Search Results (233)

Tumor initiation and metastatic progression are driven by context-dependent genetic alterations that disrupt tumor suppressor pathways, metabolic homeostasis, and signaling networks. However, the initial drivers that transform normal cells into malignant ones and their context dependency remain elusive. To address this, we aimed to systematically identify and characterize these drivers across cancer types, species, and microenvironments. We constructed customized clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) knockout (KO) libraries targeting high-frequency mutated and downregulated genes associated with liver hepatocellular carcinoma (LIHC) and breast carcinoma (BRCA) and conducted parallel functional screens in non-cancerous mouse and human fibroblast cell lines under two-dimensional (2D), three-dimensional (3D), and in vivo conditions. Strikingly, TP53 and NF1 emerged as pan-context drivers consistently enriched across immortalization, tumorigenesis, and metastasis in both LIHC and BRCA settings, while most other identified drivers were largely species-, tissue-, and microenvironment-specific with limited cross-model overlap. Despite this heterogeneity, all drivers converge on core pathways including epigenetic regulation, metabolic reprogramming, and growth factor signaling. Unlike prior studies on established cancer cells, this work defines the genetic barriers restricting the malignant transformation of primary normal cells, offering a new framework for early cancer evolution. Full article

MicroRNA-122 (miR-122) is the most abundant hepatic microRNA and a key regulator of hepatocyte proliferation, metabolism and differentiation. Although widely studied in hepatocellular carcinoma, its role in liver regeneration remains unexplored. This study investigated how miR-122 deficiency modulates liver regeneration under physiological conditions and during chronic liver injury. A miR-122-deficient mouse model (miR-122^−/−) was generated using CRISPR/Cas9, and liver regeneration was assessed after two-thirds partial hepatectomy (PHx) in healthy and CCl₄-induced fibrotic livers. In healthy liver, miR-122 expression was transiently downregulated within 24 h after PHx, suggesting a physiological role in cell cycle entry. After PHx in non-fibrotic livers, miR-122^−/− mice showed increased basal proliferation and accelerated regeneration, associated with Cyclin D1 and RhoA overexpression, enhanced cytokinesis and a predominance of diploid hepatocytes. In contrast, miR-122 deficiency markedly exacerbated CCl₄-induced fibrosis, leading to cirrhosis-like architecture, impaired hepatocyte function, and severe metabolic dysregulation. Despite increased proliferation after PHx, fibrotic miR-122^−/− mice exhibited severely impaired regeneration and near-complete mortality. Proteomic analyses revealed metabolic failure, oxidative stress, and inflammatory activation, creating an unfavorable environment for tissue repair. In conclusion, miR-122 plays a dual role in liver regeneration. While its suppression enhances regeneration in healthy liver, loss of miR-122 under fibrotic conditions drives pathological repair, metabolic failure and lethality, highlighting its critical role in chronic liver disease. Full article

Ubiquitin-specific protease 2 (USP2) is a deubiquitinase that controls various cellular events, including cell cycle progression and tumorigenesis. Along with cell culture models, mouse models induced using chemical blockers and gene engineering have substantially contributed to our knowledge of the crucial roles of USP2 in energy metabolism and metabolic disorders. This review summarizes the evidence of the role of USP2 in regulating energy metabolism in mice and cells under physiological and pathological conditions. In hepatocytes, a short isoform of USP2, USP2b, aggravates type 2 diabetes and metabolic dysfunction-associated steatotic liver disease. Meanwhile, a long isoform of USP2 in adipose tissue macrophages, USP2a, attenuates the onset of diabetes. USP2a mitigates insulin resistance and subsequent muscle atrophy. In ventromedial hypothalamic neurons, USP2b inhibits an increase in blood glucose by repressing hepatic glycogenolysis. In addition to regulating diabetes, USP2 isoforms potentially regulate the progression of atherosclerosis by modulating macrophages and hepatocytes. In brown adipose tissue, USP2a regulates thermogenesis, thus influencing systemic energy control. Meanwhile, in testicular macrophages, USP2 protects the mitochondrial respiration of sperm and consequently contributes to maintaining the quality of frozen sperm for use in the treatment of male infertility. As USP2 is distributed to multiple cellular components, it mediates the polyubiquitination of various molecules. For instance, USP2 modulates the stability of various transcription regulators, including C/EBP-α, PPARγ, EBF2, and PGC1α. The accumulating evidence indicates that USP2 functions as a modulatory molecule for energy metabolism across organs. Full article

