BACKGROUND: Lung cancer remains one of the most diagnosed malignancies, being the second most diagnosed cancer, while still being the leading cause of cancer-related deaths. Late diagnosis remains a problem, alongside the high mutational burden encountered in lung cancer. METHODS: We assessed the genetic profile of cancer genes in lung cancer using The Cancer Genome Atlas (TCGA) datasets for mutations and validated the results in a separate cohort of 32 lung cancer patients using tumor tissue and whole blood samples for next-generation sequencing (NGS) experiments. Another separate cohort of 32 patients was analyzed to validate some of the molecular alterations depicted in the NGS experiment. RESULTS: In the TCGA analysis, we identified the most commonly mutated genes in each lung cancer dataset, with differences among the three histotypes analyzed. NGS analysis revealed TP53, CSF1R, PIK3CA, FLT3, ERBB4, and KDR as being the genes most frequently mutated. We validated the c.1621A>C mutation in KIT. The correlation analysis indicated negative correlation between adenocarcinoma and altered PIK3CA (r = -0.50918; p = 0.0029). TCGA survival analysis indicated that NRAS and IDH2 (LUAD), STK11 and TP53 (LUSC), and T53 (SCLC) alterations are correlated with the survival of patients. CONCLUSIONS: The study revealed differences in the mutational landscape of lung cancer histotypes.
- Publikační typ
- časopisecké články MeSH
Circular RNAs (circRNA) have gained recent interest due to their functional versatility due to their interactions with other RNA species and proteins, all of which underline complex regulatory networks involved in pathogenic mechanisms. As a result, recent insights in circRNA biology are investigating their biomarker and therapeutic potential. One such circRNA is CircFOXO3, which consists of the circularized second exon of the FOXO3 mRNA, a member of the forkhead box transcription factor family involved in the regulation of developmental programs. Recent research focused on the role of circFOXO3 in the context of cancer has highlighted several implications in key tumorigenesis mechanisms, thus consolidating its relevance among other identified circRNAs. In this paper, we will focus on the currently identified case-specific implications of circFOXO3 in cancer, with a focus on the circFOXO3-miRNA-mRNA regulatory networks, its interactions with different proteins, and their cumulated biological effects upon tumor development. Therefore, we aim to provide an integrated perspective of the mechanistic implications of circFOXO3 in different cancers while also highlighting its biomarker or therapeutic potential based on the current evidence.
- MeSH
- genové regulační sítě * MeSH
- kruhová RNA genetika MeSH
- lidé MeSH
- messenger RNA genetika metabolismus MeSH
- mikro RNA genetika MeSH
- nádory genetika patologie MeSH
- regulace genové exprese u nádorů * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Communications among cells can be achieved either via direct interactions or via secretion of soluble factors. The emergence of extracellular vesicles (EVs) as entities that play key roles in cell-to-cell communication offer opportunities in exploring their features for use in therapeutics; i.e., management and treatment of various pathologies, such as those used for cancer. The potential use of EVs as therapeutic agents is attributed not only for their cell membrane-bound components, but also for their cargos, mostly bioactive molecules, wherein the former regulate interactions with a recipient cell while the latter trigger cellular functions/molecular mechanisms of a recipient cell. In this article, we highlight the involvement of EVs in hallmarks of a cancer cell, particularly focusing on those molecular processes that are influenced by EV cargos. Moreover, we explored the roles of RNA species and proteins carried by EVs in eliciting drug resistance phenotypes. Interestingly, engineered EVs have been investigated and proposed as therapeutic agents in various in vivo and in vitro studies, as well as in several clinical trials.
