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
Inzulinu podobný růstový faktor 2 patří, spolu s několika dalšími inzulinu podobnými peptidy, do evolučně konzervované rodiny signalizačních molekul, které jsou nezbytné pro normální buněčnou proliferaci a vývoj mozku. Dřívější studie se zaměřovaly převážně na jeho úlohu v embryonálním vývoji a kancerogenezi. V posledních letech byly odhaleny nové poznatky týkající se role inzulinu podobného růstového faktoru 2 v centrální nervové soustavě, zejména jeho význam pro učení, konsolidaci paměti a zlepšení kognitivních funkcí. I přes stále ne zcela prozkoumanou fyziologickou roli inzulinu podobného růstového faktoru 2 se v našem článku snažíme podrobněji popsat a vysvětlit jeho známé funkce a diskutovat jeho potenciální využití, včetně možné aplikace v léčbě neurodegenerativních onemocnění.
Insulin-like growth factor 2 (IGF2), along with several other insulin-like peptides, belongs to an evolutionarily conserved family of signalling molecules essential for normal cell proliferation and brain development. Previous studies have mainly focused on its role in embryonic development and carcinogenesis. In recent years, new insights revealed the role of IGF2 in the central nervous system, particularly its importance in learning, memory consolidation and enhancement. Despite the still not fully explored physiological role of IGF2, in this article we aim to describe and explain its known functions in more detail and discuss its potential uses, including its possible application in the treatment of neurodegenerative diseases.
- MeSH
- exprese genu genetika MeSH
- insulinu podobný růstový faktor II * fyziologie genetika metabolismus ultrastruktura MeSH
- inzulin fyziologie MeSH
- karcinogeneze genetika metabolismus MeSH
- kognice fyziologie MeSH
- lidé MeSH
- neurodegenerativní nemoci etiologie genetika klasifikace MeSH
- receptor IGF typ 2 fyziologie metabolismus ultrastruktura MeSH
- receptor inzulinu fyziologie genetika ultrastruktura MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Birds, especially the chick and hen, have been important biomedical research models for centuries due to the accessibility of the avian embryo and the early discovery of avian viruses. Comprehension of avian tumor virology was a milestone in basic cancer research, as was that of non-viral genesis, as it enabled the discovery of oncogenes. Furthermore, studies on avian viruses provided initial insights into Kaposi's sarcoma and EBV-induced diseases. However, the role of birds in human carcinogenesis extends beyond the realm of virology research. Utilization of CAM, the chorioallantoic membrane, an easily accessible extraembryonic tissue with rich vasculature, has enabled studies on tumor-induced angiogenesis and metastasis and the efficient screening of potential anti-cancer compounds. Also, the chick embryo alone is an effective preclinical in vivo patient-derived xenograft model, which is important for the development of personalized therapies. Furthermore, adult birds may also closely resemble human oncogenesis, as evidenced by the laying hen, which is the only animal model of a spontaneous form of ovarian cancer. Avian models may create an interesting alternative compared with mammalian models, enabling the creation of a relatively cost-effective and easy-to-maintain platform to address key questions in cancer biology.
- MeSH
- karcinogeneze * patologie genetika MeSH
- kur domácí MeSH
- kuřecí embryo MeSH
- lidé MeSH
- modely nemocí na zvířatech * MeSH
- nádory patologie genetika MeSH
- ptáci MeSH
- zvířata MeSH
- Check Tag
- kuřecí embryo MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Simian virus 40 (SV40) is a monkey virus with tumorigenic potential in rodents and is associated with several types of human cancers, including lymphomas. A related Merkel cell polyomavirus causes carcinoma in humans by expressing truncated large tumor antigen (LT), with truncations caused by APOBEC family of cytidine deaminase-induced mutations. AID (activation-induced cytidine deaminase), a member of the APOBEC family, is the initiator of the antibody diversification process known as somatic hypermutation and its aberrant expression and targeting is a frequent source of lymphomagenesis. In this study, we investigated whether AID could cause mutations in SV40 LT. We demonstrate that the SV40 enhancer has strong somatic hypermutation targeting activity in several cell types and that AID-induced mutations accumulate in SV40 LT in B cells and kidney cells and cause truncated LT expression in B cells. Our results argue that the ability of the SV40 enhancer to target somatic hypermutation to LT is a potential source of LT truncation events that could contribute to tumorigenesis in various cell types, thereby linking SV40 infection with malignant development through a novel mutagenic pathway.
