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Parecoxib, a well‐recognized nonsteroidal anti‐inflammatory drug, has been reported to possess anticancer properties in various tumor types. In this work, we aimed to investigate the potential anticancer effects of parecoxib on hepatocellular carcinoma (HCC) cells. To assess the impact of parecoxib on HCC cell proliferation, we employed Cell Counting Kit‐8, colony formation, and 5‐ethynyl‐2′‐deoxyuridine assays. Hoechst/propidium iodide (PI) double staining and flow cytometry were performed to evaluate apoptosis and cell cycle analysis. Wound healing and transwell assays were utilized to assess cell migration and invasion. Tube formation assay was employed to analyze angiogenesis. Protein levels were determined using western blotting, and mRNA expression levels were assessed using quantitative real‐time polymerase chain reaction (PCR). A xenograft mouse model was used to confirm the antitumor effects of parecoxib on HCC tumors in vivo. Our data demonstrated that parecoxib effectively inhibited the proliferation of HCC cells in a dose‐ and time‐dependent manner. In addition, parecoxib induced cell cycle arrest in the G2 phase and promoted apoptosis. Moreover, parecoxib hindered tumor migration and invasion by impeding the epithelial–mesenchymal transition process. Further investigation showed that parecoxib could significantly suppress angiogenesis through the inhibition of extracellular signal‐regulated kinase (ERK)–vascular endothelial growth factor (VEGF) axis. Notably, treatment with the ERK activator phorbol myristate acetate upregulated the expression of matrix metalloproteinase (MMP)‐2, MMP‐9, and VEGF and reversed the function of parecoxib in HCC cells. Besides, parecoxib displayed its antitumor efficacy in vivo. Collectively, our results suggest that parecoxib ameliorates HCC progression by regulating proliferation, cell cycle, apoptosis, migration, invasion, and angiogenesis through the ERK–VEGF/MMPs signaling pathway. [ABSTRACT FROM AUTHOR]

The presence of microplastics within the human body has raised significant concerns about their potential health implications. Numerous studies have supported the hypothesis that the accumulation of microplastics can trigger inflammatory responses, disrupt the microbiome, and provoke immune reactions due to their physicochemical properties. Chronic inflammation, characterized by tissue damage, angiogenesis, and fibrosis, plays a crucial role in cancer development. It influences cancer progression by altering the tumor microenvironment and impairing immune surveillance, thus promoting tumorigenesis and metastasis. This review explores the fundamental properties and bioaccumulation of microplastics, as well as their potential role in the transition from chronic inflammation to carcinogenesis. Additionally, it provides a comprehensive overview of the associated alterations in signaling pathways, microbiota disturbances, and immune responses. Despite this, the current understanding of the toxicity and biological impacts of microplastics remains limited. To mitigate their harmful effects on human health, there is an urgent need to improve the detection and removal methods for microplastics, necessitating further research and elucidation. [ABSTRACT FROM AUTHOR]

Glypican-3 (GPC-3) is predominantly found in the placenta and fetal liver, with limited expression in adult tissues. Its re-expression in hepatocellular carcinoma (HCC) and secretion into the serum highlights its potential as a diagnostic marker. GPC-3 is involved in important cellular processes such as proliferation, metastasis, apoptosis, and epithelial–mesenchymal transition through various signaling pathways including Wnt, IGF, YAP, and Hedgehog. To review the structure, biosynthesis, and post-translational modifications of GPC-3, and to elucidate its signaling mechanisms and role as a pro-proliferative protein in HCC, emphasizing its diagnostic and therapeutic potential. A comprehensive literature review was conducted, focusing on the expression of GPC-3 in various tumors, with a special emphasis on HCC. The review synthesized findings from experimental studies and clinical trials, analyzing the overexpression of GPC-3 in HCC, its differentiation from other liver diseases, and its potential as a diagnostic and therapeutic target. GPC-3 overexpression in HCC is linked to aggressive tumor behavior and poor prognosis, including shorter overall and disease-free survival. Additionally, GPC-3 has emerged as a promising therapeutic target. Ongoing investigations, including immunotherapies such as monoclonal antibodies and CAR-T cell therapies, demonstrate potential in inhibiting tumor growth and improving clinical outcomes. The review details the multifaceted roles of GPC-3 in tumorigenesis, including its impact on tumor-associated macrophages, glucose metabolism, and epithelial–mesenchymal transition, all contributing to HCC progression. GPC-3's re-expression in HCC and its involvement in key tumorigenic processes underscore its value as a biomarker for early diagnosis and a target for therapeutic intervention. Further research is warranted to fully exploit GPC-3's diagnostic and therapeutic potential in HCC management. [ABSTRACT FROM AUTHOR]

The Herpesviridae include the Epstein–Barr Virus (EBV) and the Kaposi Sarcoma-associated Herpesvirus (KSHV), both of which are oncogenic gamma-herpesviruses. These viruses manipulate host cellular mechanisms, including through ubiquitin-mediated pathways, to promote viral replication and oncogenesis. Ubiquitin, a regulatory protein which tags substrates for degradation or alters their function, is manipulated by both EBV and KSHV to facilitate viral persistence and cancer development. EBV infects approximately 90% of the global population and is implicated in malignancies including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), post-transplant lymphoproliferative disorder (PTLD), and nasopharyngeal carcinoma. EBV latency proteins, notably LMP1 and EBNA3C, use ubiquitin-mediated mechanisms to inhibit apoptosis, promote cell proliferation, and interfere with DNA repair, contributing to tumorigenesis. EBV's lytic proteins, including BZLF1 and BPLF1, further disrupt cellular processes to favor oncogenesis. Similarly, KSHV, a causative agent of Kaposi's Sarcoma and lymphoproliferative disorders, has a latency-associated nuclear antigen (LANA) and other latency proteins that manipulate ubiquitin pathways to degrade tumor suppressors, stabilize oncogenic proteins, and evade immune responses. KSHV's lytic cycle proteins, such as RTA and Orf64, also use ubiquitin-mediated strategies to impair immune functions and promote oncogenesis. This review explores the ubiquitin-mediated interactions of EBV and KSHV proteins, elucidating their roles in viral oncogenesis. Understanding these mechanisms offers insights into the similarities between the viruses, as well as provoking thought about potential therapeutic targets for herpesvirus-associated cancers. [ABSTRACT FROM AUTHOR]

EBV infects more than 90% of people globally, causing lifelong infection. The phases of the EBV life cycle encompass primary infection, latency, and subsequent reactivation or lytic phase. The primary infection usually happens without noticeable symptoms, commonly in early life stages. If it manifests after childhood, it could culminate in infectious mononucleosis. Regarding potential late consequences, EBV is associated with multiple sclerosis, rheumatoid arthritis, chronic active EBV infection, lymphomas, and carcinomas. Previous reports that the lytic phase plays a negligible or merely secondary role in the oncogenesis of EBV-related tumors are steadily losing credibility. The right mechanisms through which the lytic cycle contributes to carcinogenesis are still unclear, but it is now recognized that lytic genes are expressed to some degree in different cancer-type cells, implicating their role here. The lytic infection is a persistent aspect of virus activity, continuously stimulating the immune system. EBV shows different strategies to modulate and avoid the immune system, which is thought to be a key factor in its ability to cause cancer. So, the principal goal of our review is to explore the EBV's lytic phase contribution to oncogenesis. [ABSTRACT FROM AUTHOR]

