EMT-epithelial to mesenchymal transition
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PURPOSE: Docetaxel resistance is a significant obstacle in the treatment of prostate cancer (PCa), resulting in unfavorable patient prognoses. Intratumoral heterogeneity, often associated with epithelial-to-mesenchymal transition (EMT), has previously emerged as a phenomenon that facilitates adaptation to various stimuli, thus promoting cancer cell diversity and eventually resistance to chemotherapy, including docetaxel. Hence, understanding intratumoral heterogeneity is essential for better patient prognosis and the development of personalized treatment strategies. METHODS: To address this, we employed a high-throughput single-cell flow cytometry approach to identify a specific surface fingerprint associated with docetaxel-resistance in PCa cells and complemented it with proteomic analysis of extracellular vesicles. We further validated selected antigens using docetaxel-resistant patient-derived xenografts in vivo and probed primary PCa specimens to interrogate of their surface fingerprint. RESULTS: Our approaches revealed a 6-molecule surface fingerprint linked to docetaxel resistance in primary PCa specimens. We observed consistent overexpression of CD95 (FAS/APO-1), and SSEA-4 surface antigens in both in vitro and in vivo docetaxel-resistant models, which was also observed in a cell subpopulation of primary PCa tumors exhibiting EMT features. Furthermore, CD95, along with the essential enzymes involved in SSEA-4 synthesis, ST3GAL1, and ST3GAL2, displayed a significant increase in patients with PCa undergoing docetaxel-based therapy, correlating with poor survival outcomes. CONCLUSION: In summary, we demonstrate that the identified 6-molecule surface fingerprint associated with docetaxel resistance pre-exists in a subpopulation of primary PCa tumors before docetaxel treatment. Thus, this fingerprint warrants further validation as a promising predictive tool for docetaxel resistance in PCa patients prior to therapy initiation.
- MeSH
- chemorezistence * MeSH
- docetaxel * farmakologie terapeutické užití MeSH
- epitelo-mezenchymální tranzice účinky léků MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory prostaty * patologie farmakoterapie metabolismus MeSH
- protinádorové látky farmakologie terapeutické užití MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
From tumorigenesis to the establishment of local or metastatic high-grade tumours, an integral part of the cellular lifespan relies on various signalling pathways. Particular pathways that allow cells to proliferate by creating a network of new blood vessels have been documented, whereas other pathways are primarily involved with a migration to distant body parts, partially through the process of epithelial-mesenchymal transition (EMT). This review will discuss the different signalling pathways, such as TGF-β, Cripto-1, Wnt pathways, Hedgehog, Notch and NF-κB pathways, and how they promote tumour initiation and progression by influencing diverse cellular processes and EMT in general and in benign and malignant prostate tumours. This review will discuss only the critical pathways. Therefore, many other types of signalling pathways which are related to prostate cancer will not be discussed. Possibilities for further investigation will be mentioned, as many underlying mechanisms involved in these pathways have potential as targets in future tumour therapy. This review will also introduce some novel clinical trials relating to the inhibition of signalling pathways and their clinical outcomes.
- MeSH
- epitelo-mezenchymální tranzice fyziologie MeSH
- lidé MeSH
- nádory prostaty * patologie metabolismus terapie farmakoterapie MeSH
- NF-kappa B metabolismus MeSH
- proteiny hedgehog metabolismus MeSH
- signální transdukce * fyziologie MeSH
- transformující růstový faktor beta metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
PURPOSE: To document the expression of apical-basal polarity (ABP) determinants in the mouse corneal epithelium (CE) and elucidate the functions of Pard3 in establishment and maintenance of ABP, stratification, homeostasis, and barrier function in the CE. METHODS: Pard3Δ/ΔC mice (Pard3LoxP/LoxP; Aldh3A1-Cre/+) with cornea-specific Pard3 ablation were generated by breeding Aldh3A1-Cre/+ with Pard3LoxP/LoxP mice. The control (Aldh3A1-Cre/+ or Pard3LoxP/LoxP alone) and Pard3Δ/ΔC corneal histology, ocular surface properties, barrier function, and actin cytoskeleton were assessed by Haematoxylin and Eosin staining of paraformaldehyde-fixed, paraffin-embedded tissues, scanning electron microscopy, fluorescein staining, and phalloidin staining, respectively. The expression of specific markers of interest was evaluated by qRT-PCR, immunoblots and immunofluorescent staining. RESULTS: Dynamic changes were observed in the expression and localization of ABP determinants as the CE stratified and matured between post-natal day 5 (PN5) and PN52. Adult Pard3Δ/ΔC CE contained fewer cell layers with rounded basal cells, and loosely adherent superficial cells lacking microplicae. Adult Pard3Δ/ΔC CE also displayed impaired barrier function with decreased expression of tight junction, adherens junction, and desmosome components, disrupted actin cytoskeletal organization, increased proliferation, and upregulation of transcription factors that drive epithelial-mesenchymal transition (EMT). CONCLUSIONS: Disruption of ABP in Pard3Δ/ΔC CE, altered expression of cell junction complex components and disorganized actin cytoskeleton, increased cell proliferation, and upregulated EMT transcription factors suggest that the ABP-determinant Pard3 promotes CE features while suppressing mesenchymal cell fate. Collectively, these results elucidate that Pard3-mediated ABP is essential for CE stratification, homeostasis and barrier function.
