scholarly journals Epithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Chenqiang Jia ◽  
Zhuqing Zhang ◽  
Jun Tang ◽  
Mei-Chun Cai ◽  
Jingyu Zang ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcriptional Activation ◽  
Promoter Region ◽  
Drug Exposure ◽  
Epithelial Mesenchymal Transition ◽  
Experimental Models ◽  
Cytokine Release ◽  
Functional Importance ◽  
Bioinformatics Analyses ◽  
Mesenchymal Transition

GSDME is a newly recognized executor of cellular pyroptosis, and has been recently implicated in tumor growth and immunity. However, knowledge about the molecular regulators underlying GSDME abundance remains limited. Here, we performed integrative bioinformatics analyses and identified that epithelial-mesenchymal transition (EMT) gene signatures exhibited positive correlation with GSDME levels across human cancers. A causal role was supported by the observation that EMT dictated GSDME reversible upregulation in multiple experimental models. Mechanistically, transcriptional activation of GSDME was directly driven by core EMT-activating transcription factors ZEB1/2, which bound to the GSDME promoter region. Of functional importance, elevated GSDME in mesenchymally transdifferentiated derivatives underwent proteolytic cleavage upon antineoplastic drug exposure, leading to pyroptotic cell death and consequent cytokine release. Taken together, our findings pinpointed a key transcriptional machinery controlling GSDME expression and indicated potential therapeutic avenues to exploit GSDME-mediated inflammatory pyroptosis for the treatment of mesenchymal malignancies.

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

Oncogene ◽  
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.

scholarly journals A radiosensitizer, gallotannin-rich extract from Bouea macrophylla seeds, inhibits radiation-induced epithelial-mesenchymal transition in breast cancer cells

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jiraporn Kantapan ◽  
Siwaphon Paksee ◽  
Aphidet Duangya ◽  
Padchanee Sangthong ◽  
Sittiruk Roytrakul ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition ◽  
Mammosphere Formation ◽  
Radiation Induced

Abstract Background Radioresistance can pose a significant obstacle to the effective treatment of breast cancers. Epithelial–mesenchymal transition (EMT) is a critical step in the acquisition of stem cell traits and radioresistance. Here, we investigated whether Maprang seed extract (MPSE), a gallotannin-rich extract of seed from Bouea macrophylla Griffith, could inhibit the radiation-induced EMT process and enhance the radiosensitivity of breast cancer cells. Methods Breast cancer cells were pre-treated with MPSE before irradiation (IR), the radiosensitizing activity of MPSE was assessed using the colony formation assay. Radiation-induced EMT and stemness phenotype were identified using breast cancer stem cells (CSCs) marker (CD24−/low/CD44+) and mammosphere formation assay. Cell motility was determined via the wound healing assay and transwell migration. Radiation-induced cell death was assessed via the apoptosis assay and SA-β-galactosidase staining for cellular senescence. CSCs- and EMT-related genes were confirmed by real-time PCR (qPCR) and Western blotting. Results Pre-treated with MPSE before irradiation could reduce the clonogenic activity and enhance radiosensitivity of breast cancer cell lines with sensitization enhancement ratios (SERs) of 2.33 and 1.35 for MCF7 and MDA-MB231cells, respectively. Pretreatment of breast cancer cells followed by IR resulted in an increased level of DNA damage maker (γ-H2A histone family member) and enhanced radiation-induced cell death. Irradiation induced EMT process, which displayed a significant EMT phenotype with a down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker vimentin in comparison with untreated breast cancer cells. Notably, we observed that pretreatment with MPSE attenuated the radiation-induced EMT process and decrease some stemness-like properties characterized by mammosphere formation and the CSC marker. Furthermore, pretreatment with MPSE attenuated the radiation-induced activation of the pro-survival pathway by decrease the expression of phosphorylation of ERK and AKT and sensitized breast cancer cells to radiation. Conclusion MPSE enhanced the radiosensitivity of breast cancer cells by enhancing IR-induced DNA damage and cell death, and attenuating the IR-induced EMT process and stemness phenotype via targeting survival pathways PI3K/AKT and MAPK in irradiated breast cancer cells. Our findings describe a novel strategy for increasing the efficacy of radiotherapy for breast cancer patients using a safer and low-cost natural product, MPSE.