R-loops are triple-stranded nucleic acid structures that occur when newly synthesized single-stranded RNA anneals to duplex DNA upon the collision of replication forks with transcription complexes. These RNA–DNA hybrids facilitate several transcriptional processes in the cell and have been described extensively in the literature. Recently, evidence has emerged that R-loops are key regulators of DNA tumor virus transcription and the replication of their lifecycle. Studies have demonstrated that R-loops on the Human Papillomavirus (HPV) genome must be resolved to maintain genome maintenance and avoid viral integration, a hallmark of HPV cancers. For Epstein–Barr virus (EBV), R-loops are formed at the oriLyt to establish lytic replication. Structural maintenance of chromosome proteins 5/6 (SMC5/6) bind to these viral R-loops to repress EBV lytic replication. Most viruses in the herpesvirales order, such as KSHV, contain R-loop-forming sequences. In this perspective, we will describe the current, although limited, literature demonstrating the importance of RNA–DNA hybrids to regulate DNA virus transcription. We will also detail potential new areas of R-loop research and how these viruses can be used as tools to study the growing field of R-loops. [ABSTRACT FROM AUTHOR]

Protein post-translational modifications (PTMs) represent a crucial aspect of cellular regulation, occurring after protein synthesis from mRNA. These modifications, which include phosphorylation, ubiquitination, acetylation, methylation, glycosylation, Sumoylation, and palmitoylation, play pivotal roles in modulating protein function. PTMs influence protein localization, stability, and interactions, thereby orchestrating a variety of cellular processes in response to internal and external stimuli. Dysregulation of PTMs is linked to a spectrum of diseases, such as cancer, inflammatory diseases, and neurodegenerative disorders. UFMylation, a type of PTMs, has recently gained prominence for its regulatory role in numerous cellular processes, including protein stability, response to cellular stress, and key signaling pathways influencing cellular functions. This review highlights the crucial function of UFMylation in the development and progression of tumors, underscoring its potential as a therapeutic target. Moreover, we discuss the pivotal role of UFMylation in tumorigenesis and malignant progression, and explore its impact on cancer immunotherapy. The article aims to provide a comprehensive overview of biological functions of UFMylation and propose how targeting UFMylation could enhance the effectiveness of cancer immunotherapy strategies. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.

Abstract The presence of microplastics within the human body has raised significant concerns about their potential health implications. Numerous studies have supported the hypothesis that the accumulation of microplastics can trigger inflammatory responses, disrupt the microbiome, and provoke immune reactions due to their physicochemical properties. Chronic inflammation, characterized by tissue damage, angiogenesis, and fibrosis, plays a crucial role in cancer development. It influences cancer progression by altering the tumor microenvironment and impairing immune surveillance, thus promoting tumorigenesis and metastasis. This review explores the fundamental properties and bioaccumulation of microplastics, as well as their potential role in the transition from chronic inflammation to carcinogenesis. Additionally, it provides a comprehensive overview of the associated alterations in signaling pathways, microbiota disturbances, and immune responses. Despite this, the current understanding of the toxicity and biological impacts of microplastics remains limited. To mitigate their harmful effects on human health, there is an urgent need to improve the detection and removal methods for microplastics, necessitating further research and elucidation.

Abstract Glypican-3 (GPC-3) is predominantly found in the placenta and fetal liver, with limited expression in adult tissues. Its re-expression in hepatocellular carcinoma (HCC) and secretion into the serum highlights its potential as a diagnostic marker. GPC-3 is involved in important cellular processes such as proliferation, metastasis, apoptosis, and epithelial–mesenchymal transition through various signaling pathways including Wnt, IGF, YAP, and Hedgehog. To review the structure, biosynthesis, and post-translational modifications of GPC-3, and to elucidate its signaling mechanisms and role as a pro-proliferative protein in HCC, emphasizing its diagnostic and therapeutic potential. A comprehensive literature review was conducted, focusing on the expression of GPC-3 in various tumors, with a special emphasis on HCC. The review synthesized findings from experimental studies and clinical trials, analyzing the overexpression of GPC-3 in HCC, its differentiation from other liver diseases, and its potential as a diagnostic and therapeutic target. GPC-3 overexpression in HCC is linked to aggressive tumor behavior and poor prognosis, including shorter overall and disease-free survival. Additionally, GPC-3 has emerged as a promising therapeutic target. Ongoing investigations, including immunotherapies such as monoclonal antibodies and CAR-T cell therapies, demonstrate potential in inhibiting tumor growth and improving clinical outcomes. The review details the multifaceted roles of GPC-3 in tumorigenesis, including its impact on tumor-associated macrophages, glucose metabolism, and epithelial–mesenchymal transition, all contributing to HCC progression. GPC-3’s re-expression in HCC and its involvement in key tumorigenic processes underscore its value as a biomarker for early diagnosis and a target for therapeutic intervention. Further research is warranted to fully exploit GPC-3’s diagnostic and therapeutic potential in HCC management.

Human cytomegalovirus (HCMV) infection is common in tumor tissues across different types of cancer. While HCMV has not been recognized as a cancer-causing virus, numerous studies hint at its potential role in cancer development where its presence in various cancers corresponds with the hallmarks of cancer. Herein, we discuss and demonstrate that high-risk HCMV-DB and BL strains have the potential to trigger transformation in epithelial cells, including human mammary epithelial cells (HMECs), ovarian epithelial cells (OECs), and prostate epithelial cells (PECs), through the generation of polyploid giant cancer cells (PGCCs). A discussion is provided on how HCMV infection creates a cellular environment that promotes oncogenesis, supporting the continuous growth of CMV-transformed cells. The aforementioned transformed cells, named CTH, CTO, and CTP cells, underwent giant cell cycling with PGCC generation parallel to dedifferentiation, displaying stem-like characteristics and an epithelial–mesenchymal transition (EMT) phenotype. Furthermore, we propose that giant cell cycling through PGCCs, increased EZH2 expression, EMT, and the acquisition of malignant traits represent a deleterious response to the cellular stress induced by high-risk oncogenic HCMV strains, the latter being the origin of the transformation process in epithelial cells upon HCMV infection and leading to adenocarcinoma of poor prognosis. [ABSTRACT FROM AUTHOR]

The gut microbiome is being frequently acknowledged for its impact on intestinal and extra-intestinal conditions, notably cancer. Here, diet is the most extensively researched modulator of gut microbiota among various environmental factors, demonstrating the ability to enrich its diversity and composition. Recent insights from clinical and preclinical trials emphasize the reciprocal influence between gut microbiota and anticancer therapies, impacting treatment responses and mitigating associated toxicities. Understanding these intricate connections is pivotal, given the potential of the gut microbiota to enhance the efficacy of existing chemotherapeutic agents while reducing their adverse effects. A systematic literature review was conducted using PubMed and Google Scholar, employing keywords like "gut microbiome," "cancer therapy," "chemotherapy," "diet," and "microbial fermentation." Thus, this review seeks to examine the interplay between the gut microbiome and cancer therapies, while also delving into nutritional strategies that can modulate the gut microbiome to improve cancer treatments. [ABSTRACT FROM AUTHOR]

The dysfunction of several types of regulators, including miRNAs, has recently attracted scientific attention for their role in cancer-associated changes in gene expression. MiRNAs are small RNAs of ~22 nt in length that do not encode protein information but play an important role in post-transcriptional mRNA regulation. Studies have shown that miRNAs are involved in tumour progression, including cell proliferation, cell cycle, apoptosis, and tumour angiogenesis and invasion, and play a complex and important role in the regulation of tumourigenesis. The detection of selected miRNAs may help in the early detection of cancer cells, and monitoring changes in their expression profile may serve as a prognostic factor in the course of the disease or its treatment. MiRNAs may serve as diagnostic and prognostic biomarkers, as well as potential therapeutic targets for colorectal cancer. In recent years, there has been increasing evidence for an epigenetic interaction between DNA methylation and miRNA expression in tumours. This article provides an overview of selected miRNAs, which are more frequently expressed in colorectal cancer cells, suggesting an oncogenic nature. [ABSTRACT FROM AUTHOR]