- MeSH
- adaptorové proteiny signální transdukční * MeSH
- cytoskelet * metabolismus MeSH
- homeostáza fyziologie MeSH
- mikroskopie elektronová rastrovací MeSH
- myši MeSH
- polarita buněk * fyziologie MeSH
- rohovkový epitel * metabolismus ultrastruktura MeSH
- těsný spoj * metabolismus fyziologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Biological mechanisms related to cancer development can leave distinct molecular fingerprints in tumours. By leveraging multi-omics and epidemiological information, we can unveil relationships between carcinogenesis processes that would otherwise remain hidden. Our integrative analysis of DNA methylome, transcriptome, and somatic mutation profiles of kidney tumours linked ageing, epithelial-mesenchymal transition (EMT), and xenobiotic metabolism to kidney carcinogenesis. Ageing process was represented by associations with cellular mitotic clocks such as epiTOC2, SBS1, telomere length, and PBRM1 and SETD2 mutations, which ticked faster as tumours progressed. We identified a relationship between BAP1 driver mutations and the epigenetic upregulation of EMT genes (IL20RB and WT1), correlating with increased tumour immune infiltration, advanced stage, and poorer patient survival. We also observed an interaction between epigenetic silencing of the xenobiotic metabolism gene GSTP1 and tobacco use, suggesting a link to genotoxic effects and impaired xenobiotic metabolism. Our pan-cancer analysis showed these relationships in other tumour types. Our study enhances the understanding of kidney carcinogenesis and its relation to risk factors and progression, with implications for other tumour types.
- MeSH
- DNA vazebné proteiny genetika metabolismus MeSH
- epigeneze genetická MeSH
- epitelo-mezenchymální tranzice * genetika MeSH
- glutathion-S-transferasa fí genetika metabolismus MeSH
- histonlysin-N-methyltransferasa genetika metabolismus MeSH
- karcinogeneze * genetika MeSH
- lidé MeSH
- metylace DNA * MeSH
- multiomika MeSH
- mutace * MeSH
- nádorové supresorové proteiny genetika metabolismus MeSH
- nádory ledvin * genetika patologie MeSH
- regulace genové exprese u nádorů MeSH
- stárnutí genetika MeSH
- thiolesterasa ubikvitinu MeSH
- transkripční faktory genetika metabolismus MeSH
- transkriptom MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Hepatocellular carcinoma (HCC) is primary liver cancer, frequently diagnosed at advanced stages with limited therapeutic options. MicroRNAs (miRNAs) regulate target gene expression and through inhibitory competitive binding of miRNA influence cellular processes including carcinogenesis. Extensive evidence proved that certain miRNA's are specifically expressed in neoplastic tissues of HCC patients and are confirmed as important factors that can participate in the regulation of key signalling pathways in cancer cells. As such, miRNAs have a great potential in the clinical diagnosis and treatment of HCC and can improve the limitations of standard diagnosis and treatment. Long non-coding RNAs (lncRNAs) have a critical role in the development and progression of HCC. HCC-related lncRNAs have been demonstrated to exhibit abnormal expression and contribute to transformation process (such as proliferation, apoptosis, accelerated vascular formation, and gain of invasive potential) through their interaction with DNA, RNA, or proteins. LncRNAs can bind mRNAs to release their target mRNA and enable its translation. These lncRNA-miRNA networks regulate cancer cell expression and so its proliferation, apoptosis, invasion, metastasis, angiogenesis, epithelial-mesenchymal transition (EMT), drug resistance, and autophagy. In this narrative review, we focus on miRNA and lncRNA in HCC tumor tissue and their interaction as current tools, and biomarkers and therapeutic targets unravelled in recent years.