Cigarette smoking promotes keratinocyte malignancy via generation of cancer stem-like cells.
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ABSTRACT:
SUBMITTER: Lin S
PROVIDER: S-EPMC7797662 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND & AIMS:Cigarette smoking is a major risk factor for pancreatic cancer. Aggressive pancreatic tumors contain cancer cells with stem cell features. We investigated whether cigarette smoke induces stem cell features in pancreatic cancer cells. METHODS:KrasG12D; Pdx1-Cre mice were exposed to cigarette smoke or clean air (controls) for up to 20 weeks; pancreata were collected and analyzed by histology, quantitative reverse transcription polymerase chain reaction, and confocal immunofluorescence microscopy. HPNE and Capan1 cells were exposed to cigarette smoke extract (CSE), nicotine and nicotine-derived carcinogens (NNN or NNK), or clean air (controls) for 80 days and evaluated for stem cell markers and features using flow cytometry-based autofluorescence, sphere formation, and immunoblot assays. Proteins were knocked down in cells with small interfering RNAs. We performed RNA sequencing analyses of CSE-exposed cells. We used chromatin immunoprecipitation assays to confirm the binding of FOS-like 1, AP-1 transcription factor subunit (FOSL1) to RNA polymerase II-associated factor (PAF1) promoter. We obtained pancreatic ductal adenocarcinoma (PDAC) and matched nontumor tissues (n = 15) and performed immunohistochemical analyses. RESULTS:Chronic exposure of HPNE and Capan1 cells to CSE caused them to increase markers of stem cells, including autofluorescence and sphere formation, compared with control cells. These cells increased expression of ABCG2, SOX9, and PAF1, via cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) signaling to mitogen-activated protein kinase 1 and FOSL1. CSE-exposed pancreatic cells with knockdown of PAF1 did not show stem cell features. Exposure of cells to NNN and NNK led to increased expression of CHRNA7, FOSL1, and PAF1 along with stem cell features. Pancreata from KrasG12D; Pdx1-Cre mice exposed to cigarette smoke had increased levels of PAF1 mRNA and protein, compared with control mice, as well as increased expression of SOX9. Levels of PAF1 and FOSL1 were increased in PDAC tissues, especially those from smokers, compared with nontumor pancreatic tissue. CSE exposure increased expression of PHD-finger protein 5A, a pluripotent transcription factor and its interaction with PAF1. CONCLUSIONS:Exposure to cigarette smoke activates stem cell features of pancreatic cells, via CHRNA7 signaling and FOSL1 activation of PAF1 expression. Levels of PAF1 are increased in pancreatic tumors of humans and mice with chronic cigarette smoke exposure.
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Project description:The prognosis of breast cancer patients is related to the degree of metastasis. However, the mechanisms by which epithelial tumor cells escape from the primary tumor and colonize at a distant site are not entirely understood. Here, we analyzed expression levels of pituitary tumor-transforming gene-1 (PTTG1), a relatively uncharacterized oncoprotein, in patient-derived breast cancer tissues with corresponding normal breast tissues. We found that PTTG1 is highly expressed in breast cancer patients, compared with normal tissues. Also, PTTG1 expression levels were correlated with the degree of malignancy in breast cancer cell lines; the more migratory and invasive cancer cell lines MDA-MB-231 and BT549 displayed the higher expression levels of PTTG1 than the less migratory and invasive MCF7 and SK-BR3 and normal MCF10A cell lines. By modulating PTTG1 expression levels, we found that PTTG1 enhances the migratory and invasive properties of breast cancer cells by inducing epithelial to mesenchymal transition, as evidenced by altered morphology and epithelial/mesenchymal cell marker expression patterns and up-regulation of the transcription factor Snail. Notably, down-regulation of PTTG1 also suppressed cancer stem cell population in BT549 cells by decreasing self-renewing ability and tumorigenic capacity, accompanying decreasing CD44(high) CD24(low) cells and Sox2 expression. Up-regulation of PTTG1 had the opposite effects, increasing sphere-forming ability and Sox2 expression. Importantly, PTTG1-mediated malignant tumor properties were due, at least in part, to activation of AKT, known to be a key regulator of both EMT and stemness in cancer cells. Collectively, these results suggest that PTTG1 may represent a new therapeutic target for malignant breast cancer.