- MeSH
- AICDA (aktivací indukovaná cytidindeamináza) MeSH
- antigeny transformující polyomavirové genetika metabolismus MeSH
- antigeny virové nádorové genetika metabolismus MeSH
- B-lymfocyty virologie metabolismus imunologie MeSH
- buněčné linie MeSH
- cytidindeaminasa * genetika metabolismus MeSH
- infekce onkogenními viry genetika virologie MeSH
- karcinogeneze genetika MeSH
- lidé MeSH
- mutace MeSH
- opičí virus SV40 * genetika MeSH
- polyomavirové infekce genetika virologie MeSH
- somatická hypermutace imunoglobulinových genů genetika MeSH
- zesilovače transkripce * genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The intestinal epithelium, a rapidly renewing tissue, is characterized by a continuous cell turnover that occurs through a well-coordinated process of cell proliferation and differentiation. This dynamic is crucial for the long-term function of the gastrointestinal tract. Disruption of this process can lead to colorectal carcinoma, a common malignancy worldwide. The first part of the review focuses on the cellular composition of the epithelium and the molecular mechanisms that control its functions, and describes the pathways that lead to epithelial transformation and tumor progression. This forms the basis for understanding the development and progression of advanced colorectal cancer. The second part deals with current therapeutic approaches and presents the latest treatment options, ongoing clinical trials and new drugs. In addition, the biological and medical perspectives of the adverse effects of therapies and models of regeneration of the intestinal epithelium are highlighted and, finally, future treatment options are discussed.
- MeSH
- kolorektální nádory * terapie patologie MeSH
- lidé MeSH
- nádorová transformace buněk MeSH
- onkologové MeSH
- střevní sliznice patologie účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Úvod a cíl: Retrospektivní studie se zaměřila na klinicko-biopticky verifikované případy proliferativní verukózní leukoplakie (PVL). Cílem práce je poukázat na nutnost korelace orálních projevů PVL s klinickým, ale i rentgenologickým vyšetřením parodontu. Metodika: Studie hodnotila průběh onemocnění PVL u 53 pacientů sledovaných v letech 1994 až 2024 na Oddělení orální medicíny Stomatologické kliniky FN Plzeň. Mimo anamnesticko-patologické korelace byly posuzovány rovněž aspekty koincidence s dalšími lézemi ústní sliznice, tvorba dysplazie v průběhu tohoto agresivního onemocnění a četnost maligní transformace. Slizniční projev onemocnění byl pravidelně porovnáván s klinickým i rentgenologicky ověřeným stavem parodontu. Výsledky: Za dispenzarizace došlo k recidivě v 56 % případů (n = 30/53) a ke zvratu v orální dlaždicobuněčný karcinom (OSCC) u 38 % pacientů (n = 20/53). Onkologická recidiva nastala v pěti případech (9 %). Většinu pacientů s maligní transformací tvořily ženy, a to 70 % (n = 14/20). Závěr: Na rozdíl od ostatních onemocnění ústní sliznice je v rámci dispenzarizace PVL zhotovení snímků OPG nebo CBCT diagnosticky přínosnější. U mnoha pacientů s lézemi v oblasti alveolární sliznice a gingivy dochází v odpovídajících lokalitách k výrazné resorpci až usuraci alveolární kosti v případě probíhající maligní transformace. Maligní transformace PVL je skutečně četná, v naší skupině až v 38 %. Pro riziko diagnostické záměny orálního lichen planus a chronické hyperplastické kandidózy s počínající PVL je nutno zpřísnit dispenzární pravidla i u těchto případů.
Introduction and aim: Retrospective study focused on clinically and biopsy-proven cases of proliferative verrucous leukoplakia (PVL). The aim of the work is to point out the necessity of correlation of oral manifestations of PVL with clinical and radiological examination of the periodontium. Methods: The study evaluated the process of PVL disease in 53 patients followed between 1994 and 2024 at the Oral Medicine Department, Dentistry Clinic, University hospital in Pilsen. Apart from anamnestic-pathological correlations, also the aspects of coincidence with other lesions of the oral mucosa, the formation of dysplasia during this aggressive disease and the frequency of malignant transformation were assessed. The mucosal manifestation of the disease was regularly compared to the clinical and radiological state of the periodontium. Results: During dispensary, recurrence occurred in 56% of cases (n = 30/53) and transformation into oral squamous cell carcinoma (OSCC) in 38% of patients (n = 20/53). Oncological recurrence was in five cases (9%). The majority of patients with malignant transformation were women with 70% (n = 14/20). Conclusion: In contrary to other diseases of the oral mucosa, taking OPG or CBCT images is diagnostically more beneficial within the PVL dispensary. In several patients with lesions in the area of the alveolar mucosa and gingiva, there is significant resorption of the alveolar bone in the corresponding locations in the case of an ongoing malignant transformation. Malignant transformation of PVL is indeed high, up to 38% in our group. Due to the risk of diagnostic confusion of oral lichen planus and chronic hyperplastic candidiasis with incipient PVL, it is necessary to tighten the dispensary rules for these cases as well.