A model for accelerated aging in mice was developed: CB6F2 mice aged 39-45 days were exposed to fractionated 4-fold relatively uniform γ-radiation (137Cs, 0.98 Gy/min) at a total dose of 6.8 Gy. Radiation exposure led to delayed active growth, leukopenia, and lymphopenia for over 1 year during the post-radiation period. The death of irradiated males and females occurred significantly earlier than in control group animals. Median lifespans in the experimental group were 35-38% lower than in the control group (p<0.001). Ionizing radiation exposure led to the early development of hair depigmentation, cachexia, and the development of aging-associated diseases. In irradiated mice, oncological pathology constituted 30-35% in the mortality structure, which is twice as often as in the control group. The developed model can be used to study the pathogenesis of accelerated aging under radiation exposure and the search for means of its prevention and treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer remains a debilitating disease and a worldwide health burden, and their treatment has been a forefront interest for researchers and clinicians for centuries. The search for novel approaches to selectively target certain proteins in just cancer cells, while sparing normal, healthy cells, has been the holy grail to limit side effects of treatments. This review aims to assess the potential of tBid, a pro-apoptotic mitochondrial protein found in normal and healthy cells, as a target for treating cancers. Cancer cells with tBid accumulation at mitochondria are "primed" for apoptosis, and, surprisingly, may be resistant to apoptosis owing to the association of tBid with antiapoptotic proteins. These cancer cells are more vulnerable to drugs that target these associations, with the possibility of limiting the use of chemo- or other cancer therapies. Effective cancer therapy with limited adverse effects is a major challenge in the medical field. This is especially complicated by the development of acquired chemoresistance. Understanding the mechanisms that underlie these processes remains a major effort in cancer research. In this review, we focus on the dual role that Bid protein plays in apoptotic cell death via the mitochondrial pathway, in oncogenesis and in cancer therapeutics. The BH3 domain in Bid and the anti-apoptotic mitochondrial proteins (Bcl-2, Bcl-XL, mitochondrial ATR) it associates with at the outer mitochondrial membrane provides us with a viable target in cancer therapy. We will discuss the roles of Bid, mitochondrial ATR, and other anti-apoptotic proteins in intrinsic apoptosis, exploring how their interaction sustains cellular viability despite the initiation of upstream death signals. The unexpected upregulation of this Bid protein in cancer cells can also be instrumental in explaining the mechanisms behind acquired chemoresistance. The stable protein associations at the mitochondria between tBid and anti-apoptotic mitochondrial ATR play a crucial role in maintaining the viability of cancer cells, suggesting a novel mechanism to induce cancer cell apoptosis by freeing tBid from the ATR associations at mitochondria. [ABSTRACT FROM AUTHOR]

Simple Summary: Discovering new oncoviruses is a main goal of virology research. In addition to its deleterious role in immunocompromised patients and during pregnancy leading to birth defects, the human cytomegalovirus's (HCMV) potential role as an oncogenic agent has garnered significant attention recently. This perspective article focuses on the transforming potential of HCMV based on recently unveiled molecular and cellular characteristics of HCMV-infected cells. Epstein–Barr virus (EBV), Kaposi sarcoma human virus (KSHV), human papillomavirus (HPV), hepatitis B and C viruses (HBV, HCV), human T-lymphotropic virus-1 (HTLV-1), and Merkel cell polyomavirus (MCPyV) are the seven human oncoviruses reported so far. While traditionally viewed as a benign virus causing mild symptoms in healthy individuals, human cytomegalovirus (HCMV) has been recently implicated in the pathogenesis of various cancers, spanning a wide range of tissue types and malignancies. This perspective article defines the biological criteria that characterize the oncogenic role of HCMV and based on new findings underlines a critical role for HCMV in cellular transformation and modeling the tumor microenvironment as already reported for the other human oncoviruses. [ABSTRACT FROM AUTHOR]

Metabolism includes anabolism and catabolism, which play an essential role in many biological processes. Chromatin modifications are post‐translational modifications of histones and nucleic acids that play important roles in regulating chromatin‐associated processes such as gene transcription. There is a tight connection between metabolism and chromatin modifications. Many metabolic enzymes and metabolites coordinate cellular activities with alterations in nutrient availability by regulating gene expression through epigenetic mechanisms such as DNA methylation and histone modifications. The dysregulation of gene expression by metabolism and epigenetic modifications may lead to diseases such as diabetes and cancer. Recent studies reveal that metabolic enzymes and metabolites specifically regulate chromatin modifications, including modification types, modification residues and chromatin regions. This specific regulation has been implicated in the development of human diseases, yet the underlying mechanisms are only beginning to be uncovered. In this review, we summarise recent studies of the molecular mechanisms underlying the metabolic regulation of histone and DNA modifications and discuss how they contribute to pathogenesis. We also describe recent developments in technologies used to address the key questions in this field. We hope this will inspire further in‐depth investigations of the specific regulatory mechanisms involved, and most importantly will shed lights on the development of more effective disease therapies. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is one of the most aggressive tumors known to occur in the brain. Metabolism is one of the driving factors enabling the successful proliferation of tumor cells, thus increasing the tumor mass. Tumor metabolism is now recognized as a major hallmark of oncogenesis. Since the brain largely relies on its glucose supply for growth, glucose metabolism significantly contributes to oncogenesis in brain cancers. Here, we review the major metabolic pathways seen in normal brain physiology in addition to the Warburg effect, aberrant tricarboxylic acid cycle, and oxidative phosphorylation observed in GBM. We highlight the important differences in glucose metabolism between the normal and cancerous environments. In addition, we provide insights into lactate shuttling, the pentose phosphate pathway, and immune interactions with glucose metabolism, which drive the nutritional pathways in both the normal and cancerous environment.

CC (CC) remains a significant global health concern, imposing a substantial health burden on women worldwide due to its high incidence and mortality rates. To address this issue, there is a need for ongoing research to uncover the underlying molecular mechanisms of CC and to discover novel diagnostic and therapeutic strategies. Recent progress in non-coding RNAs (ncRNAs) has opened new avenues for investigation, and circular RNAs (circRNAs) have emerged as molecules with diverse roles in various cellular processes. These circRNAs are distinct in structure, forming a closed loop, setting them apart from their linear counterparts. They are intricately involved in regulating different aspects of cellular functions, particularly in cell growth and development. Remarkably, circRNAs can have varying functions, either promoting or inhibiting oncogenic processes, depending on the specific cellular context. Recent studies have identified abnormal circRNAs expression patterns associated with CC, indicating their significant involvement in disease development. The differing circRNAs profiles linked to CC present promising opportunities for early detection, precise prognosis evaluation, and personalized treatment strategies. In this comprehensive review, we embark on a detailed exploration of CC-related circRNAs, elucidating their distinct roles and providing insights into the intricate molecular mechanisms governing CC's onset and progression. A growing body of evidence strongly suggests that circRNAs can serve as valuable biomarkers for early CC detection and hold potential as therapeutic targets for intervention. By delving into the complex interplay between circRNAs and CC, we are paving the way for innovative, individualized approaches to combat this serious disease, with the goal of reducing its impact on women's health globally and improving patient outcomes. As our understanding of circRNAs in the context of CC continues to deepen, the outlook for breakthroughs in diagnosis and treatment becomes increasingly promising.

