Search Results (6,432)

Background: Colorectal cancer (CRC) is strongly influenced by miRNAs as well as the circadian system. Methods: High-throughput sequencing of miRNAs expressed in the rat colon during 24 h light (L)/dark (D) cycle was performed to identify rhythmically expressed miRNAs. The role of miR-150-5p in CRC progression was analyzed in DLD1 cell line and human CRC tissues. Results: Nearly 10% of mature miRNAs showed a daily rhythm in expression. A peak of miRNAs’ levels was in most cases observed during the first half of the D phase of the LD cycle. The highest amplitude was detected in expression of miR-150-5p and miR-142-3p. In the L phase of the LD cycle, the maximum in miR-30d-5p expression was detected. Gene ontology enrichment analysis revealed that genes interfering with miRNAs with peak expression during the D phase influence apoptosis, angiogenesis, the immune system, and EGF and TGF-beta signaling. Rhythm in miR-150-5p, miR-142-3p, and miR-30d-5p expression was confirmed by real-time PCR. Oncogenes bcl2 and myb and clock gene cry1 were identified as miR-150-5p targets. miR-150-5p administration promoted camptothecin-induced apoptosis. Expression of myb showed a rhythmic profile in DLD1 cells with inverted acrophase with respect to miR-150-5p. miR-150-5p was decreased in cancer compared to adjacent tissue in CRC patients. Decrease in miR-150-5p was age dependent. Older patients with lower expression of miR-150-5p and higher expression of cry1 showed worse survival in comparison with younger patients. Conclusions: miRNA signaling differs between the L and D phases of the LD cycle. miR-150-5p, targeting myb, bcl2, and cry1, can influence CRC progression in a phase-dependent manner. Full article

Cancer disparities in low- and middle-income countries (LMICs) arise from multifaceted interactions between environmental exposures, infectious agents, and systemic inequities, such as limited access to care. The exposome, a framework encompassing the totality of non-genetic exposures throughout life, offers a powerful lens for understanding these disparities. In LMICs, populations are disproportionately affected by air and water pollution, occupational hazards, and oncogenic infections, including human papillomavirus (HPV), hepatitis B virus (HBV), Helicobacter pylori (H. pylori), human immunodeficiency virus (HIV), and neglected tropical diseases, such as schistosomiasis. These infectious agents contribute to increased cancer susceptibility and poor outcomes, particularly in immunocompromised individuals. Moreover, climate change, food insecurity, and barriers to healthcare access exacerbate these risks. This review adopts a population-level exposome approach to explore how environmental and infectious exposures intersect with genetic, epigenetic, and immune mechanisms to influence cancer incidence and progression in LMICs. We highlight the critical pathways linking chronic exposure and inflammation to tumor development and evaluate strategies such as HPV and HBV vaccination, antiretroviral therapy, and environmental regulation. Special attention is given to tools such as exposome-wide association studies (ExWASs), which offer promise for exposure surveillance, early detection, and public health policy. By integrating exposomic insights into national health systems, especially in regions such as sub-Saharan Africa (SSA) and South Asia, LMICs can advance equitable cancer prevention and control strategies. A holistic, exposome-informed strategy is essential for reducing global cancer disparities and improving outcomes in vulnerable populations. Full article

Ribosome biogenesis is a highly coordinated, multi-step process that assembles the ribosomal machinery responsible for translating mRNAs into proteins. It begins with the rate-limiting step of RNA polymerase I (Pol I) transcription of the 47S ribosomal RNA (rRNA) genes within a specialised nucleolar region in the nucleus, followed by rRNA processing, modification, and assembly with ribosomal proteins and the 5S rRNA produced by Pol III. The ribosomal subunits are then exported to the cytoplasm to form functional ribosomes. This process is tightly regulated by the PI3K/RAS/MYC oncogenic network, which is frequently deregulated in many cancers. As a result, ribosome synthesis, mRNA translation, and protein synthesis rates are increased. Growing evidence supports the notion that dysregulation of ribosome biogenesis and mRNA translation plays a pivotal role in the pathogenesis of cancer, positioning the ribosome as a promising therapeutic target. In this review, we summarise current understanding of dysregulated ribosome biogenesis and function in cancer, evaluate the clinical development of ribosome targeting therapies, and explore emerging targets for therapeutic intervention in this rapidly evolving field. Full article

