The significance of long non-coding RNAs (lncRNAs) in the development and progression of human cancers has attracted increasing attention in recent years of investigations. Having versatile interactions and diverse functions, lncRNAs can act as oncogenes or tumor-suppressors to actively regulate cell proliferation, survival, stemness, drug resistance, invasion and metastasis. LINC00467, an oncogenic member of long intergenic non-coding RNAs, is upregulated in numerous malignancies and its high expression is often related to poor clinicopathological features. LINC00467 facilitates the progression of cancer via sponging tumor-suppressive microRNAs, inhibiting cell death cascade, modulating cell cycle controllers, and regulating signalling pathways including AKT, STAT3, NF-κB and Wnt/β-catenin. A growing number of studies have revealed that LINC00467 may serve as a novel prognostic biomarker and its inhibitory targeting has a valuable therapeutic potential to suppress the malignant phenotypes of cancer cells. In the present review, we discuss the importance of LINC00467 and provide a comprehensive collection of its functions and molecular mechanisms in a variety of cancer types.
- MeSH
- beta-katenin genetika MeSH
- biologické markery MeSH
- karcinogeneze genetika MeSH
- lidé MeSH
- mikro RNA * genetika MeSH
- nádorové buněčné linie MeSH
- nádory * genetika MeSH
- NF-kappa B MeSH
- onkogeny genetika MeSH
- proliferace buněk genetika MeSH
- protoonkogenní proteiny c-akt genetika MeSH
- regulace genové exprese u nádorů MeSH
- RNA dlouhá nekódující * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND/AIM: Gliomas are primary malignancies of the central nervous system (CNS). High-grade gliomas are associated with poor prognosis and modest survival rates despite intensive multimodal treatment strategies. Targeting gene fusions is an emerging therapeutic approach for gliomas that allows application of personalized medicine principles. The aim of this study was to identify detectable fusion oncogenes that could serve as predictors of currently available or newly developed targeted therapeutics in cross-sectional samples from glioma patients using next-generation sequencing (NGS). PATIENTS AND METHODS: A total of 637 patients with glial and glioneuronal tumours of the CNS who underwent tumour resection between 2017 and 2020 were enrolled. Detection of fusion transcripts in FFPE tumour tissue was performed by a TruSight Tumour 170 assay and two FusionPlex kits, Solid Tumour and Comprehensive Thyroid and Lung. RESULTS: Oncogene fusions were identified in 33 patients. The most common fusion was the KIAA1549-BRAF fusion, detected in 13 patients, followed by FGFR fusions (FGFR1-TACC1, FGFR2-CTNNA3, FGFR3-TACC3, FGFR3-CKAP5, FGFR3-AMBRA1), identified in 10 patients. Other oncogene fusions were also infrequently diagnosed, including MET fusions (SRPK2-MET and PTPRZ1-MET) in 2 patients, C11orf95-RELA fusions in 2 patients, EGFR-SEPT14 fusion in 2 patients, and individual cases of SRGAP3-BRAF, RAF1-TRIM2, EWSR1-PALGL1 and TERT-ALK fusions. CONCLUSION: The introduction of NGS techniques provides additional information about tumour molecular alterations that can aid the multimodal management of glioma patients. Patients with gliomas positive for particular targetable gene fusions may benefit from experimental therapeutics, enhancing their quality of life and prolonging survival rates.