Metabolic diseases, including type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated fatty liver disease (MAFLD), are chronic disorders characterized by dysregulated glucose and lipid homeostasis and represent major contributors to insulin resistance, cardiovascular complications, and liver injury. Despite considerable progress in elucidating their pathogenesis, effective preventive and therapeutic strategies remain limited. N6-methyladenosine (m⁶A) RNA demethylase AlkB homolog 5 (ALKBH5), a nuclear epitranscriptomic “eraser,” broadly regulates post-transcriptional gene expression by modulating RNA splicing, nuclear export, stability, and translation. Dysregulation of ALKBH5 has been implicated in tumorigenesis, immune dysfunction, and stress responses, underscoring its wide-ranging biological significance. Emerging evidence further indicates that ALKBH5 plays a pivotal role in maintaining metabolic homeostasis. However, most existing reviews have focused primarily on its roles in cancer, leaving its functions in metabolic diseases relatively unexplored. In this context, this review summarizes the structural characteristics and molecular mechanisms of ALKBH5 and discusses its emerging roles across a spectrum of metabolic diseases, including MAFLD, metabolic complications such as diabetic retinopathy (DR), diabetes-associated cognitive impairment (DACI), atherosclerosis (AS), and diabetic cardiomyopathy (DCM), as well as metabolism-related inflammatory diseases represented by rheumatoid arthritis (RA). Furthermore, recent pharmacological strategies targeting ALKBH5 are discussed, with attention to the challenges posed by its context-dependent, tissue-specific, and disease stage-specific activities. Overall, ALKBH5 emerges as a key epitranscriptomic regulator in metabolic diseases, and advancing therapeutic strategies that account for molecular context and tissue specificity will be critical for achieving safe and effective clinical interventions. Full article

Background and Objectives: A combination of chemotherapy and immunotherapy may improve cancer treatment outcomes; however, determining which patient groups will benefit from immunotherapy is critical. Triple-negative breast cancer (TNBC) achieves limited benefit from immune checkpoint inhibitors (ICIs) and anti-PD-L1 blockade therapy. Materials and Methods: In this study, PD-L1 expression levels in myeloid-derived cells in the tumor microenvironment were determined in an experimental TNBC model. Results: Compared with tumor cells, granulocytes, monocytes, and macrophages had significantly higher PD-L1 expression. CD206⁺ tumor-associated macrophages (TAMs) expressed the highest level of PD-L1. PD-L1 positivity in TAMs was also significantly high in the lung, liver, lymph node, and spleen. Despite treatment initiation in late-stage tumorigenesis, the combination of paclitaxel and the anti-PD-L1 monoclonal antibody atezolizumab significantly reduced tumor growth. In addition, lung metastasis burden was reduced with combined treatment compared with chemotherapy or anti-PD-L1 monotherapy alone. Conclusions: As a result, alterations in PD-L1⁺ myeloid cells and immune infiltration can be associated with atezolizumab and paclitaxel therapy success in triple-negative breast cancer. Full article