The 13th International Foamy Virus (FV) Conference was held from 8 to 10 November 2023 at the BioParque/Zoological Garden in Rio de Janeiro, Brazil. This was the first conference on spumaretroviruses to be held in the Southern Hemisphere and in the unique environment of the rainforest. New developments and current perspectives in FV research were presented. Highlights of the conference included the structural biology of the envelope protein (Env) and insights into its function and evolution, epidemiologic identification of Amazonian indigenous people with a high prevalence of simian FV (SFV) infections, investigations of virus biology and genomics using synthetic FV DNAs, studies of humoral immune response, and development and applications of SFV vectors. The last day of the meeting was a special tour of the Centro de Primatologia do Rio de Janeiro, located northeast of Rio de Janeiro amidst the protected rainforest, where New World primate hosts of spumaretroviruses are rescued and studied. Our report summarizes the meeting highlights and outcomes for future discussions. Full article

The Chromobox (CBX) family comprises key epigenetic regulators involved in transcriptional repression through chromatin modifications. Dysregulation of polycomb CBX proteins has been linked to epigenetic gene silencing and cancer progression. However, the specific roles and prognostic value of CBX family members in colorectal cancer (CC) remain unclear. In this study, we show that CBX genes are significantly dysregulated in CC tissues and cell models compared to normal colorectal tissue. Among them, CBX4 and CBX8 emerged as the most upregulated isoforms in tumors. Functional analyses revealed that CBX4 overexpression enhances CC cell proliferation, while its silencing reduces tumor growth. Similarly, pharmacological inhibition of CBX4 in patient-derived tumor organoids led to decreased proliferation, supporting its pro-tumorigenic role. Immunofluorescence analysis further revealed alterations in NF-κB signaling upon CBX4 inhibition, along with reduced mRNA levels of pathway components including NF-κB, TNF, IL-1, and c-Myc. These findings point to a potential interplay between CBX4 and inflammation-related pathways in CC. Overall, our study highlights the oncogenic role of CBX4 in colorectal cancer and supports its potential as a novel therapeutic target and early biomarker for disease progression. Full article

Background/Objectives: Hepatic cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are major global health concerns due to rising incidence and limited therapeutic success. While traditional risk factors include chronic liver disease and environmental exposures, recent evidence underscores the significance of genetic alterations and gut microbiota in liver cancer development and progression. This review aims to integrate emerging knowledge on the interplay between host genomic changes and gut microbial dynamics in the pathogenesis and treatment of hepatic cancers. Methods: We conducted a comprehensive review of current literature on genetic and epigenetic drivers of HCC and CCA, focusing on commonly mutated genes such as TP53, CTNNB1, TERT, IDH1/2, and FGFR2. In parallel, we evaluated studies addressing the gut–liver axis, including the roles of dysbiosis, microbial metabolites, and immune modulation. Key clinical and preclinical findings were synthesized to explore how host–microbe interactions influence tumorigenesis and therapeutic response. Results: HCC and CCA exhibit distinct but overlapping genomic landscapes marked by recurrent mutations and epigenetic reprogramming. Alterations in the gut microbiota contribute to hepatic inflammation, genomic instability, and immune evasion, potentially enhancing oncogenic signaling pathways. Furthermore, microbiota composition appears to affect responses to immune checkpoint inhibitors. Emerging therapeutic strategies such as probiotics, fecal microbiota transplantation, and precision oncology based on mutational profiling demonstrate potential for personalized interventions. Conclusions: The integration of host genomics with microbial ecology provides a promising paradigm for advancing diagnostics and therapies in liver cancer. Targeting the gut–liver axis may complement genome-informed strategies to improve outcomes for patients with HCC and CCA. Full article

Background: Effective triage of women testing positive for high-risk HPV DNA is essential to reduce unnecessary colposcopies while preserving cancer prevention. Cytology, the current standard, has limited specificity and reproducibility. The genotype-specific 7-type HPV E6/E7 mRNA test (PreTect HPV-Proofer’7), targeting HPV types 16, 18, 31, 33, 45, 52, and 58, detects transcriptionally active infections and may enhance risk stratification. Methods: Between 2019 and 2023, 34,721 women aged 25–69 underwent primary HPV DNA screening with the Cobas 4800 assay at the University Hospital of North Norway, within the national screening program. Of these, 1896 HPV DNA-positive women were triaged with liquid-based cytology with atypical squamous cells of undetermined significance or worse (≥ASC-US) and the 7-type HPV mRNA test. Histological outcomes were followed through October 2024. Diagnostic performance for CIN2+ was evaluated overall and by genotype. Results: CIN2+ prevalence was 13.3%. The mRNA test reduced test positivity from 50.3% to 33.4% while maintaining comparable sensitivity (70.6% vs. 72.2%) and improving specificity (72.3% vs. 53.0%) and PPV (28.1% vs. 19.1%). Genotype-specific PPVs were highest for HPV16 mRNA (47.7%), followed by HPV33 (39.2%) and HPV31 (32.2%), all exceeding corresponding DNA-based estimates. Conclusion: Genotype-specific HPV mRNA triage offers superior risk discrimination compared to cytology, supporting more targeted, efficient, and accessible cervical cancer screening. Full article