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The endothelial-mesenchymal transition (EndMT) of endothelial progenitor cells (EPCs) plays a notable role in pathological vascular remodeling. Emerging evidence indicated that long non-coding RNA-regulator of reprogramming (linc-ROR) can promote epithelial-mesenchymal transition (EMT) in a variety of cancer cells. Nevertheless, the function of linc-ROR in EPC EndMT has not been well elucidated. The present study investigated the effect and possible mechanisms of function of linc-ROR on the EndMT of EPCs. A linc-ROR overexpression lentiviral vector (LV linc-ROR) or a linc-ROR short hairpin RNA lentiviral vector (LV-shlinc-ROR) was used to up or downregulate linc-ROR expression in EPCs isolated from human umbilical cord blood. Functional experiments demonstrated that LV-linc-ROR promoted the proliferation and migration of EPCs, but inhibited EPC angiogenesis in vitro. In the meantime, reverse transcription-quantitative PCR and western blotting results showed that the expression of the endothelial cell markers vascular endothelial-cadherin and CD31 was decreased, while the expression of the mesenchymal cell markers ?-smooth muscle actin and SM22? was increased at both mRNA and protein levels in LV-linc-ROR-treated EPCs, indicating that linc-ROR induced EPC EndMT. Mechanistically, the dual-luciferase reporter assay demonstrated that microRNA (miR/miRNA)-145 was a direct target of linc-ROR, and miR-145 binds to the 3'-untranslated region of Smad3. Moreover, LV-shlinc-ROR increased the expression of miR-145, but decreased the expression of Smad3. In conclusion, linc-ROR promotes EPC EndMT, which may be associated with the miR-145/Smad3 signaling pathway. Keywords: Endothelial progenitor cells, Endothelial to mesenchymal transition, Linc-ROR, MiR-145, Atherosclerosis.
- MeSH
- endotel-mezenchymální transformace MeSH
- endoteliální progenitorové buňky * metabolismus MeSH
- epitelo-mezenchymální tranzice * MeSH
- kultivované buňky MeSH
- lidé MeSH
- mikro RNA * metabolismus genetika MeSH
- pohyb buněk fyziologie MeSH
- proliferace buněk MeSH
- protein Smad3 * metabolismus genetika MeSH
- RNA dlouhá nekódující * genetika metabolismus MeSH
- signální transdukce * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Východiska: N-myc downstream-regulovaný gen 1 (NDRG1) má významnou funkci při progresi nádorů. U karcinomu prostaty (prostate cancer – PCa) však regulační mechanizmus NDRG1 zůstává nejasný. Materiál a metody: Hladiny exprese miR-96-5p a NDRG1 byly hodnoceny v buněčných liniích PCa a v tkáních prostaty a validovány ve veřejných databázích pomocí polymerázové řetězové reakce v reálném čase, analýzy western blot a imunohistochemie. Funkce miR-96-5p a NDRG1 byla zkoumána pomocí testů hojení ran a transwell testů in vitro a testu myšího xenoimplantátu in vivo. Dráha regulovaná pomocí NDRG1 byla testována technikou sekvenování nové generace. K detekci vztahu mezi miR-96-5p, NDRG1 a NF-kB dráhou byl použit imunofluorescenční test a test s luciferázou. Výsledky: Nadměrná exprese NDRG1 potlačuje migraci, invazi a epiteliálně-mezenchymální přechod (EMT) in vitro a inhibuje metastázy in vivo. Navíc miR-96-5p přispívá k deficitu NDRG1 a podporuje migraci a invazi buněk PCa. Kromě toho ztráta NDRG1 aktivuje dráhu NF-kB, která stimuluje fosforylaci p65 a IKBa a indukuje EMT v PCa. Závěr: MiR-96-5p podporuje migraci a invazi PCa tím, že cílí na NDRG1 a reguluje dráhu NF-kB.