Alternative splicing products of AIMP2 and AIMP2-DX2 (DX2) have been reported to be associated with human lung cancer. In fact, DX2 expression is elevated in human lung cancers, and DX2 transgenic mice also develop lung cancer, in particular small cell lung cancer (SCLC). However, the mechanism by which DX2 is induced during cancer progression has not been clearly elucidated. Here, we show that DX2 is induced by nicotine, the main component of smoking-related chemicals, which can stabilize the human epidermal growth factor receptor 2 (HER2) protein and transcriptionally increase sonic hedgehog (Shh). Indeed, nicotine showed tumorigenicity via DX2 by promoting spheroid formation and in vivo lung and kidney cancer progression. Moreover, the elimination of DX2 using small interfering RNA (siRNA) or an optimized inhibitor (SNU-14) blocked the induction of HER2 and Shh and completely suppressed tumor sphere formation in response to nicotine. These results indicate that DX2 is critical for lung cancer progression, and a specific DX2 inhibitor would be useful for the treatment of human cancers, including SCLC and non-SCLC (NSCLC).

ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis. This is due to the fact that most cases are only diagnosed at an advanced and palliative disease stage, and there is a high incidence of therapy resistance. Despite ongoing efforts, to date, the mechanisms underlying PDAC oncogenesis and its poor responses to treatment are still largely unclear. As the study of the microbiome in cancer progresses, growing evidence suggests that bacteria or fungi might be key players both in PDAC oncogenesis as well as in its resistance to chemo- and immunotherapy, for instance through modulation of the tumor microenvironment and reshaping of the host immune response. Here, we review how the microbiota exerts these effects directly or indirectly via microbial-derived metabolites. Finally, we further discuss the potential of modulating the microbiota composition as a therapy in PDAC.

Circadian clock dysregulation has been implicated in various types of cancer and represents an area of growing research. However, the role of the circadian clock in prostate cancer has been relatively unexplored. This literature review will highlight the potential role of circadian clock dysregulation in prostate cancer by examining molecular, epidemiologic, and clinical data. The influence of melatonin, light, night shift work, chronotherapy, and androgen independence are discussed as they relate to the existing literature on their role in prostate cancer.

In recent years, microRNAs (miRNAs) have garnered increasing attention for their potential implications in cancer pathogenesis, functioning either as oncogenes or tumor suppressors. Notably, angiosarcoma, along with various other cardiovascular tumors such as lipomas, rhabdomyomas, hemangiomas, and myxomas, has shown variations in the expression of specific miRNA subtypes. A substantial body of evidence underscores the pivotal involvement of miRNAs in the genesis of angiosarcoma and certain cardiovascular tumors. This review aims to delve into the current literature on miRNAs and their prospective applications in cardiovascular malignancies, with a specific focus on angiosarcoma. It comprehensively covers diagnostic methods, prognostic evaluations, and potential treatments while providing a recapitulation of angiosarcoma's risk factors and molecular pathogenesis, with an emphasis on the role of miRNAs. These insights can serve as the groundwork for designing randomized control trials, ultimately facilitating the translation of these findings into clinical applications. Moving forward, it is imperative for studies to thoroughly scrutinize the advantages and disadvantages of miRNAs compared to current diagnostic and prognostic approaches in angiosarcoma and other cardiovascular tumors. Closing these knowledge gaps will be crucial for harnessing the full potential of miRNAs in the realm of angiosarcoma and cardiovascular tumor research. [ABSTRACT FROM AUTHOR]

This review examines the complex role of Pin1 in the development and treatment of cancer. Pin1 is the only peptidyl-prolyl isomerase (PPIase) that can recognize and isomerize phosphorylated Ser/Thr-Pro peptide bonds. Pin1 catalyzes a structural change in phosphorylated Ser/Thr-Pro motifs that can modulate protein function and thereby impact cell cycle regulation and tumorigenesis. The molecular mechanisms by which Pin1 contributes to oncogenesis are reviewed, including Pin1 overexpression and its correlation with poor cancer prognosis, and the contribution of Pin1 to aggressive tumor phenotypes involved in therapeutic resistance is discussed, with an emphasis on cancer stem cells, the epithelial-to-mesenchymal transition (EMT), and immunosuppression. The therapeutic potential of Pin1 inhibition in cancer is discussed, along with the promise and the difficulties in identifying potent, drug-like, small-molecule Pin1 inhibitors. The available evidence supports the efficacy of targeting Pin1 as a novel cancer therapeutic by analyzing the role of Pin1 in a complex network of cancer-driving pathways and illustrating the potential of synergistic drug combinations with Pin1 inhibitors for treating aggressive and drugresistant tumors. [ABSTRACT FROM AUTHOR]

Oncoviruses utilize the host cell signaling pathways. The role of the host cellular kinases as the main signaling factors in the viral replication and assembly has been reported before. The c-Jun NH2-terminal kinases (JNKs) as members of the mitogen-activated protein kinase (MAPK) family are stress-activated protein kinases that can be triggered by radiation, growth factors, cell stress, and inflammatory cytokines. They are involved in the cell proliferation, migration/ invasion, various forms of cell deaths including apoptosis, autophagy, and necroptosis, and also cell survival-mediated cancer therapeutic resistance. The JNK pathway plays a key role in oncoviruses replication process. It can be triggered through viral infection and is involved in the replication of some viruses including herpes viruses and rotaviruses. It plays a key role in oncogenesis mechanism of oncoviruses by influencing both oncogenic events and tumor suppressive mechanisms. The present study aimed to highlight and increase our understanding regarding the effects of JNK pathway on the oncogenesis mechanism of oncoviruses including HBV, HCV, HTLV, HPV, KSHV, and EBV. [ABSTRACT FROM AUTHOR]

Simple Summary: Individuals with metabolic syndrome exhibit simultaneously pro-thrombotic and a pro-inflammatory conditions which more probably can lead to cardiovascular disease progression, type 2 diabetes mellitus, and some types of cancer. The present scoping review is aimed at highlighting any relations between cancer risk, inflammation, and metabolic syndrome. A total of 20 manuscripts were identified and, among them, we identified some associations with breast cancer, colorectal cancer, esophageal adenocarcinoma, hepatocellular carcinoma (HCC), and cancer in general. Therefore, it could be deducted that cancer and its related progression may also depend on a latent chronic inflammatory condition associated with other concomitant conditions, including type 2 diabetes mellitus, metabolic syndrome, and obesity. Therefore, prevention may potentially help individuals to protect themselves from cancer. Background: Individuals with metabolic syndrome exhibit simultaneously pro-thrombotic and pro-inflammatory conditions which more probably can lead to cardiovascular diseases progression, type 2 diabetes mellitus, and some types of cancer. The present scoping review is aimed at highlighting the association between cancer risk, inflammation, and metabolic syndrome. Methods: A search strategy was performed, mixing keywords and MeSH terms, such as "Cancer Risk", "Inflammation", "Metabolic Syndrome", "Oncogenesis", and "Oxidative Stress", and matching them through Boolean operators. A total of 20 manuscripts were screened for the present study. Among the selected papers, we identified some associations with breast cancer, colorectal cancer, esophageal adenocarcinoma, hepatocellular carcinoma (HCC), and cancer in general. Conclusions: Cancer and its related progression may also depend also on a latent chronic inflammatory condition associated with other concomitant conditions, including type 2 diabetes mellitus, metabolic syndrome, and obesity. Therefore, prevention may potentially help individuals to protect themselves from cancer. [ABSTRACT FROM AUTHOR]

