Notch signaling pathway in cancer: from mechanistic insights to targeted therapies.

Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The Notch receptor and its ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical Notch signaling transduction. Accumulating evidence indicates that the Notch signaling pathway serves as both an oncogenic factor and a tumor suppressor in various cancer types. Dysregulation of this pathway promotes epithelial-mesenchymal transition and angiogenesis in malignancies, closely linked to cancer proliferation, invasion, and metastasis. Furthermore, the Notch signaling pathway contributes to maintaining stem-like properties in cancer cells, thereby enhancing cancer invasiveness. The regulatory role of the Notch signaling pathway in cancer metabolic reprogramming and the tumor microenvironment suggests its pivotal involvement in balancing oncogenic and tumor suppressive effects. Moreover, the Notch signaling pathway is implicated in conferring chemoresistance to tumor cells. Therefore, a comprehensive understanding of these biological processes is crucial for developing innovative therapeutic strategies targeting Notch signaling. This review focuses on the research progress of the Notch signaling pathway in cancers, providing in-depth insights into the potential mechanisms of Notch signaling regulation in the occurrence and progression of cancer. Additionally, the review summarizes pharmaceutical clinical trials targeting Notch signaling for cancer therapy, aiming to offer new insights into therapeutic strategies for human malignancies.

Mechanisms and therapeutic prospect of the JAK-STAT signaling pathway in liver cancer.

Liver cancer (LC) poses a significant global health challenge due to its high incidence and poor prognosis. Current systemic treatment options, such as surgery, chemotherapy, radiofrequency ablation, and immunotherapy, have shown limited effectiveness for advanced LC patients. Moreover, owing to the heterogeneous nature of LC, it is crucial to uncover more in-depth pathogenic mechanisms and develop effective treatments to address the limitations of the existing therapeutic modalities. Increasing evidence has revealed the crucial role of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in the pathogenesis of LC. The specific mechanisms driving the JAK-STAT pathway activation in LC, participate in a variety of malignant biological processes, including cell differentiation, evasion, anti-apoptosis, immune escape, and treatment resistance. Both preclinical and clinical investigations on the JAK-STAT pathway inhibitors have exhibited potential in LC treatment, thereby opening up avenues for the development of more targeted therapeutic strategies for LC. In this study, we provide an overview of the JAK-STAT pathway, delving into the composition, activation, and dynamic interplay within the pathway. Additionally, we focus on the molecular mechanisms driving the aberrant activation of the JAK-STAT pathway in LC. Furthermore, we summarize the latest advancements in targeting the JAK-STAT pathway for LC treatment. The insights presented in this review aim to underscore the necessity of research into the JAK-STAT signaling pathway as a promising avenue for LC therapy.

Development of a promising PPAR signaling pathway-related prognostic prediction model for hepatocellular carcinoma.

The peroxisome proliferator-activated receptor (PPAR) signaling pathway plays a crucial role in systemic cell metabolism, energy homeostasis and immune response inhibition. However, its significance in hepatocellular carcinoma (HCC) has not been well documented. In our study, based on the RNA sequencing data of HCC, consensus clustering analyses were performed to identify PPAR signaling pathway-related molecular subtypes, each of which displaying varying survival probabilities and immune infiltration status. Following, a prognostic prediction model of HCC was developed by using the random survival forest method and Cox regression analysis. Significant difference in survival outcome, immune landscape, drug sensitivity and pathological features were observed between patients with different prognosis. Additionally, decision tree and nomogram models were adopted to optimize the prognostic prediction model. Furthermore, the robustness of the model was verified through single-cell RNA-sequencing data. Collectively, this study systematically elucidated that the PPAR signaling pathway-related prognostic model has good predictive efficacy for patients with HCC. These findings provide valuable insights for further research on personalized treatment approaches for HCC.

Non-coding RNA methylation modifications in hepatocellular carcinoma: interactions and potential implications.