(1) Background: Sertoli–Leydig cell tumors (SLCTs) are rare ovarian neoplasms that account for less than 0.5% of all ovarian tumors. They usually affect young women and often present with androgenic symptoms. We report a unique case of a 40-year-old woman diagnosed with both SLCT and clear cell papillary renal cell carcinoma (CCP-RCC), a rare tumor association with unclear pathogenesis. (2) Methods: Both tumors were treated surgically. The diagnostic workup included hormonal testing, imaging studies, and extensive genetic testing, including DICER1 mutation analysis and multiplex ligation-dependent probe amplification (MLPA), as well as the examination of a next-generation sequencing (NGS) panel covering ~280 cancer-related genes. (3) Results: Histopathologic examination confirmed a well-differentiated SLCT and CCP-RCC. No pathogenic variants in DICER1 were identified by WES or MLPA. No clinically relevant changes were found in the extended NGS panel either, so a known hereditary predisposition could be ruled out. The synchronous occurrence of both tumors without genomic alterations could indicate a sporadic event or as yet unidentified mechanisms. (4) Conclusions: This case highlights the importance of a multidisciplinary approach in the management of rare tumor compounds. The exclusion of DICER1 mutations and the absence of genetic findings adds new evidence to the limited literature and underscores the importance of long-term surveillance and further research into potential shared oncogenic pathways. Full article

Background/Objectives: Increasing evidence suggests that lncRNAs are core regulators in the field of tumor progression, with context-specific functions in oncogenic tumorigenesis. LINC01133, a lncRNA that has been identified as both an oncogene and a tumor suppressor, remains largely unexplored in terms of its molecular mechanisms. The purpose of this study was to conduct an in silico analysis, incorporating literature research on various cancer types, to investigate the structural and functional duality of LINC01133. This analysis aimed to identify pathways influenced by LINC01133 and evaluate its mechanism of action as a potential therapeutic target and diagnostic biomarker. Methods: In silico analyses and a narrative review of the literature were performed to predict conserved structural elements, functional internal loops, and overall conservation of the LINC01133 sequence among different vertebrate organisms, summarizing the empirical evidence regarding its roles as a tumor suppressor and tumor-promoting roles in various types of tumors. Results: LINC01133 harbors the evolutionarily conserved structural regions that might allow for binding to relevant driver signaling pathways, substantiating its specific functionality. Its action extends beyond classical tumor mechanisms, affecting proliferation, migration, invasion, and epigenetic pathways in various types of tumors, as indicated by the in silico results and narrative review of the literature we present here. Clinical outcome associations pointed to its potential as a biomarker. Conclusions: The dual character of LINC01133 in tumor biology further demonstrates its prospective therapeutic value, but complete elucidation of its mechanisms of action requires further investigation. This study establishes LINC01133 as a multifaceted lncRNA, supporting context-specific strategies in targeting its pathways, and calls for expanded research to harness its full potential in oncology. Full article

Background: Melanoma metastasis, driven by tumor microenvironment (TME)-mediated crosstalk facilitated by extracellular vesicles (EVs), remains a major therapeutic challenge. A critical barrier to clinical translation is the overlap in protein cargo between tumor-derived and healthy cell EVs. Objective: To address this, we developed Scaffold-free Functional Deconvolution (SFD), a novel computational approach that leverages a comprehensive healthy cell EV protein database to deconvolute non-oncogenic background signals. Methods: Beginning with 1915 proteins (identified by MS/MS analysis on an Orbitrap Fusion Lumos Mass Spectrometer using the IonStar workflow) from melanoma EVs isolated using REIUS, SFD applies four sequential filters: exclusion of normal melanocyte EV proteins, prioritization of metastasis-linked entries (HCMDB), refinement via melanocyte-specific databases, and validation against TCGA survival data. Results: This workflow identified 21 high-confidence targets implicated in metabolic-associated acidification, immune modulation, and oncogenesis, and were analyzed for reduced disease-free and overall survival. SFD’s versatility was further demonstrated by surfaceome profiling, confirming enrichment of H7-B3 (CD276), ICAM1, and MIC-1 (GDF-15) in metastatic melanoma EV via Western blot and flow cytometry. Meta-analysis using Vesiclepedia and STRING categorized these targets into metabolic, immune, and oncogenic drivers, revealing a dense interaction network. Conclusions: Our results highlight SFD as a powerful tool for identifying clinically relevant biomarkers and therapeutic targets within melanoma EVs, with potential applications in drug development and personalized medicine. Full article