- MeSH
- adaptorové proteiny signální transdukční genetika MeSH
- gliom * genetika patologie MeSH
- kvalita života MeSH
- lidé MeSH
- onkogenní fúze * MeSH
- onkogeny genetika MeSH
- protein-serin-threoninkinasy MeSH
- proteiny asociované s mikrotubuly genetika MeSH
- průřezové studie MeSH
- tyrosinfosfatasy receptorového typu, třída 5 genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Cystic fibrosis (CF) is a monogenetic disease resulting from mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene encoding an anion channel. Recent evidence indicates that CFTR plays a role in other cellular processes, namely in development, cellular differentiation and wound healing. Accordingly, CFTR has been proposed to function as a tumour suppressor in a wide range of cancers. Along these lines, CF was recently suggested to be associated with epithelial-mesenchymal transition (EMT), a latent developmental process, which can be re-activated in fibrosis and cancer. However, it is unknown whether EMT is indeed active in CF and if EMT is triggered by dysfunctional CFTR itself or a consequence of secondary complications of CF. In this study, we investigated the occurrence of EMT in airways native tissue, primary cells and cell lines expressing mutant CFTR through the expression of epithelial and mesenchymal markers as well as EMT-associated transcription factors. Transepithelial electrical resistance, proliferation and regeneration rates, and cell resistance to TGF-β1induced EMT were also measured. CF tissues/cells expressing mutant CFTR displayed several signs of active EMT, namely: destructured epithelial proteins, defective cell junctions, increased levels of mesenchymal markers and EMT-associated transcription factors, hyper-proliferation and impaired wound healing. Importantly, we found evidence that the mutant CFTR triggered EMT was mediated by EMT-associated transcription factor TWIST1. Further, our data show that CF cells are over-sensitive to EMT but the CF EMT phenotype can be reversed by CFTR modulator drugs. Altogether, these results identify for the first time that EMT is intrinsically triggered by the absence of functional CFTR through a TWIST1 dependent mechanism and indicate that CFTR plays a direct role in EMT protection. This mechanistic link is a plausible explanation for the high incidence of fibrosis and cancer in CF, as well as for the role of CFTR as tumour suppressor protein.
- MeSH
- cystická fibróza metabolismus patologie MeSH
- epitelo-mezenchymální tranzice MeSH
- HEK293 buňky MeSH
- jaderné proteiny metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- onkogeny genetika MeSH
- protein CFTR metabolismus MeSH
- transkripční faktor Twist metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cell growth requires a high level of protein synthesis and oncogenic pathways stimulate cell proliferation and ribosome biogenesis. Less is known about how cells respond to dysfunctional mRNA translation and how this feeds back into growth regulatory pathways. The Epstein-Barr virus (EBV)-encoded EBNA1 causes mRNA translation stress in cis that activates PI3Kδ. This leads to the stabilization of MDM2, induces MDM2's binding to the E2F1 mRNA and promotes E2F1 translation. The MDM2 serine 166 regulates the interaction with the E2F1 mRNA and deletion of MDM2 C-terminal RING domain results in a constitutive E2F1 mRNA binding. Phosphorylation on serine 395 following DNA damage instead regulates p53 mRNA binding to its RING domain and prevents the E2F1 mRNA interaction. The p14Arf tumour suppressor binds MDM2 and in addition to preventing degradation of the p53 protein it also prevents the E2F1 mRNA interaction. The data illustrate how two MDM2 domains selectively bind specific mRNAs in response to cellular conditions to promote, or suppress, cell growth and how p14Arf coordinates MDM2's activity towards p53 and E2F1. The data also show how EBV via EBNA1-induced mRNA translation stress targets the E2F1 and the MDM2 - p53 pathway.
- MeSH
- buněčný cyklus genetika MeSH
- fosforylace genetika MeSH
- karcinogeneze genetika MeSH
- lidé MeSH
- messenger RNA genetika MeSH
- nádorový supresorový protein p14ARF genetika MeSH
- nádorový supresorový protein p53 genetika MeSH
- nádory genetika virologie MeSH
- onkogeny genetika MeSH
- poškození DNA genetika MeSH
- proliferace buněk genetika MeSH
- proteinové domény genetika MeSH
- protoonkogenní proteiny c-mdm2 genetika MeSH
- RRM proteiny genetika MeSH
- transkripční faktor E2F1 genetika MeSH
- tumor supresorové geny MeSH
- virus Epsteinův-Barrové genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Uterine leiomyosarcomas (uLMS) are rare, aggressive malignancies for which limited treatment options are available. To gain novel molecular insights into uLMS and identify potential novel therapeutic targets, we characterized 84 uLMS samples for genome-wide somatic copy number alterations, mutations, gene fusions and gene expression and performed a data integration analysis. We found that alterations affecting TP53, RB1, PTEN, MED12, YWHAE and VIPR2 were present in the majority of uLMS. Pathway analyses additionally revealed that the PI3K/AKT/mTOR, estrogen-mediated S-phase entry and DNA damage response signaling pathways, for which inhibitors have already been developed and approved, frequently harbored genetic changes. Furthermore, a significant proportion of uLMS was characterized by amplifications and overexpression of known oncogenes (CCNE1, TDO2), as well as deletions and reduced expression of tumor suppressor genes (PTEN, PRDM16). Overall, it emerged that the most frequently affected gene in our uLMS samples was VIPR2 (96%). Interestingly, VIPR2 deletion also correlated with unfavorable survival in uLMS patients (multivariate analysis; HR = 4.5, CI = 1.4-14.3, p = 1.2E-02), while VIPR2 protein expression was reduced in uLMS vs. normal myometrium. Moreover, stimulation of VIPR2 with its natural agonist VIP decreased SK-UT-1 uLMS cell proliferation in a dose-dependent manner. These data suggest that VIPR2, which is a negative regulator of smooth muscle cell proliferation, might be a novel tumor suppressor gene in uLMS. Our work further highlights the importance of integrative molecular analyses, through which we were able to uncover the genes and pathways most frequently affected by somatic alterations in uLMS.