Co-infection with avian leukemia and Pullorum Disease severely compromises poultry health, yet its pathogenic mechanisms remain unclear. We employed transcriptome sequencing to analyze gene expression changes and enriched pathways in kidney, spleen, and liver tissues of Chongqing Chengkou mountain chickens under single-infection (avian leukemia virus or Pullorum Disease) and co-infection conditions. Significant differences were observed in the number and pathways of differentially expressed genes between co-infected and single-infected groups. These genes were predominantly enriched in pathways involving extracellular matrix–receptor interactions, PPAR signaling, and calcium ion signaling. RT-qPCR validation confirmed significant upregulation of MAPK10 and SQLE, alongside downregulation of genes such as FOXG1. This study identifies multiple differentially expressed genes and pathways associated with immunity and tumorigenesis, providing crucial molecular insights into the regulatory mechanisms underlying avian leukemia and Pullorum Disease co-infection. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. It usually arises in cirrhotic liver, where chronic inflammation and fibrosis create a tumor-permissive microenvironment. Dysregulation of microRNAs (miRNAs), particularly upregulation of the oncomiR miR-221 and loss of the tumor suppressor miR-199a-3p represent key drivers of liver carcinogenesis. The TG221 transgenic mouse, designed to overexpress miR-221 in hepatocytes, provides a relevant in vivo platform for mechanistic studies and for testing preventive and therapeutic approaches. The TG221 model recapitulates miR-221-driven tumorigenesis, including suppression of p27, p57 and Bmf. It is characterized by steatohepatitic injury and accelerated tumor formation after genotoxic challenge. In the cirrhotic CCl₄-induced background, TG221 mice develop fibrosis and cirrhosis followed by dysplastic and malignant lesions, mirroring the natural history of human HCC. Metformin administered during early fibrosis prevented macroscopic tumor formation and suppressed PI3K/AKT/mTOR signaling. Anti-miR-221 and miR-199a-3p mimics reduced tumor burden, restored tumor-suppressive pathways and improved liver integrity, thus indicating feasible chemopreventive strategies. From a therapeutic point of view, miR-199a-3p replacement synergized with palbociclib and overcame sorafenib resistance. A miR-199a-3p-responsive oncolytic adenovirus achieved tumor-selective replication with minimal toxicity. This review highlights the importance of the TG221 transgenic mouse as a powerful model for studying miRNA-driven hepatocarcinogenesis and enables preclinical evaluation of RNA-based chemopreventive and therapeutic approaches. Metformin, miRNA inhibition, miRNA replacement and miRNA-guided viral therapies emerge as promising approaches for advancing precision prevention and treatment strategies in HCC. Full article

Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an RNA-binding protein known to play critical roles in metabolism, cell proliferation, and tumorigenesis. Although its involvement in muscle development has been documented in several species, the function of goose IGF2BP2 remains largely unexplored. In this study, we cloned and characterized the full-length cDNA and genomic DNA sequences of goose IGF2BP2. The cDNA is 2957 bp in length and contains a 1662 bp open reading frame encoding a 553-amino acid protein with five conserved RNA-binding domains. The genomic sequence spans 12,183 bp and consists of 12 exons and 11 introns. A total of 60 genetic variants were identified, including a deletion of a G base at position 2299 (g.2299delG) that results in a frameshift mutation. Expression analysis revealed high levels of IGF2BP2 mRNA in the liver, heart, and muscle tissues of female geese across embryonic (E25d), growing (A70d), and laying (L270d) stages, consistent with a potential role in muscle development (p < 0.05). Functionally, overexpression of IGF2BP2 in skeletal muscle satellite cells (SMSCs) was associated with significant changes in the expression of several genes linked to muscle development and signaling pathways, including upregulation of IGF1, EGFR, FGF19, BMP6, BMP2, ACVR1C and WNT5A and downregulation of MYBPC3, NODAL, HOXD13, TNXB, and ADD2 (Padj < 0.01). Furthermore, protein–protein interaction (PPI) network analysis of these genes suggests that IGF2BP2 may coordinate key genes, contributing to its potential role in skeletal muscle development in geese. Full article

Arsenic, a ubiquitous metalloid, is commonly found in surface waters; as well as serious human health issues, it also induces systemic diseases and carcinogenesis upon chronic exposure. To better understand how arsenic potentially alters the immune system, it is important to study its effects on macrophage polarization. Micro-RNA plays an epigenetic regulatory role in organisms. The miR-125 family regulates macrophage polarization and tumorigenesis, yet its role in arsenic-induced macrophage polarization remains unexplored. This study investigated the mechanism of sodium arsenite (NaAsO₂)-driven macrophage polarization via miR-125a-5p. In vivo, rats exposed to 10 or 50 mg/L NaAsO₂ for 12 weeks exhibited elevated M2 markers (CD206, Arg1) and reduced M1 markers (iNOS, IL-1β, TNF-α) in liver and bladder tissues. In vitro, THP-1-derived macrophages treated with NaAsO₂ (2–8 μM) for 48 h showed dose-dependent M2 polarization, marked by upregulated CD206, Arg1, and IL-10. Flow cytometry results show that the proportion of M2/M1-type cells has increased significantly. Notably, NaAsO₂ suppressed miR-125a-5p expression and elevated interferon regulatory factor 4 (IRF4), a predicted target of miR-125a-5p. Overexpression of miR-125a-5p reversed NaAsO₂-induced M2 polarization by inhibiting IRF4, thereby reducing M2 markers and restoring M1-associated proteins. These findings reveal that NaAsO₂ promotes M2 macrophage polarization through the miR-125a-5p/IRF4 axis, highlighting a novel epigenetic mechanism in arsenic-associated tumor microenvironments and immune dysfunction. This study provides critical insights into targeting miR-125a-5p as a therapeutic strategy. Full article

