scholarly journals USP29 enhances chemotherapy-induced stemness in non-small cell lung cancer via stabilizing Snail1 in response to oxidative stress

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Yueguang Wu ◽  
Yingqiu Zhang ◽  
Duchuang Wang ◽  
Yang Zhang ◽  
Jinrui Zhang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
Transcriptional Activation ◽  
Epithelial Mesenchymal Transition ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
E3 Ligases ◽  
Tumor Dissemination

Abstract Chemotherapy remains an essential part of diverse treatment regimens against human malignancies. However, recent progressions have revealed a paradoxical role of chemotherapies to induce the cancer stem cell-like features that facilitate chemoresistance and tumor dissemination, with the underlying mechanisms underinvestigated. The zinc-finger transcription factor Snail1 is a central regulator during the epithelial-mesenchymal transition process and is closely implicated in cancer progression. Snail1 expression is strictly regulated at multiple layers, with its stability governed by post-translational ubiquitylation that is counterbalanced by the activities of diverse E3 ligases and deubiquitylases. Here we identify the deubiquitylase USP29 as a novel stabilizer of Snail1, which potently restricts its ubiquitylation in a catalytic activity-dependent manner. Bioinformatic analysis reveals a reverse correlation between USP29 expression and prognosis in lung adenocarcinoma patients. USP29 is unique among Snail1 deubiquitylases through exhibiting chemotherapy-induced upregulation. Mechanistically, oxidative stresses incurred by chemotherapy stimulate transcriptional activation of USP29. USP29 upregulation enhances the cancer stem cell-like characteristics in lung adenocarcinoma cells to promote tumorigenesis in athymic nude mice. Our findings uncover a novel mechanism by which chemotherapy induces cancer stemness and suggest USP29 as a potential therapeutic target to impede the development of chemoresistance and metastasis in lung adenocarcinoma.

scholarly journals Cooperation of Cancer Stem Cell Properties and Epithelial-Mesenchymal Transition in the Establishment of Breast Cancer Metastasis

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Tetsu Hayashida ◽  
Hiromitsu Jinno ◽  
Yuko Kitagawa ◽  
Masaki Kitajima
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Tumor ◽  
Breast Cancer Metastasis ◽  
Cell Junctions ◽  
Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) is a multistep process in which cells acquire molecular alterations such as loss of cell-cell junctions and restructuring of the cytoskeleton. There is an increasing understanding that this process may promote breast cancer progression through promotion of invasive and metastatic tumor growth. Recent observations imply that there may be a cross-talk between EMT and cancer stem cell properties, leading to enhanced tumorigenicity and the capacity to generate heterogeneous tumor cell populations. Here, we review the experimental and clinical evidence for the involvement of EMT in cancer stem cell theory, focusing on the common characteristics of this phenomenon.

scholarly journals Long-Term Helicobacter pylori Infection Switches Gastric Epithelium Reprogramming towards Cancer Stem Cell-Related Differentiation Program in Hp-Activated Gastric Fibroblast-TGFβ Dependent Manner

2020 ◽  
Vol 8 (10) ◽  
pp. 1519
Author(s):  
Gracjana Krzysiek-Maczka ◽  
Aneta Targosz ◽  
Urszula Szczyrk ◽  
Tomasz Wrobel ◽  
Malgorzata Strzalka ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Epithelial Mesenchymal Transition ◽  
Gastric Epithelium ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Cancer Associated Fibroblast ◽  
Activated Fibroblasts

Helicobacter pylori (Hp)-induced inflammatory reaction leads to a persistent disturbance of gastric mucosa and chronic gastritis evidenced by deregulation of tissue self-renewal and local fibrosis with the crucial role of epithelial–mesenchymal transition (EMT) in this process. As we reported before, Hp activated gastric fibroblasts into cells possessing cancer-associated fibroblast properties (CAFs), which secreted factors responsible for EMT process initiation in normal gastric epithelial RGM1 cells. Here, we showed that the long-term incubation of RGM1 cells in the presence of Hp-activated gastric fibroblast (Hp-AGF) secretome induced their shift towards plastic LGR5+/Oct4high/Sox-2high/c-Mychigh/Klf4low phenotype (l.t.EMT+RGM1 cells), while Hp-non-infected gastric fibroblast (GF) secretome prompted a permanent epithelial–myofibroblast transition (EMyoT) of RGM1 cells favoring LGR−/Oct4high/Sox2low/c-Myclow/Klf4high phenotype (l.t.EMT−RGM1 cells). TGFβ1 rich secretome from Hp-reprogrammed fibroblasts prompted phenotypic plasticity and EMT of gastric epithelium, inducing pro-neoplastic expansion of post-EMT cells in the presence of low TGFβR1 and TGFβR2 activity. In turn, TGFβR1 activity along with GF-induced TGFβR2 activation in l.t.EMT−RGM1 cells prompted their stromal phenotype. Collectively, our data show that infected and non-infected gastric fibroblast secretome induces alternative differentiation programs in gastric epithelium at least partially dependent on TGFβ signaling. Hp infection-activated fibroblasts can switch gastric epithelium microevolution towards cancer stem cell-related differentiation program that can potentially initiate gastric neoplasm.

scholarly journals Single-Cell RNA-Seq Analysis Reveals the Acquisition of Cancer Stem Cell Traits and Increase of Cell–Cell Signaling during EMT Progression

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5726
Author(s):  
Federico Bocci ◽  
Peijie Zhou ◽  
Qing Nie
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cell Signaling ◽  
Single Cell ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Intermediate Cell ◽  
Rna Seq ◽  
Mesenchymal Transition ◽  
Cell Cell