scholarly journals NRF1-Mediated Oncogenic Reprogramming Drives Estrogen-Induced Breast Carcinogenesis

2018 ◽  
Author(s):  
Jayanta Kumar Das ◽  
Quentin Felty ◽  
Robert Poppiti ◽  
Robert M. Jackson ◽  
Deodutta Roy
Keyword(s):  
Breast Cancer ◽  
Transcriptional Activation ◽  
Epithelial Mesenchymal Transition ◽  
Confocal Imaging ◽  
Cancer Tissue ◽  
Causative Role ◽  
Dependent Manner ◽  
Breast Carcinogenesis ◽  
Human Breast Cancer Tissue ◽  
Mesenchymal Transition

Transcription factor activity of the nuclear respiratory factor 1 protein (NRF1) is increased in breast cancer. Whether this gain of NRF1 activity is directly involved in breast cancer remains unknown. Herein, we report a novel oncogenic function of NRF1 supporting its causative role in breast cancer development and progression. The gain of NRF1 and/or treatment with 17β-estradiol (E2) produced heterogeneous breast cancer stem cells (BCSCs) composed of more than ten distinct cell sub-populations. Flow sorting combined with confocal imaging of markers for pluripotency, epithelial mesenchymal transition (EMT), and BCSCs phenotypically confirmed that the sub-populations of BCSCs arise from cell re-programming. Thus, we determined the molecular actions of NRF1 on its target gene CXCR4 because of its known role in the acquisition of BCSCs through EMT. CXCR4 was activated by NRF1 in a redox dependent manner during malignant transformation. NRF1-induced BCSCs were able to form xenograft tumors in vivo, while inhibiting transcription of CXCR4 prevented xenograft tumor growth. Consistent with our observation of NRF1 driven breast tumorigenesis in the experimental model, higher levels of NRF1 protein expression were also found in human breast cancer tissue specimens. This highly novel role of NRF1 in the stochastic acquisition of BCSCs and their progression to a malignant phenotype may open an entirely new research direction targeting NRF1 signaling in invasive breast cancer. Additionally, the discovery of targeting transcriptional activation of CXCR4 to inhibit NRF1-induced oncogenic transformation provides a mechanistic explanation for estrogen-dependent breast carcinogenesis and opens the new avenues for mechanistic therapeutic strategy against breast cancer.

scholarly journals FEZF1-AS1: a novel vital oncogenic lncRNA in multiple human malignancies

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Changlong Shi ◽  
Li Sun ◽  
Yongsheng Song
Keyword(s):  
Transcriptional Activation ◽  
Epithelial Mesenchymal Transition ◽  
Chromatin Modification ◽  
Research Progress ◽  
Organ Specificity ◽  
Signal Pathways ◽  
Protein Coding ◽  
Mesenchymal Transition ◽  
Regulatory Processes ◽  
Transcription 3

AbstractLong noncoding RNAs (LncRNAs) refer to the RNA with a length of >200 nucleotides, which lack or have no open reading coding frame and have higher tissue and organ specificity compared with the protein coding genes. A surging number of studies have shown that lncRNA is involved in numerous essential regulatory processes, such as X chromosome silencing, genomic imprinting, chromatin modification, transcriptional activation, transcriptional interference and nuclear transport, which are closely related to the occurrence and development of human malignancies. FEZ family Zinc Finger 1-Antisense RNA 1 (FEZF1-AS1) of FEZ family is a recently discovered lncRNA. FEZF1-AS1 is highly expressed in pancreatic cancer, colorectal cancer, lung adenocarcinoma and other human malignancies, and is associated with poor prognosis. As an oncogene, it plays crucial role in the proliferation, migration, invasion and Warburg effect of various tumor cells. In addition, FEZF1-AS1 is also involved in the regulation of multiple signal pathways such as epithelial–mesenchymal transition (EMT), signal transducer and activator of transcription 3 (STAT3) and Wnt/ β-catenin. In this paper, the recent research progress of FEZF1-AS1 in tumorigenesis and development is reviewed systematically.