- MeSH
- dospělí MeSH
- karcinogeneze MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory úst patofyziologie MeSH
- orální leukoplakie * diagnostické zobrazování komplikace patofyziologie patologie MeSH
- retrospektivní studie MeSH
- senioři MeSH
- spinocelulární karcinom patofyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- klinická studie MeSH
- MeSH
- karcinogeneze MeSH
- klinická studie jako téma MeSH
- kolorektální nádory etiologie farmakoterapie MeSH
- lidé MeSH
- mastné kyseliny * metabolismus terapeutické užití MeSH
- nádory prostaty etiologie farmakoterapie MeSH
- nádory prsu farmakoterapie metabolismus MeSH
- nádory * etiologie farmakoterapie klasifikace metabolismus MeSH
- omega-3 mastné kyseliny farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Cell cycle checkpoints, oncogene-induced senescence and programmed cell death represent intrinsic barriers to tumorigenesis. Protein phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of the tumour suppressor p53 and has been implicated in termination of the DNA damage response. Here, we addressed the consequences of increased PPM1D activity resulting from the gain-of-function truncating mutations in exon 6 of the PPM1D. We show that while control cells permanently exit the cell cycle and reside in senescence in the presence of DNA damage caused by ionising radiation or replication stress induced by the active RAS oncogene, RPE1-hTERT and BJ-hTERT cells carrying the truncated PPM1D continue proliferation in the presence of DNA damage, form micronuclei and accumulate genomic rearrangements revealed by karyotyping. Further, we show that increased PPM1D activity promotes cell growth in the soft agar and formation of tumours in xenograft models. Finally, expression profiling of the transformed clones revealed dysregulation of several oncogenic and tumour suppressor pathways. Our data support the oncogenic potential of PPM1D in the context of exposure to ionising radiation and oncogene-induced replication stress.
- MeSH
- buněčná smrt genetika MeSH
- lidé MeSH
- myši MeSH
- nádorová transformace buněk * genetika MeSH
- nádorový supresorový protein p53 genetika metabolismus MeSH
- poškození DNA * genetika MeSH
- proliferace buněk genetika MeSH
- proteinfosfatasa 2C * genetika metabolismus MeSH
- proteinfosfatasy genetika metabolismus MeSH
- stárnutí buněk * genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
UNLABELLED: Tobacco use is a major modifiable risk factor for adverse health outcomes, including cancer, and elicits profound epigenetic changes thought to be associated with long-term cancer risk. While electronic cigarettes (e-cigarettes) have been advocated as harm reduction alternatives to tobacco products, recent studies have revealed potential detrimental effects, highlighting the urgent need for further research into the molecular and health impacts of e-cigarettes. Here, we applied computational deconvolution methods to dissect the cell- and tissue-specific epigenetic effects of tobacco or e-cigarette use on DNA methylation (DNAme) in over 3,500 buccal/saliva, cervical, or blood samples, spanning epithelial and immune cells at directly and indirectly exposed sites. The 535 identified smoking-related DNAme loci [cytosine-phosphate-guanine sites (CpG)] clustered into four functional groups, including detoxification or growth signaling, based on cell type and anatomic site. Loci hypermethylated in buccal epithelial cells of smokers associated with NOTCH1/RUNX3/growth factor receptor signaling also exhibited elevated methylation in cancer tissue and progressing lung carcinoma in situ lesions, and hypermethylation of these sites predicted lung cancer development in buccal samples collected from smokers up to 22 years prior to diagnosis, suggesting a potential role in driving carcinogenesis. Alarmingly, these CpGs were also hypermethylated in e-cigarette users with a limited smoking history. This study sheds light on the cell type-specific changes to the epigenetic landscape induced by smoking-related products. SIGNIFICANCE: The use of both cigarettes and e-cigarettes elicits cell- and exposure-specific epigenetic effects that are predictive of carcinogenesis, suggesting caution when broadly recommending e-cigarettes as aids for smoking cessation.
- MeSH
- dospělí MeSH
- epigeneze genetická * MeSH
- karcinogeneze * genetika MeSH
- kouření cigaret * škodlivé účinky genetika MeSH
- lidé MeSH
- metylace DNA * MeSH
- nádory plic genetika etiologie patologie MeSH
- receptor Notch1 genetika MeSH
- systémy dodávající nikotin elektronicky * MeSH
- vaping škodlivé účinky MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