Zinc finger E-box binding homeobox 1 (ZEB1) is a member of the zinc finger homeodomain transcription factor family, with a pivotal role in regulating the epithelial to mesenchymal transition (EMT) process. Increasing evidence suggests that ZEB1 is overexpressed in liver tumors, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), and it correlates with advanced disease features and reduced overall survival. Here, we examine ZEB1 molecular functions, regulatory networks and contribution to tumorigenesis. We also discuss the emerging therapeutic strategies and future research directions aimed at targeting the ZEB1 molecular network to improve the outcome of liver cancer patients. Full article

Intestinal homeostasis disorders (IHDs), driven by food safety issues, pollution, and drug-resistant pathogens, threaten global health. Key factors in intestinal and metabolic diseases (like IBD, obesity, and liver disease) include barrier dysfunction, gut microbiota imbalance, and excessive immune activation. Transcription factors in intestinal epithelial cells are crucial regulators. ELF4, an ETS family transcription factor, plays vital roles in transcriptional regulation, impacting tumorigenesis, the DNA damage response, and the cell cycle. ELF4 deficiency exacerbates alcoholic liver disease (ALD). Significantly, ELF4 is a novel IFN-I transcription factor with antiviral capabilities. Its regulation of the type I IFN response offers new avenues for developing antiviral and anticancer strategies and managing IFN-induced autoimmune disorders. Thus, ELF4 emerges as a promising target for preventing and treating IHD-related diseases. Mechanistic studies could help identify diets or antimicrobials that activate intestinal ELF4 to combat pathogen/virus-induced intestinal diseases. Full article

Several major cancer types exhibit significant sex dimorphism in incidence and survival. Whether and how sex as a biological factor impacts tumorigenesis, progression, and survival warrants full investigation, as such knowledge may lead to novel, precise prevention and treatment strategies. We reviewed epidemiological and molecular data on sex differences in cancers of the esophagus, bladder, head and neck, lung, liver, kidney, stomach, and skin melanoma, as well as the potential role of androgens and androgen receptor (AR) activity in these cancers. The potential molecular mechanisms are briefly discussed. Elevated testosterone (T) levels seemed to be associated with increased liver cancer and cutaneous melanoma incidences, and with reduced esophageal cancer risk. AR activity does not always correlate with T levels in tumorigenesis and progression. Higher AR expressions are associated with poorer survival in ESCC, whereas the role of AR in the survival of HNSCC and melanoma patients is inconsistent. The molecular impact of AR in liver cancer, kidney cancer, melanoma, and lung cancer is controversial. However, AR is likely to promote tumor growth and/or progression in esophagus, bladder, head and neck, and stomach cancers, and thus is associated with poor survival. Patients diagnosed with a tumor in this latter group could potentially benefit from therapeutic approaches targeting AR. Overall, the research on sex hormone androgens and AR in these cancers is limited. Further research is needed to determine a possible U-shaped relationship of T with cancer risk, and to decipher the role of testosterone and AR in some of these tumors to facilitate our understanding of sex dimorphism and to explore novel T/AR-based treatment options. Full article