Eukaryotic elongation factor 1A (eEF1A), the second most abundant intracellular protein, not only plays a key role in peptide elongation, but is also capable of numerous moonlighting functions. Within malignant cells, eEF1A is by no means a neutral bystander but instead actively participates in oncogenic transformations via a myriad of molecular pathways. Thus far, a broad range of small-molecule inhibitors have been identified, which, despite their structural diversity, suppress tumor growth by targeting eEF1A. Interestingly, just as eEF1A enables its oncogenic potential far beyond boosting protein translation, these targeted agents disrupt this oncoprotein via multiple axes distinct from mere protein synthesis inhibition. Whereas the oncogenic mechanisms of eEF1A has been well documented, there lacks a systemic survey of the eEF1A-targeting agents in terms of their mechanisms. Accordingly, the present work aims to examine their multifaceted modes of action more than just blocking protein synthesis. By unveiling these insights, our deepened knowledge of these eEF1A-binding inhibitors will inform the development of future eEF1A-targeted drugs for cancer treatment. Full article

Immunotherapy has revolutionized cancer treatments but still faces challenges, particularly with response rates plateauing around 20–40%. This is primarily due to the immunosuppressive nature of the tumor microenvironment (TME) and the lack of required antigen availability. This emphasizes finding agents that can improve these response rates, and curcumin has emerged as a promising natural compound with the potential to reengineer the TME by establishing its anti-inflammatory, antioxidant, pro-apoptotic, and anti-angiogenic effects. This review synthesizes the mechanisms by which curcumin affects major oncogenic pathways to synergize with immunotherapies, including immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccinations. Finally, we discuss future directions, current clinical trials, and bioavailability issues with utilizing curcumin clinically. Full article

Osteosarcoma (OS), the most common primary bone cancer of mesenchymal origin in children and young adolescents, remains a challenge due to metastasis and resistance to chemotherapy. It displays severe aneuploidy and a high mutation frequency which drive tumor initiation and progression; however, recent studies have highlighted the role of epigenetic modifications as a key driver of OS pathogenesis, independent of genetic mutations. DNA and RNA methylation, histone modifications and non-coding RNAs are among the major epigenetic modifications which can modulate the expression of oncogenes. Abnormal activity of these mechanisms contributes to gene dysregulation, metastasis and immune evasion. Therapeutic targeting against these epigenetic mechanisms, including inhibitors of DNA and RNA methylation as well as regulators of RNA modifications, can enhance tumor suppressor gene activity. In this review, we examine recent studies elucidating the role of epigenetic regulation in OS pathogenesis and discuss emerging drugs or interventions with potential clinical utility. Understanding of tumor- specific epigenetic alterations, coupled with innovative therapeutic strategies and AI-driven biomarker discovery, could pave the way for personalized therapies based on the molecular profile of each tumor and improve the management of patients with OS. Full article

Breast cancer is the second most common cancer in the United States and consists of 30% of all new female cancer each year. PKC iota (PKC-$\iota$) is a bonafide human oncogene and is overexpressed in many types of cancer, including breast cancer. This study explores the role of PKC-$\iota$ in regulating the transcription factor Jun proto-oncogene (c-Jun), pro-inflammatory cytokine Tumor Necrosis Factor-alpha (TNF-$\alpha$), and the Mitogen-Activated Protein Kinase/Jun N-terminal kinase (MAPK/JNK) pathway, which also exhibits an oncogenic role in breast cancer. ICA-1S, a PKC-$\iota$ specific inhibitor, was used to inhibit PKC-$\iota$ to observe the subsequent effect on the levels of c-Jun, TNF-$\alpha$, and the MAPK/JNK signaling pathway. To obtain the results, cell proliferation assay, Western blotting, co-immunoprecipitation, small interfering RNA (siRNA), immunofluorescence, flow cytometry, cycloheximide (CHX) chase assay, and reverse transcription quantitative PCR (RT-qPCR) techniques were implemented. ICA-1S significantly inhibited cell proliferation and induced apoptosis in both breast cancer cell lines. Treatment with ICA-1S and siRNA also reduced the expression levels of the MAPK/JNK pathway protein, c-Jun, and TNF-$\alpha$ in both cell lines. PKC-$\iota$ was also found to be strongly associated with c-Jun, via which it regulated the MAPK/JNK pathway. Additionally, ICA-1S was found to promote the degradation of c-Jun and decrease the mRNA levels of c-Jun. We concluded that PKC-$\iota$ plays a crucial role in regulating breast cancer, and the inhibition of PKC-$\iota$ by ICA-1S reduces breast cancer cell proliferation and induces apoptosis. Therefore, targeting PKC-$\iota$ as a potential therapeutic target in breast cancer could be a significant approach in breast cancer research. Full article

Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10⁻⁵). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article