Although lymphoma is the most frequent malignancy in common variable immunodeficiency (CVID), solid tumors, especially affected by oncogenic viruses, are not considered. Furthermore, in vitro genetic studies and cell cultures are not adequate for immune system and HBV interaction. We adopted a previously introduced clinical model of host–virus interaction (i.e., infectious process in immunodeficiency) for analysis of B cells and the specific IgG role (an observational study of a CVID patient who received intravenous immunoglobulin (IVIG). Suddenly, the patient deteriorated and a positive results of for HBs and HBV-DNA (369 × 106 copies) were detected. Despite lamivudine therapy and IVIG escalation (from 0.3 to 0.4 g/kg), CT showed an 11 cm intrahepatic tumor (hepatocellular carcinoma). Anti-HBs were positive in time-lapse analysis (range 111–220 IU/mL). Replacement therapy intensification was complicated by an immune complex disease with renal failure. Fulminant HCC in CVID and the development of a tumor as the first sign is of interest. Unfortunately, treatment with hepatitis B immune globulins (HBIG) plays a major role in posttransplant maintenance therapy. Anti-HB substitution has not been proven to be effective, oncoprotective, nor safe. Therefore, immunosuppression in HBV-infected recipients should be carefully minimized, and patient selection more precise with the exclusion of HBV-positive donors. Our clinical model showed an HCC pathway with important humoral host factors, contrary to epidemiological/cohort studies highlighting risk factors only (e.g., chronic hepatitis). The lack of cell cooperation as well as B cell deficiency observed in CVID play a crucial role in high HBV replication, especially in carcinogenesis. [ABSTRACT FROM AUTHOR]

The oncogenicity of the human cytomegalovirus (CMV) is currently being widely debated. Most recently, mounting clinical evidence suggests an anti-cancer effect via CMV-induced T cell-mediated tumor destruction. However, the data were mostly obtained from single-center studies and in vitro experiments. Broad geographic coverage is required to offer a global perspective. Our study examined the correlation between country-specific CMV seroprevalence (across 73 countries) and the age-standardized incidence rate (of 34 invasive tumors). The populations studied were stratified according to decadal age periods as the immunologic effects of CMV seropositivity may depend upon age at initial infection. The International Agency for Research on Cancer of the World Health Organization (IARC WHO) database was used. The multivariate linear regression analysis revealed a worldwide inverse correlation between CMV seroprevalence and the incidences of 62.8% tumors. Notably, this inverse link persists for all cancers combined (Spearman's ρ = −0.732, p < 0.001; β = −0.482, p < 0.001, adjusted R2 = 0.737). An antithetical and significant correlation was also observed in particular age groups for the vast majority of tumors. Our results corroborate the conclusions of previous studies and indicate that this oncopreventive phenomenon holds true on a global scale. It applies to a wide spectrum of cancer histologies, additionally supporting the idea of a common underlying mechanism—CMV-stimulated T cell tumor targeting. Although these results further advance the notion of CMV-based therapies, in-depth investigation of host–virus interactions is still warranted. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis. Each year, approximately 880,000 patients are newly diagnosed with HNSCC worldwide, and 450,000 patients with HNSCC die. Risk factors for developing HNSCC have been identified, with cigarette smoking, alcohol consumption, and viral infections being the major factors. Owing to the prevalence of human papillomavirus infection, the number of HNSCC cases is increasing considerably. Surgery and chemoradiotherapy are the primary treatments for HNSCC. With advancements in tumor biology, patients are eligible for novel treatment modalities, namely targeted therapies, immunotherapy, and photoimmunotherapy. Because this area of research has rapidly progressed, clinicians should understand the basic biology of HNSCC to choose an appropriate therapy in the upcoming era of personalized medicine. This review summarized recent developments in tumor biology, focusing on epidemiology, genetic/epigenetic factors, the tumor microenvironment, microbiota, immunity, and photoimmunotherapy in HNSCC, as well as how these findings can be translated into clinical settings. [ABSTRACT FROM AUTHOR]

Cervical cancer (CC) is a significant health problem, especially in low-income countries. Functional studies on the human papillomavirus have generated essential advances in the knowledge of CC. However, many unanswered questions remain. This mini-review discusses the latest results on CC pathogenesis, HPV oncogenesis, and molecular changes identified through next-generation technologies. Interestingly, the percentage of samples with HPV genome integrations correlates with the degree of the cervical lesions, suggesting a role in the development of CC. Also, new functions have been described for the viral oncoproteins E5, E6, and E7, resulting in the acquisition and maintenance of cancer hallmarks, including proliferation, immune response evasion, apoptosis, and genomic instability. Remarkably, E5 oncoprotein affects signaling pathways involved in the expression of interferon-induced genes and EGFR-induced proliferation, while E6 and E7 oncoproteins regulate the DNA damage repair and cell cycle continuity pathways. Furthermore, next-generation technologies provide vast amounts of information, increasing our knowledge of changes in the genome, transcriptome, proteome, metabolome, and epigenome in CC. These studies have identified novel molecular traits associated with disease susceptibility, degree of progression, treatment response, and survival as potential biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Approximately 15–20% of global cancer cases are attributed to virus infections. Oncoviruses employ various molecular strategies to enhance replication and persistence. Human cytomegalovirus (HCMV), acting as an initiator or promoter, enables immune evasion, supporting tumor growth. HCMV activates pro-oncogenic pathways within infected cells and direct cellular transformation. Thus, HCMV demonstrates characteristics reminiscent of oncoviruses. Cumulative evidence emphasizes the crucial roles of EZH2 and Myc in oncogenesis and stemness. EZH2 and Myc, pivotal regulators of cellular processes, gain significance in the context of oncoviruses and HCMV infections. This axis becomes a central focus for comprehending the mechanisms driving virus-induced oncogenesis. Elevated EZH2 expression is evident in various cancers, making it a prospective target for cancer therapy. On the other hand, Myc, deregulated in over 50% of human cancers, serves as a potent transcription factor governing cellular processes and contributing to tumorigenesis; Myc activates EZH2 expression and induces global gene expression. The Myc/EZH2 axis plays a critical role in promoting tumor growth in oncoviruses. Considering that HCMV has been shown to manipulate the Myc/EZH2 axis, there is emerging evidence suggesting that HCMV could be regarded as a potential oncovirus due to its ability to exploit this critical pathway implicated in tumorigenesis. [ABSTRACT FROM AUTHOR]

RAS guanyl releasing protein 1 (RASGRP1) is a guanine nucleotide exchange factor (GEF) characterized by the presence of a RAS superfamily GEF domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor, specifically activating RAS through the exchange of bound GDP for GTP. Activation of RAS by RASGRP1 has a wide range of downstream effects at the cellular level. Thus, it is not surprising that many diseases are associated with RASGRP1 disorders. Here, we present an overview of the structure and function of RASGRP1, its crucial role in the development, expression, and regulation of immune cells, and its involvement in various signaling pathways. This review comprehensively explores the relationship between RASGRP1 and various diseases, elucidates the underlying molecular mechanisms of RASGRP1 in each disease, and identifies potential therapeutic targets. This study provides novel insights into the role of RASGRP1 in insulin secretion and highlights its potential as a therapeutic target for diabetes. The limitations and challenges associated with studying RASGRP1 in disease are also discussed. [ABSTRACT FROM AUTHOR]

MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) orchestrates diverse environmental signals to facilitate cell growth and is frequently activated in cancer. Translocation of MTORC1 from the cytosol to the lysosomal surface by the RRAG GTPases is the key step in MTORC1 activation. Here, we demonstrated that transcription factors MEF2A and MEF2D synergistically regulated MTORC1 activation via modulating its cyto-lysosome shutting. Mechanically, MEF2A and MEF2D controlled the transcription of FNIP1 and FNIP2, the components of the FLCN-FNIP1 or FNIP2 complex that acts as a RRAGC-RRAGD GTPase-activating element to promote the recruitment of MTORC1 to lysosome and its activation. Furthermore, we determined that the pro-oncogenic protein kinase SRC/c-Src directly phosphorylated MEF2D at three conserved tyrosine residues. The tyrosine phosphorylation enhanced MEF2D transcriptional activity and was indispensable for MTORC1 activation. Finally, both the protein and tyrosine phosphorylation levels of MEF2D are elevated in human pancreatic cancers, positively correlating with MTORC1 activity. Depletion of both MEF2A and MEF2D or expressing the unphosphorylatable MEF2D mutant suppressed tumor cell growth. Thus, our study revealed a transcriptional regulatory mechanism of MTORC1 that promoted cell anabolism and proliferation and uncovered its critical role in pancreatic cancer progression. Abbreviation: ACTB: actin beta; ChIP: chromatin immunoprecipitation; EGF: epidermal growth factor; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; FLCN: folliculin; FNIP1: folliculin interacting protein 1; FNIP2: folliculin interacting protein 2; GAP: GTPase activator protein; GEF: guanine nucleotide exchange factors; GTPase: guanosine triphosphatase; LAMP2: lysosomal associated membrane protein 2; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEF2: myocyte enhancer factor 2; MEF2A: myocyte enhancer factor 2A; MEF2D: myocyte enhancer factor 2D; MEF2D-3YF: Y131F, Y333F, Y337F mutant; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NR4A1: nuclear receptor subfamily 4 group A member 1; RPTOR: regulatory associated protein of MTOR complex 1; RHEB: Ras homolog, mTORC1 binding; RPS6KB1: ribosomal protein S6 kinase B1; RRAG: Ras related GTP binding; RT-qPCR: real time-quantitative PCR; SRC: SRC proto-oncogene, non-receptor tyrosine kinase; TMEM192: transmembrane protein 192; WT: wild-type. [ABSTRACT FROM AUTHOR]

Abstract Background Lung cancer is a leading cause of cancer-related mortality worldwide, and effective therapies are limited. Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective therapy. Sorafenib is a multi-tyrosine kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clinical application. This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5-methoxytryptophan (5-MTP) on cell growth and metastasis of Lewis lung carcinoma (LLC) cells. Method The anticancer effect of the combination treatment of sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combination treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combination treatment on the tumorigenic ability of LLC cells. Result Our results demonstrated that the sorafenib and 5-MTP combination synergistically reduced viability and proliferation compared to sorafenib or 5-MTP treatment alone. Reduction of cyclin D1 expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthermore, the sorafenib-5-MTP combination significantly increased the inhibitory effect on migration and invasion of LLC cells compared to the single treatments. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on proliferation and metastasis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of sorafenib alone. Conclusions In conclusion, our data indicate that 5-MTP sensitizes the antitumor activity of sorafenib in LLC cells in vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer.

In the modern world, oncological diseases occupy the leading positions in the structure of mortality. An integrated approach to oncotherapy is not only aimed at immediate affection of malignant tumors, but also directed at reducing the risk of tumor recurrence and metastasis, as well as alleviating side effects of chemotherapy and radiotherapy of the disease. In oncologic disorders, blood viscosity increases, thus being associated with hypercoagulation syndrome. To prevent its consequences, the direct and indirect anticoagulants, especially heparin and its derivatives, are actively used. Biological functions and structural features of heparin make it a potential universal platform of a drug development for broad application, including oncology. With the advent of heparin fractionation technology and preparation of low-molecular weight forms and their derivatives, it has become possible to focus not only on anticoagulant activity but also to obtain fractions with targeted pharmacological activity. Usage of the anticoagulants has shown their antitumor activity in some cases, thus providing a basis for a more detailed study of pharmacotherapeutic effects of this group of drugs. Currently, some data suggest various pathways of interaction between heparin and tumor cells. There are multiple common features in development of a primary tumor and formation of secondary distant metastases, which may be attributed to similar molecular cellular mechanisms. The molecules mediating intercellular interactions, both between the tumor cells and between malignant cells and tumor-associated immune cells (e.g., lymphocytes and macrophages) may serve as targets for heparin thus helping the tumor to evade immune surveillance. The cytokines that stimulate tumor angiogenesis represent another important therapeutic target. Heparin derivatives are able to suppress tumor activity and prevent metastatic processes at various stages by inhibiting heparanase, P-/L-selectin, and angiogenesis activity, modulating the CXCL12-CXCR4 chemokine axis, and regulating OAM activity.This brief review addresses the current understanding and application of the potentially antimetastatic properties of heparin and its derivatives in malignant bone tumors since the heparin-based drugs are used as anticoagulants in arthroplasty of large joints and bone defects in patients with osteosarcoma.

In normal tissue, cellular homeostasis is largely driven by two catabolic pathways: apoptosis and autophagy. Apoptosis, or programmed cell death, is regulated by pro-apoptotic factors, and promotes the removal of problematic cells. Autophagy, which in turn includes three forms: macro-, micro-, and chaperone-mediated autophagy, can promote both cell survival by selectively removing potentially apoptosis-inducing factors and raising the threshold of stress required for the induction of cell death. Recently, evidence has been accumulating suggesting the existence of common molecular pathways between autophagy and apoptosis, as well as the influence of the extracellular matrix on these processes. One of the important enzymes involved in the coordination and regulation of these processes is transglutaminase 2 (TG2). Different types of TG2 activities are involved in maintaining the dynamic balance between extracellular matrix and intracellular autophagy/apoptosis processes, while dysregulation of these processes may contribute to the pathogenesis of various human diseases, including oncogenesis. For example, TG2 can promote the degradation of pro-apoptotic proteins and the survival of renal cell carcinoma cells under nutrient-deficient conditions by modulating the autophagy process. In cells of various tissues deprived of TG2, aggregates of ubiquitinated proteins and damaged mitochondria are observed, which in turn induces proteotoxic stress and cell death. conversely, the transamidase activity of TG2 was observed to inhibit anti-apoptotic signaling in a human leukemic monocytic lymphoma model. In the present review, a number of important functions of TG2 in oncogenesis are described, along with the dual role of TG2 in modulating such opposite processes as cell survival and cell death.

R-loops are triple-stranded nucleic acid structures that occur when newly synthesized single-stranded RNA anneals to duplex DNA upon the collision of replication forks with transcription complexes. These RNA–DNA hybrids facilitate several transcriptional processes in the cell and have been described extensively in the literature. Recently, evidence has emerged that R-loops are key regulators of DNA tumor virus transcription and the replication of their lifecycle. Studies have demonstrated that R-loops on the Human Papillomavirus (HPV) genome must be resolved to maintain genome maintenance and avoid viral integration, a hallmark of HPV cancers. For Epstein–Barr virus (EBV), R-loops are formed at the oriLyt to establish lytic replication. Structural maintenance of chromosome proteins 5/6 (SMC5/6) bind to these viral R-loops to repress EBV lytic replication. Most viruses in the herpesvirales order, such as KSHV, contain R-loop-forming sequences. In this perspective, we will describe the current, although limited, literature demonstrating the importance of RNA–DNA hybrids to regulate DNA virus transcription. We will also detail potential new areas of R-loop research and how these viruses can be used as tools to study the growing field of R-loops.