Intermediate cell states (ICSs) during the epithelial–mesenchymal transition (EMT) are emerging as a driving force of cancer invasion and metastasis. ICSs typically exhibit hybrid epithelial/mesenchymal characteristics as well as cancer stem cell (CSC) traits including proliferation and drug resistance. Here, we analyze several single-cell RNA-seq (scRNA-seq) datasets to investigate the relation between several axes of cancer progression including EMT, CSC traits, and cell–cell signaling. To accomplish this task, we integrate computational methods for clustering and trajectory inference with analysis of EMT gene signatures, CSC markers, and cell–cell signaling pathways, and highlight conserved and specific processes across the datasets. Our analysis reveals that “standard” measures of pluripotency often used in developmental contexts do not necessarily correlate with EMT progression and expression of CSC-related markers. Conversely, an EMT circuit energy that quantifies the co-expression of epithelial and mesenchymal genes consistently increases along EMT trajectories across different cancer types and anatomical locations. Moreover, despite the high context specificity of signal transduction across different cell types, cells undergoing EMT always increased their potential to send and receive signals from other cells.

scholarly journals Partial acquisition of stemness properties in tumorspheres obtained from interleukin-8-treated MCF-7 cells

Tumor Biology ◽  
2020 ◽  
Vol 42 (12) ◽  
pp. 101042832097943
Author(s):  
Natalia Ospina-Muñoz ◽  
Jean-Paul Vernot
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
First Generation ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Cell Line ◽  
Interleukin 8 ◽  
Self Renewal ◽  
Mesenchymal Transition ◽  
Sphere Formation ◽  
Mcf 7

The interleukin-8 is an important regulator of the tumor microenvironment, promoting the epithelial–mesenchymal transition and the acquisition of stem-like cell properties in cancer cells. The tumorsphere-formation assay has been used for the identification of cancer stem cell. Interleukin-8 induces the formation of larger tumorspheres in Michigan Cancer Foundation-7 (MCF-7) cells, suggesting cancer stem cell enrichment. In this work, we aimed to study the phenotypic and functional characteristics of the cells present within the tumorspheres of MCF-7 cells previously treated with interleukin-8. MCF-7 cells treated for 5 days or not with this cytokine were further cultivated in ultralow attachment plates for another 5 days to allow tumorspheres formation. We showed that the enhanced sphere formation by MCF-7 cells was not a consequence of higher cell proliferation by interleukin-8 stimulation. Despite maintaining an epithelial–mesenchymal transition phenotype with the presence of epithelial and mesenchymal markers, basic stemness properties were impaired in tumorspheres and in those treated with interleukin-8, while others were increased. Self-renewal capacity was increased in interleukin-8-treated cells only in the first generation of tumorspheres but was not sustained in consecutive assays. Accordingly, self-renewal and reprogramming gene expression, differentiation capacity to adipocytes, and clonogenicity were also impaired. We showed also that tumorspheres were enriched in differentiated luminal cells (EpCAM+/CD49f−). Nevertheless, cells were more quiescent and maintain a partial epithelial–mesenchymal transition, consistent with their increased resistance to Paclitaxel and Doxorubicin. They also presented higher migration and interleukin-8-directed invasion. Therefore, the breast cancer cell line MCF-7, having a low stemness index, might partially acquire some stem-like cell attributes after interleukin-8 stimulation, increasing its aggressiveness.

scholarly journals Helicobacter pylori generates cells with cancer stem cell properties via epithelial–mesenchymal transition-like changes

Oncogene ◽  
2013 ◽  
Vol 33 (32) ◽  
pp. 4123-4131 ◽  
Author(s):  
E Bessède ◽  
C Staedel ◽  
L A Acuña Amador ◽  
P H Nguyen ◽  
L Chambonnier ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition

scholarly journals HERV-K HML-2 transcription in diverse cancers is related with cancer stem cell and epithelial-mesenchymal transition markers

2018 ◽  
Author(s):  
Audrey T. Lin ◽  
Cindy G. Santander ◽  
Fabricia F. Nascimento ◽  
Emanuele Marchi ◽  
Timokratis Karamitros ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Human Genome ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Embryonic Stem ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Mesenchymal Transition

AbstractEndogenous retroviruses (ERVs) are remnants of ancient retroviral infections that make up 8% of the human genome. Although these elements are mostly fragmented and inactive, many proviruses belonging to the HERV-K (HML-2) family, the youngest lineage in the human genome, have intact open reading frames, some encoding for accessory genes called np9 and rec that interact with oncogenic pathways. Many studies have established that ERVs are transiently expressed in both stem cells and cancer, resulting in aberrant self-renewal and uncontrolled proliferation. np9 and rec expression are significantly correlated with a range of cancer stem cell (CSC) and epithelial to mesenchymal transition (EMT) biomarkers, including cellular receptors, transcription factors, and histone modifiers. Surprisingly, these ERV genes are negatively correlated with genes known to promote pluripotency in embryonic stem cell lines, such as Oct4. These results indicate that HERV-K (HML-2) is part of the transcriptional landscape responsible for cancer cells undergoing the phenotypic switch that characterises EMT. The discovery of np9 and rec’s correlation with CSC and EMT biomarkers suggest a yet undescribed role affecting the transitional CSC-like state in EMT and the shift towards cancer malignancy.ImportanceIn this study, we find that human endogenous retrovirus HERV-K (HML-2)-encoded genes np9 and rec are correlated with the expression of many biomarkers associated with cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT). There has been a significant effort to develop novel treatments targeting CSC and EMT-specific signalling pathways and cell surface markers. This research describes HERV-K (HML-2) as interacting or being part of the regulatory network that make up reversible cell state switching in EMT. Our findings suggest these specific HERVs may be good candidate biomarkers in identifying the transitional CSC-like states that are present during the progression of EMT and cancer metastasis.

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.

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