- MeSH
- extracelulární vezikuly patologie MeSH
- lékové transportní systémy MeSH
- lidé MeSH
- mezibuněčná komunikace * MeSH
- nádory patofyziologie terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and aggressive cancers with a less than 6% five-year survival rate. Circulating microRNAs (miRNAs) are emerging as a useful tool for non-invasive diagnosis and prognosis estimation in the various cancer types, including PDAC. Our study aimed to evaluate whether miRNAs in the pre-operative blood plasma specimen have the potential to predict the prognosis of PDAC patients. In total, 112 PDAC patients planned for surgical resection were enrolled in our prospective study. To identify prognostic miRNAs, we used small RNA sequencing in 24 plasma samples of PDAC patients with poor prognosis (overall survival (OS) < 16 months) and 24 plasma samples of PDAC patients with a good prognosis (OS > 20 months). qPCR validation of selected miRNA candidates was performed in the independent cohort of PDAC patients (n = 64). In the discovery phase of the study, we identified 44 miRNAs with significantly different levels in the plasma samples of the group of good and poor prognosis patients. Among these miRNAs, 23 showed lower levels, and 21 showed higher levels in plasma specimens from PDAC patients with poor prognosis. Eleven miRNAs were selected for the validation, but only miR-99a-5p and miR-365a-3p were confirmed to have significantly lower levels and miR-200c-3p higher levels in plasma samples of poor prognosis cases. Using the combination of these 3-miRNA levels, we were able to identify the patients with poor prognosis with sensitivity 85% and specificity 80% (Area Under the Curve = 0.890). Overall, 3-miRNA prognostic score associated with OS was identified in the pre-operative blood plasma samples of PDAC patients undergoing surgical resection. Following further independent validations, the detection of these miRNA may enable identification of PDAC patients who have no survival benefit from the surgical treatment, which is associated with the high morbidity rates.
- Publikační typ
- časopisecké články MeSH
Advancement in cancer research has shown that the tumor microenvironment plays a crucial role in the installation, progression, and dissemination of cancer cells. Among the heterogeneous panel of cells within the malignant microenvironment are tumor-associated macrophages that are sustaining the malignant cells through strict feedback mechanisms and spatial distribution. Considering that the presence of metastasis is one of the main feature associated with decreased survival rates among patients, in the present article we briefly present the involvement of tumor-associated macrophages in the hallmarks of metastasis and their microRNA-related regulation with a focus on lung cancer in order to coordinate the vast information under one pathology. As shown, these cells have emerged as coordinators of immunosuppression, angiogenesis and lymphangiogenesis, vessel intravasation and extravasation of cancer cells, and premetastatic niche formation, transforming the macrophages in potential therapeutic targets and also prognostic markers according to their density within the tumor and polarization phenotype. An indirect therapeutic approach on tumor-associated macrophages can be also represented by regulation of microRNAs involved in their polarization and implicit oncogenic features. Examples of these microRNAs consist in the highly studied miR-21 and miR-155, but also other microRNA with less feedback in the literature: miR-1207-5p, miR-193b, miR-320a, and others.
- MeSH
- lidé MeSH
- makrofágy metabolismus MeSH
- metastázy nádorů genetika imunologie MeSH
- mikro RNA genetika metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nádorové mikroprostředí MeSH
- nádory genetika imunologie MeSH
- pohyb buněk MeSH
- progrese nemoci MeSH
- proliferace buněk MeSH
- regulace genové exprese u nádorů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Lung cancer is one of the main causes of cancer-related death in the world, especially due to its frequency and ineffective therapeutically approaches in the late stages of the disease. Despite the recent advent of promising new targeted therapies, lung cancer diagnostic strategies still have difficulty in identifying the disease at an early stage. Therefore, the characterizations of more sensible and specific cancer biomarkers have become an important goal for clinicians. Circular RNAs (circRNAs), a type of RNA with covalently closed continuous loop structures that display high structural resistance and tissue specificity pointed toward a potential biomarker role. Current investigations have identified that circRNAs have a prominent function in the regulation of oncogenic pathways, by regulating gene expression both at transcriptional and post-transcriptional level. The aim of this review is to provide novel information regarding the implications of circRNAs in lung cancer, with an emphasis on the role in disease development and progression. Initially, we explored the potential utility of circRNAs as biomarkers, focusing on function, mechanisms, and correlation with disease progression in lung cancer. Further, we will describe the interaction between circRNAs and other non-coding species of RNA (particularly microRNA) and their biological significance in lung cancer. Describing the nature of these interactions and their therapeutic potential will provide additional insight regarding the altered molecular landscape of lung cancer and consolidate the potential clinical value of these circular transcripts. This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.