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Project description:Glioma stem-like cells (GSCs) are regarded as the sources of oncogenesis, recurrence, invasion and chemoresistance in malignant gliomas. Growing evidence suggests that the microenvironment surrounding GSCs interacts with tumor cells to influence biological behavior; however, the functional mechanisms involved are still unclear. In the present study, we investigated the modulation of GSCs triggered by fibronectin (FN), a main component of the extracellular matrix (ECM), in terms of cell adhesion, differentiation, proliferation and chemoresistance. We demonstrated that pre-coated FN prompted increased adherence by GSCs, with increased matrix metallopeptidases (MMPs)-2 and -9 expression, in a concentration-dependent manner. Decreases in sox-2 and nestin levels, and increased levels of glial fibrillary acidic protein (GFAP) and β-tubulin were also found in GSCs, indicating cell differentiation driven by FN. Further investigation revealed that FN promoted cell growth, as demonstrated by the elevation of Ki-67, with the activation of p-ERK1/2 and cyclin D1 also evident. In addition, FN suppressed p53-mediated apoptosis and upregulated P-glycoprotein expression, making GSCs more chemoresistant to alkylating agents such as carmustine. In contrast, this effect was reversed by an integrin inhibitor, cilengitide. Activation of the focal adhesion kinase/paxillin/AKT signaling pathway was involved in the modulation of GSCs by FN. Focusing on the interactions between tumor cells and the ECM may be an encouraging aspect of research on novel chemotherapeutic therapies in future.
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Project description:Human induced pluripotent stem cell (hiPSC)-derived endothelial cells (ECs) and pericytes provide a powerful tool for cardiovascular disease modelling, personalized drug testing, translational medicine, and tissue engineering. Here, we report a novel differentiation protocol that results in the fast and efficient production of ECs and pericytes from keratinocyte-derived hiPSCs. We found that the implementation of a 3D embryoid body (EB) stage significantly improves the differentiation efficiency. Compared with the monolayer-based technique, our protocol yields a distinct EC population with higher levels of EC marker expression such as CD31 and vascular endothelial cadherin (VE-cadherin). Furthermore, the EB-based protocol allows the generation of functional EC and pericyte populations that can promote blood vessel-like structure formation upon co-culturing. Moreover, we demonstrate that the EB-based ECs and pericytes can be successfully used in a microfluidic chip model, forming a stable 3D microvascular network. Overall, the described protocol can be used to efficiently differentiate both ECs and pericytes with distinct and high marker expression from keratinocyte-derived hiPSCs, providing a potent source material for future cardiovascular disease studies.
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Project description:Prostate cancer (PCa) is one of the most prevalent cancers in men. Cancer stem cells are thought to be associated with PCa relapse. Here we show that BAZ2A is required for PCa cells with a cancer stem-like state. BAZ2A genomic occupancy in PCa cells coincides with H3K14ac enriched chromatin regions. This association is mediated by BAZ2A-bromodomain (BAZ2A-BRD) that specifically binds H3K14ac. BAZ2A associates with inactive enhancers marked by H3K14ac and repressing transcription of genes frequently silenced in aggressive and poorly differentiated PCa. BAZ2A-mediated repression is also linked to EP300 that acetylates H3K14ac. BAZ2A-BRD mutations or treatment with inhibitors abrogating BAZ2A-BRD/H3K14ac interaction impair PCa stem cells. Furthermore, pharmacological inactivation of BAZ2A-BRD impairs Pten-loss oncogenic transformation of prostate organoids. Our findings indicate a role of BAZ2A-BRD in PCa stem cell features and suggest potential epigenetic-reader therapeutic strategies to target BAZ2A in aggressive PCa.