- MeSH
- dospělí MeSH
- genomika metody MeSH
- Kaplanův-Meierův odhad MeSH
- karcinogeneze genetika MeSH
- leiomyosarkom genetika mortalita patologie terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- myometrium patologie MeSH
- nádory dělohy genetika mortalita patologie terapie MeSH
- onkogeny genetika MeSH
- proliferace buněk genetika MeSH
- receptory vazoaktivního intestinálního peptidu typu II genetika MeSH
- regulace genové exprese u nádorů genetika MeSH
- sekvenční analýza RNA metody MeSH
- sekvenování celého genomu metody MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- signální transdukce genetika MeSH
- tumor supresorové geny MeSH
- vysoce účinné nukleotidové sekvenování metody MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- bronchogenní karcinom * epidemiologie etiologie genetika MeSH
- karcinogeny životního prostředí MeSH
- kouření MeSH
- lidé MeSH
- nádorové supresorové proteiny metabolismus MeSH
- onkogeny genetika MeSH
- pracovní expozice MeSH
- tumor supresorové geny MeSH
- vystavení vlivu životního prostředí MeSH
- Check Tag
- lidé MeSH
- MeSH
- bazocelulární nádory genetika MeSH
- intracelulární signální peptidy a proteiny biosyntéza metabolismus MeSH
- kožní T-buněčný lymfom genetika klasifikace MeSH
- lidé MeSH
- MAP kinasový signální systém fyziologie genetika MeSH
- melanom genetika MeSH
- Merkelův nádor genetika MeSH
- nádorová transformace buněk genetika metabolismus patologie MeSH
- nádory kožních adnex genetika MeSH
- nádory kůže * genetika patofyziologie MeSH
- nádory ze svalové tkáně genetika klasifikace MeSH
- onkogeny genetika MeSH
- protoonkogeny genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Esophageal cancer is a malignant disease with poor prognosis, increasing incidence, and ineffective treatment options. MicroRNAs are post-transcriptional regulators of gene expression involved in many biological processes including carcinogenesis. We determined miR-205 expression levels in tumor/non-tumor tissues of 45 esophageal cancer patients using qPCR and found that decreased level of miR-205 in tumor tissue correlates with poor overall survival in esophageal adenocarcinoma patients. Further, we observed significantly higher levels of miR-205 in tumor tissue of esophageal squamous cell carcinoma. Ectopic overexpression of miR-205 in adenocarcinoma cell line SK-GT-4 led to decreased cell proliferation, cell cycle arrest in G1, and decreased migration ability. Conversely, in squamous cell line KYSE-150, same effects like inhibition of proliferation, migration, and colony-forming potential and cell cycle arrest in G2 were observed after silencing of miR-205. We performed global gene expression profiling and revealed that suppressive functioning of miR-205 in adenocarcinoma could be realized through regulation of epithelial-mesenchymal transition (EMT), whereas oncogenic in squamous cell carcinoma by regulation of metalloproteinase 10. Our results suggest that miR-205 could serve as biomarker in esophageal cancer and acts as a tumor suppressor in esophageal adenocarcinoma and oncogene in esophageal squamous cell carcinoma.