- MeSH
- cílená molekulární terapie MeSH
- kruhová RNA chemie genetika MeSH
- lidé MeSH
- nádorové biomarkery * MeSH
- nádory plic farmakoterapie genetika metabolismus patologie MeSH
- regulace genové exprese u nádorů * MeSH
- RNA interference MeSH
- signální transdukce MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND/AIM: Rectal cancer accounts for approximately one-third of all colorectal cancers. Currently, the standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (CRT) with capecitabine or 5-fluorouracil followed by curative surgery. Unfortunately, only 20% of patients with LARC present complete pathological response after CRT, whereas in 20-40% cases the response is poor or absent. The aim of our study was to evaluate whether microRNAs (miRNAs) in tumor biopsy specimen have the potential to predict therapeutic response in LARC patients. PATIENTS AND METHODS: In total 87 LARC patients treated by CRT were enrolled in our prospective study. To identify predictive miRNAs, we used small RNA sequencing in 40 tumor biopsy samples of LARC patients (20 responders, 20 non-responders) and qPCR validation of selected miRNA candidates. RESULTS: In the discovery phase of the study, we identified 69 miRNAs to have significantly different expression between the group of responders (TRG 1,2) and a group of non-responders (TRG 4,5) to neoadjuvant CRT. Among these miRNAs, 48 showed a lower expression and 21 showed higher expression in tumor tissues from poorly responding LARC patients. Five miRNAs were selected for validation, but only miR-487a-3p was confirmed to have a significantly higher expression in the tumor biopsy specimens of non-responders to neoadjuvant CRT (p<0.0006, AUC=0.766). Gene Ontology (GO) clustering and pathway enrichment analysis of the miR-487a-3p mRNA targets, revealed potential mechanisms behind miR-487a-3p roles in chemoradioresistance (e.g. TGF-beta signaling pathway, protein kinase activity, double-stranded DNA binding, or microRNAs in cancer). CONCLUSION: By combination of miRNA expression profiling and integrative computational biology we identified miR-487a-3p as a potential predictive biomarker of CRT response in LARC patients.
- MeSH
- adenokarcinom genetika patologie terapie MeSH
- chemoradioterapie MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- malá nekódující RNA genetika MeSH
- mikro RNA genetika MeSH
- nádorové biomarkery genetika MeSH
- nádory rekta genetika patologie terapie MeSH
- neoadjuvantní terapie MeSH
- prospektivní studie MeSH
- ROC křivka MeSH
- sekvenční analýza RNA metody MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Head and neck squamous cell carcinoma (HNSCC) is a group of malignancies with serious impact on patient quality of life due to a reduced rate of response to chemotherapy or radiation therapy. MiR-21 has been identified as one of the most common proto-oncogenes. It is hypothesized that upregulated miR-21 could serve as a potential biomarker for human cancer diagnosis. Considering the target genes identified for miR-21 in HNSCC, this transcript is an important player in several cellular processes that control carcinogenesis. The abnormal expression of miR-21 in this group of pathologies has been assessed in several publications, but given the heterogeneity of the published results, a meta-analysis and proper bioinformatics analysis of expression databases are needed to correctly establish the prognostic potential of this molecule. The present meta-analysis comprises the published survival data on HNSCC patients, reported as HR and 95% CI, in association with the expression levels of miR-21. Our investigation revealed that miR-21 could be used successfully as a prognostic biomarker in HNSCC patients, confirming its oncogenic potential. Specifically, the upregulation of miR-21 in these patients predicts a worse outcome in terms of survival rate.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