scholarly journals Epigenetic silencing of CDKN1A and CDKN2B by SNHG1 promotes the cell cycle, migration and epithelial-mesenchymal transition progression of hepatocellular carcinoma

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Bei Li ◽  
Ang Li ◽  
Zhen You ◽  
Jingchang Xu ◽  
Sha Zhu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Luciferase Assay ◽  
Bioinformatics Analyses ◽  
Mesenchymal Transition ◽  
Rna Immunoprecipitation

Abstract Enhanced SNHG1 (small nucleolar RNA host gene 1) expression has been found to play a critical role in the initiation and progression of hepatocellular carcinoma (HCC) with its detailed mechanism largely unknown. In this study, we show that SNHG1 promotes the HCC progression through epigenetically silencing CDKN1A and CDKN2B in the nucleus, and competing with CDK4 mRNA for binding miR-140-5p in the cytoplasm. Using bioinformatics analyses, we found hepatocarcinogenesis is particularly associated with dysregulated expression of SNHG1 and activation of the cell cycle pathway. SNHG1 was upregulated in HCC tissues and cells, and its knockdown significantly inhibited HCC cell cycle, growth, metastasis, and epithelial–mesenchymal transition (EMT) both in vitro and in vivo. Chromatin immunoprecipitation and RNA immunoprecipitation assays demonstrate that SNHG1 inhibit the transcription of CDKN1A and CDKN2B through enhancing EZH2 mediated-H3K27me3 in the promoter of CDKN1A and CDKN2B, thus resulting in the de-repression of the cell cycle. Dual-luciferase assay and RNA pulldown revealed that SNHG1 promotes the expression of CDK4 by competitively binding to miR-140-5p. In conclusion, we propose that SNHG1 formed a regulatory network to confer an oncogenic function in HCC and SNHG1 may serve as a potential target for HCC diagnosis and treatment.

scholarly journals Contactin 1: An Important and Emerging Oncogenic Protein Promoting Cancer Progression and Metastasis

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 874
Author(s):  
Yan Gu ◽  
Taosha Li ◽  
Anil Kapoor ◽  
Pierre Major ◽  
Damu Tang
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
System Development ◽  
Notch Signaling Pathway ◽  
Experimental Models ◽  
Vegf Receptor ◽  
Mesenchymal Transition ◽  
Cancer Pathways ◽  
Factor C

Even with recent progress, cancer remains the second leading cause of death, outlining a need to widen the current understanding on oncogenic factors. Accumulating evidence from recent years suggest Contactin 1 (CNTN1)’s possession of multiple oncogenic activities in a variety of cancer types. CNTN1 is a cell adhesion molecule that is dysregulated in many human carcinomas and plays important roles in cancer progression and metastases. Abnormalities in CNTN1 expression associate with cancer progression and poor prognosis. Mechanistically, CNTN1 functions in various signaling pathways frequently altered in cancer, such as the vascular endothelial growth factor C (VEGFC)-VEGF receptor 3 (VEFGR3)/fms-related tyrosine kinase 4 (Flt4) axis, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), Notch signaling pathway and epithelial-mesenchymal transition (EMT) process. These oncogenic events are resulted via interactions between tumor and stroma, which can be contributed by CNTN1, an adhesion protein. CNTN1 expression in breast cancer correlates with the expression of genes functioning in cancer-stroma interactions and skeletal system development. Evidence supports that CNTN1 promotes cancer-stromal interaction, resulting in activation of a complex network required for cancer progression and metastasis (bone metastasis for breast cancer). CNTN1 inhibitions has been proven to be effective in experimental models to reduce oncogenesis. In this paper, we will review CNTN1′s alterations in cancer, its main biochemical mechanisms and interactions with its relevant cancer pathways.