- MeSH
- adenokarcinom genetika metabolismus patologie MeSH
- apoptóza genetika MeSH
- buněčný cyklus genetika MeSH
- dospělí MeSH
- epitelo-mezenchymální tranzice genetika MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA fyziologie MeSH
- míra přežití MeSH
- nádorové buněčné linie MeSH
- nádory jícnu genetika metabolismus patologie MeSH
- onkogeny genetika MeSH
- pohyb buněk genetika MeSH
- proliferace buněk genetika MeSH
- regulace genové exprese u nádorů fyziologie MeSH
- senioři MeSH
- spinocelulární karcinom genetika metabolismus patologie MeSH
- stanovení celkové genové exprese MeSH
- tumor supresorové geny MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Východiska: Epiteliální ovariální karcinomy jsou v české populaci jednou z nejčastějších příčin úmrtí na gynekologické malignity. Tato skupina nádorů je charakterizována značnou heterogenitou jak z hlediska její patogeneze, tak i odpovědí na terapii. Je otázkou, zda pokroky v objasnění molekulární patogeneze jednotlivých typů epiteliálních ovariálních karcinomů mohou v budoucnu přispět k aplikaci cílené personalizované léčby. Cíle: Tato práce se snaží shrnout současné poznatky o kancerogenezi a molekulární podstatě epiteliálních nádorů ovaria a ukázat na možné využití těchto poznatků v klinické praxi. Pro základní charakterizaci epiteliálních ovariálních karcinomů je využit dualistický model, který rozděluje tyto nádory do dvou skupin na základě odlišného původu a mechanizmu kancerogeneze. Typ I zahrnuje low-grade serózní karcinomy, endometrioidní karcinomy, mucinózní karcinomy a Brennerův tumor, typ II pak high-grade serózní karcinomy. Závěr: Nově získané poznatky získané sekvenováním nové generace ukazují zásadní odlišnosti v genetických alteracích u obou skupin nádorů. Rozdíly v genetické nestabilitě mezi oběma skupinami nádorů určují způsob jejich kancerogeneze a poukazují na nové cesty pro aplikaci cílené terapie. Porucha homologní rekombinace a vysoká genetická nestabilita u nádorů typu II je hlavní příčinou jejich senzitivity k platinovým cytostatikům a inhibitorům PARP (poly-ADP ribose polymerase). Na druhou stranu karcinogeneze méně agresivních, ale často rezistentních nádorů typu I je závislá na aktivaci signalizačních drah PI3K/AKT a RAS/BRAF/MEK/ERK. Cílená inhibice těchto drah u nádorů typu I by tak v budoucnu mohla představovat efektivnější terapii s nižší toxicitou.
Background: Epithelial ovarian carcinomas are one of the most common causes of death among gynecologic malignancies in the Czech population. This group of tumors is characterized by considerable heterogeneity in terms of its pathogenesis and response to therapy. It is questionable whether advances in the elucidation of molecular pathogenesis of various types of epithelial ovarian carcinomas can contribute to application of personalized targeted therapy. Aims: This work aims to summarize current knowledge on carcinogenesis and molecular basis of epithelial ovarian cancers and point out their potential applications in clinical practice. The characterization of the epithelial ovarian carcinomas is based on a dualistic model, which divides these tumors into two groups based on their different origins and mechanisms of carcinogenesis. Type I includes low-grade serous carcinomas, endometrioid carcinomas, mucinous carcinomas and Brenner tumor. Type II then comprises high-grade serous carcinomas. Conclusion: The new findings acquired by next generation sequencing revealed major differences in the genetic alterations in both groups of tumors. Differences in genetic instability between the two groups of tumors determine the mechanisms of their carcinogenesis and show new ways for application of targeted therapy. Deficient homologous recombination and high genetic instability in type II tumors is a prerequisite for efficient application of platinum cytostatics and PARP (poly-ADP ribose polymerase) inhibitors. On the other hand, carcinogenesis of the less aggressive, but often resistant type I tumous is dependent on the activation of signaling pathways PI3K/AKT and RAS/BRAF/MEK/ERK pathway. Targeted inhibition of these pathways could efficiently improve therapy of type I tumors and decrease serious adverse side effects.
- MeSH
- genetická heterogenita MeSH
- lidé MeSH
- mucinózní adenokarcinom diagnóza patologie MeSH
- nádorová transformace buněk genetika patologie MeSH
- nádory endometria patologie MeSH
- nádory vaječníků * diagnóza klasifikace patologie MeSH
- onkogeny fyziologie genetika MeSH
- poruchy opravy DNA genetika patologie MeSH
- protein BRCA1 fyziologie MeSH
- protein BRCA2 fyziologie MeSH
- proteiny regulující apoptózu fyziologie genetika MeSH
- transkripční faktory fyziologie genetika MeSH
- tyrosinkinasy fyziologie genetika MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