Background: The N-myc downstream-regulated gene 1 (NDRG1) has been discovered as a significant gene in the progression of cancers. However, the regulatory mechanism of NDRG1 remained obscure in prostate cancer (PCa). Methods: The miR-96-5p and NDRG1 expression levels were evaluated in PCa cell lines, and prostate tissues, and validated in public databases by real-time polymerase chain reaction, western blot analysis, and immunohistochemistry. The function of miR-96-5p and NDRG1 were investigated by scratch assay and transwell assays in vitro, and mouse xenograft assay in vivo. The candidate pathway regulated by NDRG1 was conducted by the next-generation gene sequencing technique. Immunofluorescence and luciferase assays were used to detect the relation between miR-96-5p, NDRG1, and NF-kB pathway. Results: Overexpressing NDRG1 suppresses the migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, and inhibits metastasis in vivo. Moreover, miR-96-5p contributes to NDRG1 deficiency and promotes PCa cell migration and invasion. Furthermore, NDRG1 loss activates the NF-kB pathway, which stimulates p65 and IKBa phosphorylation and induces EMT in PCa. Conclusions: MiR-96-5p promotes the migration and invasion of PCa by targeting NDRG1 and regulating the NF-kB pathway.
- Klíčová slova
- NDRG1, miR-96-5p,
- MeSH
- epitelo-mezenchymální tranzice MeSH
- genetické techniky MeSH
- imunohistochemie metody MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory prostaty * genetika patofyziologie MeSH
- NF-kappa B * MeSH
- pohyb buněk MeSH
- polymerázová řetězová reakce metody MeSH
- sekvenční analýza MeSH
- signální transdukce MeSH
- transfekce metody MeSH
- western blotting metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- klinická studie MeSH
TGFβ has roles in inflammation, wound healing, epithelial to mesenchymal transition (EMT), and cancer stem cell states, and acts as a tumor suppressor gene for squamous cell carcinoma (SCC). SCCs are also characterized by high levels of ΔNp63, which induces epithelial cell phenotypes and maintains squamous stem cells. Previous studies indicate a complex interplay between ΔNp63 and TGFβ signaling, with contradictory effects reported. We investigated the effects of TGFβ on p63 isoform proteins and mRNAs in non-malignant squamous and SCC cells, and the role of either canonical or non-canonical TGFβ signaling pathways. TGFβ selectively increased ΔNp63 protein levels in non-malignant keratinocytes in association with SMAD3 activation and was prevented by TGFβ receptor inhibition, indicating activation of canonical TGFβ pathway signaling. TP63 isoform mRNAs showed discordance from protein levels, with an initial increase in both TAP63 and ΔNP63 mRNAs followed by a decrease at later times. These data demonstrate complex and heterogeneous effects of TGFβ in squamous cells that depend on the extent of canonical TGFβ pathway aberrations. The interplay between TGFβ and p63 is likely to influence the magnitude of EMT states in SCC, with clinical implications for tumor progression and response to therapy.
The role of benzo[a]pyrene (BaP), a prominent genotoxic carcinogen and aryl hydrocarbon receptor (AhR) ligand, in tumor progression remains poorly characterized. We investigated the impact of BaP on the process of epithelial-mesenchymal transition (EMT) in normal human bronchial epithelial HBEC-12KT cells. Early morphological changes after 2-week exposure were accompanied with induction of SERPINB2, IL1, CDKN1A/p21 (linked with cell cycle delay) and chemokine CXCL5. After 8-week exposure, induction of cell migration and EMT-related pattern of markers/regulators led to induction of further pro-inflammatory cytokines or non-canonical Wnt pathway ligand WNT5A. This trend of up-regulation of pro-inflammatory genes and non-canonical Wnt pathway constituents was observed also in the BaP-transformed HBEC-12KT-B1 cells. In general, transcriptional effects of BaP differed from those of TGFβ1, a prototypical EMT inducer, or a model non-genotoxic AhR ligand, TCDD. Carcinogenic polycyclic aromatic hydrocarbons could thus induce a unique set of molecular changes linked with EMT and cancer progression.