EBV infects more than 90% of people globally, causing lifelong infection. The phases of the EBV life cycle encompass primary infection, latency, and subsequent reactivation or lytic phase. The primary infection usually happens without noticeable symptoms, commonly in early life stages. If it manifests after childhood, it could culminate in infectious mononucleosis. Regarding potential late consequences, EBV is associated with multiple sclerosis, rheumatoid arthritis, chronic active EBV infection, lymphomas, and carcinomas. Previous reports that the lytic phase plays a negligible or merely secondary role in the oncogenesis of EBV-related tumors are steadily losing credibility. The right mechanisms through which the lytic cycle contributes to carcinogenesis are still unclear, but it is now recognized that lytic genes are expressed to some degree in different cancer-type cells, implicating their role here. The lytic infection is a persistent aspect of virus activity, continuously stimulating the immune system. EBV shows different strategies to modulate and avoid the immune system, which is thought to be a key factor in its ability to cause cancer. So, the principal goal of our review is to explore the EBV’s lytic phase contribution to oncogenesis.

Background: Lung cancer is a leading cause of cancer-related mortality worldwide, and effective therapies are limited. Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective therapy. Sorafenib is a multi-tyrosine kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clinical application. This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5-methoxytryptophan (5-MTP) on cell growth and metastasis of Lewis lung carcinoma (LLC) cells. Method: The anticancer effect of the combination treatment of sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combination treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combination treatment on the tumorigenic ability of LLC cells. Result: Our results demonstrated that the sorafenib and 5-MTP combination synergistically reduced viability and proliferation compared to sorafenib or 5-MTP treatment alone. Reduction of cyclin D1 expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthermore, the sorafenib-5-MTP combination significantly increased the inhibitory effect on migration and invasion of LLC cells compared to the single treatments. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on proliferation and metastasis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of sorafenib alone. Conclusions: In conclusion, our data indicate that 5-MTP sensitizes the antitumor activity of sorafenib in LLC cells in vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a leading cause of death among women with gynecological cancers, and is often diagnosed at advanced stages, leading to poor outcomes. This review explores genetic aspects of high-grade serous, endometrioid, and clear-cell ovarian carcinomas, emphasizing personalized treatment approaches. Specific mutations such as TP53 in high-grade serous and BRAF/KRAS in low-grade serous carcinomas highlight the need for tailored therapies. Varying mutation prevalence across subtypes, including BRCA1/2, PTEN, PIK3CA, CTNNB1, and c-myc amplification, offers potential therapeutic targets. This review underscores TP53's pivotal role and advocates p53 immunohistochemical staining for mutational analysis. BRCA1/2 mutations' significance as genetic risk factors and their relevance in PARP inhibitor therapy are discussed, emphasizing the importance of genetic testing. This review also addresses the paradoxical better prognosis linked to KRAS and BRAF mutations in ovarian cancer. ARID1A, PIK3CA, and PTEN alterations in platinum resistance contribute to the genetic landscape. Therapeutic strategies, like restoring WT p53 function and exploring PI3K/AKT/mTOR inhibitors, are considered. The evolving understanding of genetic factors in ovarian carcinomas supports tailored therapeutic approaches based on individual tumor genetic profiles. Ongoing research shows promise for advancing personalized treatments and refining genetic testing in neoplastic diseases, including ovarian cancer. Clinical genetic screening tests can identify women at increased risk, guiding predictive cancer risk-reducing surgery. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a unique family of endogenous RNAs devoid of 3′ poly-A tails and 5′ end caps. These single-stranded circRNAs, found in the cytoplasm, are synthesized via back-splicing mechanisms, merging introns, exons, or both, resulting in covalently closed circular loops. They are profusely expressed across the eukaryotic transcriptome and offer heightened stability against exonuclease RNase R compared to linear RNA counterparts. This review endeavors to provide a comprehensive overview of circRNAs' characteristics, biogenesis, and mechanisms of action. Furthermore, aimed to shed light on the potential of circRNAs as significant biomarkers in various cancer types. It has been performed an exhaustive literature review, drawing on recent studies and findings related to circRNA characteristics, synthesis, function, evaluation techniques, and their associations with oncogenesis. CircRNAs are intricately associated with tumor progression and development. Their multifaceted roles encompass gene regulation through the sponging of proteins and microRNAs, controlling transcription and splicing, interacting with RNA binding proteins (RBPs), and facilitating gene translation. Due to these varied roles, circRNAs have become a focal point in tumor pathology investigations, given their promising potential as both biomarkers and therapeutic agents. CircRNAs, due to their unique biogenesis and multifunctionality, hold immense promise in the realm of oncology. Their stability, widespread expression, and intricate involvement in gene regulation underscore their prospective utility as reliable biomarkers and therapeutic targets in cancer. As our understanding of circRNAs deepens, advanced techniques for their detection, evaluation, and manipulation will likely emerge. These advancements might catalyze the translation of circRNA-based diagnostics and therapeutics into clinical practice, potentially revolutionizing cancer care and prognosis. [ABSTRACT FROM AUTHOR]

In order to avoid replicative senescence, tumor cells must acquire a telomere maintenance mechanism. Beside telomerase activation, a minority of tumors employs a recombinational mechanism called Alternative Lengthening of Telomeres (ALT). Several studies have investigated the potential ALT stimulation by inactivation of ATRX in tumor cells, obtaining contrasting results. Differently, since ALT can be viewed as a mechanism to overcome telomere shortening-mediated replicative senescence, we have investigated the effects of the inhibition of ATRX and p53 in aging primary fibroblasts. We observed that senescence leads to a phenotype that seems permissive for ALT activity, i.e. high levels of ALT-associated PML bodies (APB), telomeric damage and telomeric cohesion. On the other hand, RAD51 is highly repressed and thus telomeric recombination, upon which the ALT machinery relies, is almost absent. Silencing of ATRX greatly increases telomeric recombination in young cells, but is not able to overcome senescence-induced repression of homologous recombination. Conversely, inhibition of both p53 and ATRX leads to a phenotype reminiscent of some aspects of ALT activity, with a further increase of APB, a decrease of telomere shortening (and increased proliferation) and, above all, an increase of telomeric recombination. [ABSTRACT FROM AUTHOR]

