased PD-L1 levels, while reverting EMT can decrease these levels, indicative of a causal link between EMT drivers and PD-L1. Further, we show that hybrid E/M cells can have high levels of PD-L1, similar to those seen in cells with a full EMT phenotype, thus obviating the need for cancer cells to undergo a full EMT to evade the immune system. Finally, we identify various signalling pathways and cellular processes that can independently or in concert affect PD-L1 levels and EMT status. For instance, hybrid E/M cells can gain both immune-evasion and stemness through largely independent paths. Our results underscore another underlying reason for the high metastatic ability of hybrid E/M cells.

scholarly journals Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

2021 ◽  
Author(s):  
Samriddhi Arora ◽  
Jyoti Tanwar ◽  
Nutan Sharma ◽  
Suman Saurav ◽  
Rajender K. Motiani
Keyword(s):  
Pancreatic Cancer ◽  
Survival Time ◽  
Cell Lines ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Mesenchymal Transition

Pancreatic cancer (PC) is one of the most lethal forms of cancers with 5-year mean survival rate of less than 10%. Most of the PC associated deaths are due to metastasis to secondary sites. Calcium (Ca2+) signaling plays a critical role in regulating hallmarks of cancer progression including cell proliferation, migration and apoptotic resistance. Store operated Ca2+ entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous pathway responsible for Ca2+ influx into non-excitable cells. In this study, we performed extensive bioinformatic analysis of publicly available datasets and observed that Orai3 expression is inversely associated with the mean survival time of PC patients. Orai3 expression analysis in a battery of PC cell lines corroborated its differential expression profile. We then carried out thorough Ca2+ imaging experiments in 6 PC cell lines and found that Orai3 forms a functional SOCE in PC cells. Our in vitro functional assays show that Orai3 regulates PC cell cycle progression, apoptosis and migration. Most importantly, our in vivo xenograft studies demonstrate a critical role of Orai3 in PC tumor growth and secondary metastasis. Mechanistically, Orai3 controls G1 phase progression, matrix metalloproteinase expression and epithelial-mesenchymal transition in PC cells. Taken together, this study for the first time reports that Orai3 drives aggressive phenotypes of PC cells i.e. migration in vitro and metastasis in vivo. Considering that Orai3 expression is inversely associated with the PC patients survival time, it appears to be a highly attractive therapeutic target.

scholarly journals SPR965, a Dual PI3K/mTOR Inhibitor, as a Targeted Therapy in Ovarian Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Arthur-Quan Tran ◽  
Stephanie A. Sullivan ◽  
Leo Li-Ying Chan ◽  
Yajie Yin ◽  
Wenchuan Sun ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Transition Process ◽  
Ovarian Cancer Cells ◽  
Serous Ovarian Cancer ◽  
Mesenchymal Transition

SPR965 is an inhibitor of PI3K and mTOR C1/C2 and has demonstrated anti-tumorigenic activity in a variety of solid tumors. We sought to determine the effects of SPR965 on cell proliferation and tumor growth in human serous ovarian cancer cell lines and a transgenic mouse model of high grade serous ovarian cancer (KpB model) and identify the underlying mechanisms by which SPR965 inhibits cell and tumor growth. SPR965 showed marked anti-proliferative activity by causing cell cycle arrest and inducing cellular stress in ovarian cancer cells. Treatment with SPR965 significantly inhibited tumor growth in KpB mice, accompanied by downregulation of Ki67 and VEGF and upregulation of Bip expression in ovarian tumors. SPR965 also inhibited adhesion and invasion through induction of the epithelial–mesenchymal transition process. As expected, downregulation of phosphorylation of AKT and S6 was observed in SPR965-treated ovarian cancer cells and tumors. Our results suggest that SPR965 has significant anti-tumorigenic effects in serous ovarian cancer in vitro and in vivo. Thus, SPR965 should be evaluated as a promising targeted agent in future clinical trials of ovarian cancer.

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