- MeSH
- benzopyren * toxicita MeSH
- epitelové buňky * metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- poškození DNA MeSH
- receptory aromatických uhlovodíků genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Východiska: Triple-negativní karcinomy prsu (TNBC) jsou heterogenní skupinou nádorů s převážně agresivním chováním a špatnou prognózou. V souvislosti s jejich agresivním chováním a chemorezistencí vůči léčbě se do popředí dostal koncept epitelo-mezenchymové tranzice (EMT). Proteiny CD9 a CD29 jsou spojeny s EMT a mohou hrát roli v progresi TNBC. Naším cílem bylo prozkoumat asociaci těchto markerů s metastázami do lymfatických uzlin, gradingem tumoru, proliferační aktivitou a přežitím pacientů. Pacienti a metody: Náš soubor tvořilo 66 pacientek s TNBC bez neoadjuvantní terapie ve věku 26–81 let. Patologické stadium nádoru se pohybovalo od pT1b do pT3 a histologický stupeň od II do III podle systému Bloom-Richardson. Imunohistochemické hodnocení exprese CD9, CD29, E-cadherinu, vimentinu, androgenového receptoru a Ki-67 bylo provedeno semikvantitativně pomocí H-skóre. Exprese proteinů byla statisticky hodnocena ve vztahu ke klinicko-patologickým parametrům a přežití pacientů. Výsledky: Pozorovali jsme nižší expresi CD9 v metastázách lymfatických uzlin ve srovnání s primárním nádorem (p = 0,021). Exprese CD29 v primárním nádoru byla signifikantně nižší u pacientů s metastázami v lymfatických uzlinách ve srovnání s pacienty bez diseminace (p = 0,03). Ani exprese CD9 ani CD29 proteinu nebyla spojena s přežitím specifickým pro karcinom prsu (BCSS). Nižší exprese E-cadherinu na periferii primárního tumoru byla spojena s horším BCSS (p = 0,038). Pro grading ani přítomnost metastáz v lymfatických uzlinách nebyl nalezen signifikantní vztah s BCSS. Nižší exprese E-cadherinu na periferii byla také spojena s vyšší hladinou Ki67 (Rs −0,26) a vimentinu (Rs −0,33). Závěr: Snížená exprese proteinů CD9 a CD29 byla spojena s růstem metastáz v lymfatických uzlinách, avšak jejich souvislost s přežitím nebyla prokázána. Nižší exprese E-cadherinu na periferii primárního nádoru byla spojena s vysokou proliferací a špatným nádorově specifickým přežitím.
Background: Triple-negative breast carcinomas (TNBC) are a heterogeneous group of tumors with mostly aggressive behaviour and poor prognosis. In association with their aggressive behavior and chemoresistance to treatment, the concept of epithelial-mesenchymal transition (EMT) has come to the fore. CD9 and CD29 proteins are associated with EMT and may play a role in TNBC progression. Our aim was to investigate association of these markers with the lymph node metastasis, tumor grade, proliferative activity, and patient survival. Patients and methods: Our cohort consisted of 66 TNBC patients without neoadjuvant therapy, aged 26–81 years. The pathological tumor stages ranged from pT1b to pT3 and histological grades ranged from II to III, according to the Bloom-Richardson system. Immunohistochemical evaluation of CD9, CD29, E-cadherin, vimentin, androgen receptor and Ki-67 expression was performed semiquantitatively using the H-score. Expression of the proteins was statistically evaluated in relation to the clinicopathological parameters and survival of the patients. Results: We observed lower expression of CD9 in lymph node metastases compared to the primary tumor (P = 0.021). The CD29 expression in primary tumor was significantly lower in patients with lymph node metastases compared to patients without cancer dissemination (P = 0.03). Neither CD9 nor CD29 protein expression was associated with breast cancer-specific survival (BCSS). Lower expression of E-cadherin at the periphery of the primary tumor was associated with worse BCSS (P = 0.038). Neither grade nor the presence of lymph node metastases reached significant association with the BCSS. Lower expression of E-cadherin at the periphery was also associated with higher Ki67 (Rs −0.26) and vimentin (Rs −0.33). Conclusion: Decreased protein expression of CD9 and CD29 were associated with lymph node metastasis growth, however, their association with survival was not proved. Lower expression of E-cadherin at the periphery of the primary tumor was associated with high proliferation and poor breast cancer-specific survival.
- MeSH
- antigeny CD29 analýza MeSH
- antigeny CD9 analýza MeSH
- epitelo-mezenchymální tranzice imunologie MeSH
- imunohistochemie * metody MeSH
- kadheriny analýza MeSH
- kohortové studie MeSH
- lidé MeSH
- lymfatické metastázy diagnostické zobrazování imunologie MeSH
- prognóza MeSH
- triple-negativní karcinom prsu * diagnostické zobrazování imunologie sekundární MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