scholarly journals MicroRNA-361-5p Inhibits Tumorigenesis and the EMT of HCC by Targeting Twist1

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Liang-Chun Yin ◽  
Gang Xiao ◽  
Rui Zhou ◽  
Xiao-Ping Huang ◽  
Ning-Lei Li ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Suppressive Effect ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Bioinformatics Analyses ◽  
Mesenchymal Transition ◽  
Reporter Assays

MicroRNA-361-5p (miR-361-5p) is a tumor suppressor miRNA that is dysregulated in several types of human cancer. However, the functional significance of miR-361-5p in hepatocellular carcinoma (HCC) is unclear. This study explored the biological function of miR-361-5p in regulating the progression of HCC and the underlying molecular mechanism. RT-qPCR analysis showed that miR-361-5p was downregulated in HCC tissues and cell lines. Functional analysis revealed that miR-361-5p acted as a tumor suppressor, inhibiting cell proliferation, migration, and invasion in HCC cell lines. Bioinformatics analyses identified Twist1 as a direct target of miR-361-5p, which was validated by dual-luciferase reporter assays, RT-qPCR, and western blotting. Rescue experiments indicated that Twist1 may mediate the tumor-suppressive effect of miR-361-5p in HCC cells, and this was supported by the effect of miR-361-5p on inhibiting the epithelial-mesenchymal transition (EMT) by targeting Twist1. This study is the first to suggest that miR-361-5p inhibits tumorigenesis and EMT in HCC by targeting Twist1. These findings are valuable for the diagnosis and clinical management of HCC.

scholarly journals Slug and Vimentin Downregulation at the Metastatic Site Is Associated With Skip-N2 Metastasis of Lung Adenocarcinoma

2022 ◽  
Author(s):  
Yasemin SAYGIDEGER ◽  
Alper AVCI ◽  
Emine BAGIR ◽  
Burcu SAYGIDEĞER DEMİR ◽  
Aycan SEZAN Ms ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Survival Rates ◽  
Cancer Tissue ◽  
Mrna Levels ◽  
Bioinformatics Analyses ◽  
Tissue Samples ◽  
Mesenchymal Transition ◽  
Slug Expression ◽  
E Cadherin

Abstract Objective: Lung cancer displays heterogeneity both in the tumor itself and in its metastatic regions. One interesting behavior of the tumor is known as Skip N2 metastasis, which N2 lymph nodes contain tumor cells while N1 are clean. In this study, mRNA levels of epithelial mesenchymal transition (EMT) related genes in skip N2 and normal N2 involvements of non-small cell lung cancer tissues were investigated to evaluate the possible molecular background that may contribute to the pathogenesis of Skip N2 metastasis. Materials and Methods: Eighty-three surgically resected and paraffin embedded lymph node samples of lung cancer patients were analyzed in this study, which 40 of them were Skip N2. N2 tissues were sampled from 50% tumor containing areas and total RNA was extracted. mRNA levels for 18S, E-cadherin, Vimentin, ZEB1 and SLUG were analyzed via qPCR and E-cadherin and vimentin protein levels via immunohistochemistry (IHC). Bioinformatic analysis were adopted using online datasets to evaluate significantly co-expressed genes with SLUG in lung cancer tissue samples.Results: Skip-N2 patients who had adenocarcinoma subtype had better survival rates. Comparative analysis of PCR results indicated that Skip N2 tumor tissues had increased E-Cadherin/Vimentin ratio and ZEB1 mRNA expression, and significantly decreased levels of SLUG. E-cadherin IHC staining were higher in Skip N2 and Vimentin were in Non-Skip N2. TP63 had a strong correlation with SLUG expression in the bioinformatics analyses.Conclusion: The results indicate that, at molecular level, Skip N2 pathogenesis has different molecular background and regulation of SLUG expression may orchestrate the process.

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