| S-SCDT-EMBOR-2021-53014V1 | biostudies-other
Project description:Liver cancer is one of the most common malignant tumors in the world and metastasis is the leading cause of death associated with liver cancer. Hypoxia is a common feature of solid tumors and enhances malignant character of cancer cells. However, the exact mechanisms involved in hypoxia-driven liver cancer progression and metastasis have not been well clarified so far. The aim of this study was to investigate the contribution of long non-coding RNA (lncRNA) in hypoxia promoting liver cancer progression. We screened and revealed LINC00839 as a novel hypoxia-responsive lncRNA in liver cancer. LINC00839 expression was up-regulated in liver cancer tissues and cell lines, and the patients with high LINC00839 expression had shortened overall survival. LINC00839 further overexpressed under hypoxia and promoted liver cancer cell proliferation, migration, and invasion. Mechanistically, LINC00839 bound multiple proteins that were primarily associated with the metabolism and RNA transport, and positively regulated the expression of Formin-like protein 2 (FMNL2). LINC00839 could promote hypoxia-mediated liver cancer progression, suggesting it may be a clinically valuable biomarker and serve as a molecular target for the diagnosis, prognosis, and therapy of liver cancer.
| S-EPMC9637198 | biostudies-literature
Project description:Breast cancer stem cells (BCSCs) are the minor population of breast cancer (BC) cells that exhibit several phenotypes such as migration, invasion, self-renewal, and chemotherapy as well as radiotherapy resistance. Recently, BCSCs have been more considerable due to their capacity for recurrence of tumors after treatment. Recognition of signaling pathways and molecular mechanisms involved in stemness phenotypes of BCSCs could be effective for discovering novel treatment strategies to target BCSCs. This review introduces BCSC markers, their roles in stemness phenotypes, and the dysregulated signaling pathways involved in BCSCs such as mitogen-activated protein (MAP) kinase, PI3K/Akt/nuclear factor kappa B (NF?B), TGF-?, hedgehog (Hh), Notch, Wnt/?-catenin, and Hippo pathway. In addition, this review presents recently discovered molecular mechanisms implicated in chemotherapy and radiotherapy resistance, migration, metastasis, and angiogenesis of BCSCs. Finally, we reviewed the role of microRNAs (miRNAs) in BCSCs as well as several other therapeutic strategies such as herbal medicine, biological agents, anti-inflammatory drugs, monoclonal antibodies, nanoparticles, and microRNAs, which have been more considerable in the last decades.
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Project description:Adipocyte is the most predominant cell type in the tumor microenvironment of breast cancer and plays a pivotal role in cancer progression, yet the underlying mechanisms and functional mediators remain elusive. We isolated primary preadipocytes from mammary fat pads of human breast cancer patients and generated mature adipocytes and cancer-associated adipocytes (CAAs) in vitro. The CAAs exhibited significantly different gene expression profiles as assessed by transcriptome sequencing. One of the highly expressed genes in CAAs is granulocyte colony-stimulating factor (G-CSF). Treatment with recombinant human G-CSF protein or stable expression of human G-CSF in triple-negative breast cancer (TNBC) cell lines enhanced epithelial-mesenchymal transition, migration, and invasion of cancer cells, by activating Stat3. Accordantly, targeting G-CSF/Stat3 signaling with G-CSF-neutralizing antibody, a chemical inhibitor, or siRNAs for Stat3 could all abrogate CAA- or G-CSF-induced migration and invasion of breast cancer cells. The pro-invasive genes MMP2 and MMP9 were identified as target genes of G-CSF in TNBC cells. Furthermore, in human breast cancer tissues, elevated G-CSF expression in adipocytes is well correlated with activated Stat3 signal in cancer cells. Together, our results suggest a novel strategy to intervene with invasive breast cancers by targeting CAA-derived G-CSF.