Cholangiocarcinoma (CCA) is an aggressive malignancy of the biliary tract with rising global incidence and limited treatment options. Its pathogenesis involves a complex interplay of genetic mutations, epigenetic dysregulation, inflammatory signaling, and environmental influences. Emerging evidence highlights the pivotal role of the gut–liver axis and microbiota dysbiosis in shaping biliary homeostasis and disease progression. Alterations in microbial composition disrupt apoptosis and autophagy, two key processes regulating cell survival and death, thereby contributing to tumorigenesis, metastasis, and therapy resistance. Specific taxa, including Enterococcus, Escherichia coli, Pseudomonas, Bifidobacterium, and Bacillus, demonstrate strain-dependent effects, acting either as tumor promoters through genotoxic metabolites and immune evasion or as potential tumor suppressors by inducing apoptosis and immune activation. These findings underscore the context-dependent roles of microbiota in CCA biology. Importantly, microbiota modulation offers novel therapeutic opportunities. Dietary interventions such as probiotics, prebiotics, and nutritional strategies, alongside innovative microbiome-targeted therapies, hold promise for restoring microbial balance, enhancing antitumor immunity, and improving patient outcomes. This review integrates current molecular and microbiological evidence to propose the gut microbiota as both a biomarker and a therapeutic target in CCA, opening avenues for precision medicine approaches in hepatobiliary oncology. Full article

Positioned at the intersection of sex medicine and endocrinology, metabolic dysfunction-associated steatotic liver disease (MASLD) is often managed by specialists who may not be fully familiar with the complex roles of sex hormones in its pathogenesis and clinical course. To address this gap, we review the molecular actions of testosterone, estradiol, and progesterone on liver functions, as well as the role of sex-hormone binding globulin (SHBG) in MASLD histogenesis, highlighting disparities by sex as well as reproductive status. We also discuss how sex hormones influence fatty acid metabolism, gut dysbiosis, mitochondrial activity, gluco-lipidic homeostasis, lipotoxicity, inflammation, and MASLD-related liver tumorigenesis. Furthermore, we examine observational studies on associations between endogenous and exogenous sex hormones and SHBG with MASLD, with attention to hypogonadism in either sex or polycystic ovary syndrome. We summarize the role of sex hormones in modulating MASLD risk across life stages such as menopause, breastfeeding, and lactation. Lastly, we review the hepatic effects of hormone replacement therapy (HRT) on MASLD in both sexes, prospects, and safety of HRT and contraceptives among individuals with chronic liver disease. In conclusion, sex hormones play significant roles in MASLD pathobiology, underscoring the importance of sex-specific approaches in clinical practice and research. Full article

Pancreatic, liver, gastric, colorectal, and rectal cancers (PC, LC, GC, CRC, and RC) are highly lethal tumours, with a 5-year survival rate of 10.5% (PC) and <20% (LC), and of 5%, 12%, and 13% for IV-stage GC, CRC, and RC, respectively. Currently, PC and LC represent the third leading cause of cancer-related death, while GCs and CRCs account for 4.8 million cancer cases and 4.4 million cancer deaths worldwide. Poor prognoses are mainly due to late diagnosis, limited efficacy of available treatments, tumour recurrence, as well as therapy-induced secondary tumorigenesis and drug resistance. In recent decades, these issues have been afforded using nanomaterials (NMs), with promising results. Carbon nanotubes (CNTs) are nonpareil nano systems, which have demonstrated high potential in both cancer diagnosis and treatment, showing to be excellent vehicles for drugs, antibodies, genes, etc. Used alone or in combination with available therapeutic strategies, such as photothermal, photodynamic, drug targeting, gene, immune, and chemotherapies, CNTs have shown notable results in laboratory settings, enhancing the anticancer effects and reducing toxic outcomes of traditional treatments. Anyway, despite PC, LC, and CRC being three of the five tumours (60%) considered the most perfidious and lethal cancers, studies on the use of these innovative NMs to cure them represent only 37% of those regarding the treatment of the most known tumours. Regarding this scenario of a worrying lack of efficient treatments for highly lethal PC, LC, GC, CRC, and RC, this umbrella review was drawn up to promote filling this gap in studies by reporting the still too limited and often obsolete experimentation on the possible use of CNTs for their diagnosis and therapy. To this end, such case studies have been collected in several informative Tables which are functional for readers, and the studies have been discussed. This study wants to sensitize scientists towards more extensive research to find novel safer applications of CNTs against PC, LC, GC, CRC, and RC, both in terms of early diagnoses and efficient treatments. Such efforts should also focus on clarifying the not yet fully unveiled toxicological aspects and regulatory hurdles, both of which persist around CNTs. Research should also be finalized to produce patents rather than journal articles, thus accelerating the translation of CNTs to clinical practice. Full article