This study explored the antitubercular properties of fucoxanthin, a marine carotenoid, against clinical isolates of Mycobacterium tuberculosis (Mtb). Two vital enzymes involved in Mtb cell wall biosynthesis, UDP-galactopyranose mutase (UGM) and arylamine-N-acetyltransferase (TBNAT), were selected as drug targets to reveal the mechanism underlying the antitubercular effect of fucoxanthin. The obtained results showed that fucoxanthin showed a clear bacteriostatic action against the all Mtb strains tested, with minimum inhibitory concentrations (MIC) ranging from 2.8 to 4.1 µM, along with a good degree of selectivity index (ranging from 6.1 to 8.9) based on cellular toxicity evaluation compared with standard drug isoniazid (INH). The potent inhibitory actions of fucoxanthin and standard uridine-5'-diphosphate against UGM were recorded to be 98.2% and 99.2%, respectively. TBNAT was potently inactivated by fucoxanthin (half maximal inhibitory concentration (IC50) = 4.8 µM; 99.1% inhibition) as compared to INH (IC50 = 5.9 µM; 97.4% inhibition). Further, molecular docking approaches were achieved to endorse and rationalize the biological findings along with envisaging structure-activity relationships. Since the clinical evidence of the last decade has confirmed the correlation between bacterial infections and autoimmune diseases, in this study we have discussed the linkage between infection with Mtb and autoimmune diseases based on previous clinical observations and animal studies. In conclusion, we propose that fucoxanthin could demonstrate great therapeutic value for the treatment of tuberculosis by acting on multiple targets through a bacteriostatic effect as well as by inhibiting UGM and TBNAT. Such outcomes may lead to avoiding or decreasing the susceptibility to autoimmune diseases associated with Mtb infection in a genetically susceptible host.
- MeSH
- antituberkulotika farmakologie MeSH
- arylamin-N-acetyltransferasa metabolismus MeSH
- autoimunitní nemoci farmakoterapie MeSH
- buněčná stěna účinky léků enzymologie MeSH
- buněčné linie MeSH
- intramolekulární transferasy metabolismus MeSH
- izoenzymy metabolismus MeSH
- karotenoidy farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti metody MeSH
- Mycobacterium tuberculosis účinky léků enzymologie MeSH
- simulace molekulového dockingu metody MeSH
- tuberkulóza farmakoterapie MeSH
- xanthofyly farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
:Worldwide, breast cancer (BC) is the most common malignancy in women, in regard to incidence and mortality. In recent years, the negative role of obesity during BC development and progression has been made abundantly clear in several studies. However, the distribution of body fat may be more important to analyze than the overall body weight. In our review of literature, we reported some key findings regarding the role of obesity in BC development, but focused more on central adiposity. Firstly, the adipose microenvironment in obese people bears many similarities with the tumor microenvironment, in respect to associated cellular composition, chronic low-grade inflammation, and high ratio of reactive oxygen species to antioxidants. Secondly, the adipose tissue functions as an endocrine organ, which in obese people produces a high level of tumor-promoting hormones, such as leptin and estrogen, and a low level of the tumor suppressor hormone, adiponectin. As follows, in BC this leads to the activation of oncogenic signaling pathways: NFκB, JAK, STAT3, AKT. Moreover, overall obesity, but especially central obesity, promotes a systemic and local low grade chronic inflammation that further stimulates the increase of tumor-promoting oxidative stress. Lastly, there is a constant exchange of information between BC cells and adipocytes, mediated especially by extracellular vesicles, and which changes the transcription profile of both cell types to an oncogenic one with the help of regulatory non-coding RNAs.
- MeSH
- abdominální obezita komplikace metabolismus patofyziologie MeSH
- adiponektin škodlivé účinky metabolismus MeSH
- estrogeny škodlivé účinky metabolismus MeSH
- exozom metabolismus MeSH
- leptin imunologie metabolismus MeSH
- lidé MeSH
- menopauza metabolismus MeSH
- mikro RNA metabolismus MeSH
- nádorová transformace buněk metabolismus MeSH
- nádorové mikroprostředí imunologie MeSH
- nádory prsu etiologie metabolismus patofyziologie MeSH
- signální transdukce genetika MeSH
- tuková tkáň imunologie metabolismus MeSH
- zánět patofyziologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