| S-EPMC7749739 | biostudies-literature
Project description:BackgroundSpinal metastasis is a major challenge in patients with advanced lung cancer, but the mechanisms in the organotropism of metastasis are still unclear. Adipose-derived mesenchymal stem cells (ADSCs) exhibit cancer-promoting properties that influence the tumour microenvironment; however, there is no research on ADSCs from epidural fat thus far.MethodsIn this study, we isolated and identified ADSCs from epidural adipose tissue for the first time. We examined the activation of epidural ADSCs treated with lung cancer cell-conditioned medium by immunohistochemistry, western blot and qRT-PCR assays. The expression of interleukin (IL)-6 family cytokines in the supernatants of ADSCs were evaluated by enzyme-linked immunosorbent assay. The effects of epidural ADSCs on the growth and invasion of lung cancer cells were evaluated with the CCK-8 and Transwell assays. The expression of signal transducer and activator of transcription 3 (STAT3), matrix metalloprotease and epithelial-mesenchymal transition markers were measured by western blot assays.ResultsOur results showed that ADSCs treated with lung cancer cell-conditioned medium expressed higher levels of the myofibroblast marker α-smooth muscle actin and fibroblast activation protein than ADSCs cultured alone. Then, we found that lung cancer cells induced ADSCs to secrete high levels of IL-6 family cytokines and activate the STAT3 signalling pathway. Moreover, activated epidural ADSCs exhibited the ability to promote lung cancer cell proliferation and invasion by elevating matrix metalloprotease expression and epithelial-mesenchymal transition in cancer cells. Furthermore, blocking IL-6 can counteract the differentiation and tumour-promoting effects of ADSCs.ConclusionOur results suggest that ADSCs respond to lung cancer cells and are involved in the crosstalk between primary tumours and pre-metastatic niches in epidural fat.
| S-EPMC6567486 | biostudies-literature
Project description:BackgroundProstate cancer (PCa) is the second leading cause of cancer-related mortality among men worldwide, and its incidence has risen substantially in recent years. Therefore, there is an urgent need to identify novel biomarkers and precise therapeutic targets for managing PCa progression and recurrence.MethodsWe investigated the clinical significance of NCAPG2 in PCa by exploring public datasets and our tissue microarray. Receiver operating characteristic (ROC) curve and survival analyses were performed to evaluate the correlation between NCAPG2 and PCa progression. Cell proliferation, wound healing, transwell, flow cytometry, cell cycle, tumor sphere formation, immunofluorescence (IF), co-immunoprecipitation (co-IP), and chromatin immunoprecipitation (ChIP) assays were conducted to further elucidate the molecular mechanism of NCAPG2 in PCa. Subcutaneous and orthotopic xenograft models were applied to investigate the effects of NCAPG2 on PCa proliferation in vivo. Tandem mass tag (TMT) quantitative proteomics was utilized to detect proteomic changes under NCAPG2 overexpression.ResultsNCAPG2 was significantly upregulated in PCa, and its overexpression was associated with PCa progression and unfavorable prognosis. Knockdown of NCAPG2 inhibited the malignant behavior of PCa cells, whereas its overexpression promoted PCa aggressiveness. NCAPG2 depletion attenuated the development and growth of PCa in vivo. TMT quantitative proteomics analyses indicated that c-MYC activity was strongly correlated with NCAPG2 expression. The malignancy-promoting effect of NCAPG2 in PCa was mediated via c-MYC. NCAPG2 could directly bind to STAT3 and induce STAT3 occupancy on the MYC promoter, thus to transcriptionally activate c-MYC expression. Finally, we identified that NCAPG2 was positively correlated with cancer stem cell (CSC) markers and enhanced self-renewal capacity of PCa cells.ConclusionsNCAPG2 is highly expressed in PCa, and its level is significantly associated with PCa prognosis. NCAPG2 promotes PCa malignancy and drives cancer stemness via the STAT3/c-MYC signaling axis, highlighting its potential as a therapeutic target for PCa.
| S-EPMC10763290 | biostudies-literature