Human papillomaviruses (HPVs) cause more than 4.5% of all cancer in the world and more than half of these cases are attributed to human papillomavirus type 16 (HPV16). Prophylactic vaccines are available but antiviral drugs are not. Novel targets for therapy are urgently needed. Alternative RNA splicing is extensively used by HPVs to express all their genes and HPV16 is no exception. This process must function to perfection since mis‐splicing could perturb the HPV gene expression program by altering mRNA levels or by generating dysfunctional mRNAs. Cis‐acting RNA elements on the viral mRNAs and their cognate cellular trans‐acting factors control papillomavirus RNA splicing. The precise but delicate nature of the splicing process renders splicing sensitive to interference. As such, papillomavirus RNA splicing is a potential target for therapy. Here we summarize our current understanding of cis‐acting HPV16 RNA elements that control HPV16 mRNA splicing via cellular proteins and discuss how they may be exploited as targets for therapy to papillomavirus infections and cancer. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) represents the most common and aggressive malignant form of brain tumour in adults and is characterized by an extremely poor prognosis with dismal survival rates. Currently, expanding concepts concerning the pathophysiology of GBM are inextricably linked with neuroinflammatory phenomena. On account of this fact, the identification of novel pathomechanisms targeting neuroinflammation seems to be crucial in terms of yielding successful individual therapeutic strategies. In recent years, the pleiotropic growth factor progranulin (PGRN) has attracted significant attention in the neuroscience and oncological community regarding its neuroimmunomodulatory and oncogenic functions. This review of the literature summarizes and updates contemporary knowledge about PGRN, its associated receptors and signalling pathway involvement in GBM pathogenesis, indicating possible cellular and molecular mechanisms with potential diagnostic, prognostic and therapeutic targets in order to yield successful individual therapeutic strategies. After a review of the literature, we found that there are possible PGRN-targeted therapeutic approaches for implementation in GBM treatment algorithms both in preclinical and future clinical studies. Furthermore, PGRN-targeted therapies exerted their highest efficacy in combination with other established chemotherapeutic agents, such as temozolomide. The results of the analysis suggested that the possible implementation of routine determinations of PGRN and its associated receptors in tumour tissue and biofluids could serve as a diagnostic and prognostic biomarker of GBM. Furthermore, promising preclinical applications of PGRN-related findings should be investigated in clinical studies in order to create new diagnostic and therapeutic algorithms for GBM treatment. [ABSTRACT FROM AUTHOR]

Mutation is the major cause of phenotypic innovations. Apart from DNA mutations, the alteration on RNA such as the ADAR-mediated A-to-I RNA editing could also shape the phenotype. These two layers of variations have not been systematically combined to study their collective roles in cancers. We collected the high-quality transcriptomes of ten hepatocellular carcinoma (HCC) and the matched control samples. We systematically identified HCC-specific mutations in the exonic regions and profiled the A-to-I RNA editome in each sample. All ten HCC samples had mutations in the CDS of ADAR2 gene (dsRNA-binding domain or catalytic domain). The consequence of these mutations converged to the elevation of ADAR2 efficiency as reflected by the global increase of RNA editing levels in HCC. The up-regulated editing sites (UES) were enriched in the CDS and UTR of oncogenes and tumor suppressor genes (TSG), indicating the possible roles of these target genes in HCC oncogenesis. We present the mutation-ADAR2-UES-oncogene/TSG-HCC axis that explains how mutations at different layers would finally lead to abnormal phenotype. In the light of central dogma, our work provides novel insights into how to fully take advantage of the transcriptome data to decipher the consequence of mutations. [ABSTRACT FROM AUTHOR]

T-acute lymphoblastic leukaemia (T-ALL) accounts for 25% of adult ALL and 15% of childhood ALL. Their prognosis, long considered more unfavourable than that of B-ALL, has improved significantly in recent years. However, there remains a major challenge in this disease. Nearly 20% of patients will suffer a relapse, which is still associated with an extremely poor prognosis (less than 20% survival at five years). While advances in molecular biology in recent years have led to the identification of a large number of potentially targetable alterations involved in T oncogenesis, the therapeutic arsenal for relapsed or refractory disease remains limited to date, and only a few innovative therapies have been developed. Unlike B-ALL, T-ALL has not benefited from the immunotherapy revolution, with the development of bispecific antibodies and CAR T-cells for B haemopathies. There is therefore an urgent need to identify new therapeutic targets, which should lead in the short term to the development of new therapies that are lacking in this disease. This review presents recent advances in the oncogenesis of T-ALL and the potential therapeutic opportunities associated with them. [ABSTRACT FROM AUTHOR]

Background and Purpose: Colorectal cancer (CRC) is the second most lethal disease, with high mortality due to its heterogeneity and chemo‐resistance. Here, we have focused on the epidermal growth factor receptor (EGFR) as an effective therapeutic target in CRC and studied the effects of polyphenols known to modulate several key signalling mechanisms including EGFR signalling, associated with anti‐proliferative and anti‐metastatic properties. Experimental Approach: Using ligand‐ and structure‐based cheminformatics, we developed three potent, selective alkylaminophenols, 2‐[(3,4‐dihydroquinolin‐1(2H)‐yl)(p‐tolyl)methyl]phenol (THTMP), 2‐[(1,2,3,4‐tetrahydroquinolin‐1‐yl)(4‐methoxyphenyl)methyl]phenol (THMPP) and N‐[2‐hydroxy‐5‐nitrophenyl(4′‐methylphenyl)methyl]indoline (HNPMI). These alkylaminophenols were assessed for EGFR interaction, EGFR‐pathway modulation, cytotoxic and apoptosis induction, caspase activation and transcriptional and translational regulation. The lead compound HNPMI was evaluated in mice bearing xenografts of CRC cells. Key Results: Of the three alkylaminophenols tested, HNPMI exhibited the lowest IC50 in CRC cells and potential cytotoxic effects on other tumour cells. Modulation of EGFR pathway down‐regulated protein levels of osteopontin, survivin and cathepsin S, leading to apoptosis. Cell cycle analysis revealed that HNPMI induced G0/G1 phase arrest in CRC cells. HNPMI altered the mRNA for and protein levels of several apoptosis‐related proteins including caspase 3, BCL‐2 and p53. HNPMI down‐regulated the proteins crucial to oncogenesis in CRC cells. Assays in mice bearing CRC xenografts showed that HNPMI reduced the relative tumour volume. Conclusions and Implications: HNPMI is a promising EGFR inhibitor for clinical translation. HNPMI regulated apoptosis and oncogenesis by modulating BCL‐2/BAX and p53 in CRC cell lines, showing potential as a therapeutic agent in the treatment of CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Krüppel-like Factor-9 (KLF9) and Krüppel-like Factor-13 (KLF13) are highly related proteins that function as inducers and/or repressors of specific target gene repertoires in a variety of tissues and in diverse pathophysiological states, including neoplasia. Here, we describe the salient features of KLF9 and KLF13, the current state-of-the-art research regarding both protein's actions in cancer development and response to therapies, and where the field requires further exploration. These paralogous proteins warrant further study for multiple cancers, and with respect to their multiplicities of action in suppression or promotion of proliferative and metastatic phenotypes, and likely involvement in immune cell biology within the tumor microenvironment. Specificity Proteins/Krüppel-like Factors (SP/KLF family) are a conserved family of transcriptional regulators. These proteins share three highly conserved, contiguous zinc fingers in their carboxy-terminus, requisite for binding to cis elements in DNA. Each SP/KLF protein has unique primary sequence within its amino-terminal and carboxy-terminal regions, and it is these regions which interact with co-activators, co-repressors, and chromatin-modifying proteins to support the transcriptional activation and repression of target genes. Krüppel-like Factor 9 (KLF9) and Krüppel-like Factor 13 (KLF13) are two of the smallest members of the SP/KLF family, are paralogous, emerged early in metazoan evolution, and are highly conserved. Paradoxically, while most similar in primary sequence, KLF9 and KLF13 display many distinct roles in target cells. In this article, we summarize the work that has identified the roles of KLF9 (and to a lesser degree KLF13) in tumor suppression or promotion via unique effects on differentiation, pro- and anti-inflammatory pathways, oxidative stress, and tumor immune cell infiltration. We also highlight the great diversity of miRNAs, lncRNAs, and circular RNAs which provide mechanisms for the ubiquitous tumor-specific suppression of KLF9 mRNA and protein. Elucidation of KLF9 and KLF13 in cancer biology is likely to provide new inroads to the understanding of oncogenesis and its prevention and treatments. [ABSTRACT FROM AUTHOR]