RNA methylation modification plays a crucial role as an epigenetic regulator in the oncogenesis of hepatocellular carcinoma (HCC). Numerous studies have investigated the molecular mechanisms underlying the methylation of protein-coding RNAs in the progression of HCC. Beyond their impact on mRNA, methylation modifications also influence the biological functions of non-coding RNAs (ncRNAs). Here, we present an advanced and comprehensive overview of the interplay between methylation modifications and ncRNAs in HCC, with a specific focus on their potential implications for the tumor immune microenvironment. Moreover, we summarize promising therapeutic targets for HCC based on methylation-related proteins. In the future, a more profound investigation is warranted to elucidate the effects of ncRNA methylation modifications on HCC pathogenesis and devise valuable intervention strategies. Video Abstract.

The spectrum of opportunistic infections and malignancies among women on antiretroviral therapy in Ethiopia.

ABBREVIATIONS: AIDS: acquired immune deficiency syndrome; CI: confidence interval; EPHI: Ethiopian Public Health Institute; HAART: highly active antiretroviral therapy; HIV: human immunodeficiency virus; HR: hazard ratio; Mg/dl: milligram per deciliter; TB: tuberculosis; PCP: pneumocystis carinii pneumonia; ZJU: Zhejiang University.

Tryptophan metabolism in health and disease.

Tryptophan (Trp) metabolism primarily involves the kynurenine, 5-hydroxytryptamine, and indole pathways. A variety of bioactive compounds produced via Trp metabolism can regulate various physiological functions, including inflammation, metabolism, immune responses, and neurological function. Emerging evidence supports an intimate relationship between Trp metabolism disorder and diseases. The levels or ratios of Trp metabolites are significantly associated with many clinical features. Additionally, studies have shown that disease progression can be controlled by modulating Trp metabolism. Indoleamine-2,3-dioxygenase, Trp-2,3-dioxygenase, kynurenine-3-monooxygenase, and Trp hydroxylase are the rate-limiting enzymes that are critical for Trp metabolism. These key regulatory enzymes can be targeted for treating several diseases, including tumors. These findings provide novel insights into the treatment of diseases. In this review, we have summarized the recent research progress on the role of Trp metabolites in health and disease along with their clinical applications.

Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer.

The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism of transmembrane signal transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, and other specific molecules activate JAK-STAT signaling to drive a series of physiological and pathological processes, including proliferation, metabolism, immune response, inflammation, and malignancy. Dysregulated JAK-STAT signaling and related genetic mutations are strongly associated with immune activation and cancer progression. Insights into the structures and functions of the JAK-STAT pathway have led to the development and approval of diverse drugs for the clinical treatment of diseases. Currently, drugs have been developed to mainly target the JAK-STAT pathway and are commonly divided into three subtypes: cytokine or receptor antibodies, JAK inhibitors, and STAT inhibitors. And novel agents also continue to be developed and tested in preclinical and clinical studies. The effectiveness and safety of each kind of drug also warrant further scientific trials before put into being clinical applications. Here, we review the current understanding of the fundamental composition and function of the JAK-STAT signaling pathway. We also discuss advancements in the understanding of JAK-STAT-related pathogenic mechanisms; targeted JAK-STAT therapies for various diseases, especially immune disorders, and cancers; newly developed JAK inhibitors; and current challenges and directions in the field.

Effects of 3-HAA on HCC by Regulating the Heterogeneous Macrophages-A scRNA-Seq Analysis.

Kynurenine derivative 3-hydroxyanthranilic acid (3-HAA) is known to regulate the immune system and exhibit anti-inflammatory activity by inhibiting T-cell cytokine secretion and influencing macrophage activity. However, the definite role of 3-HAA in the immunomodulation of hepatocellular carcinoma (HCC) is largely unexplored. An orthotopic HCC model and treated with 3-HAA by intraperitoneal injection is developed. Furthermore, cytometry by time-of-flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) analyses are carried out to define the immune landscape of HCC. It is found that 3-HAA treatment can significantly suppress tumor growth in the HCC model and alter the level of various cytokines in plasma. CyTOF data shows that 3-HAA significantly increases the percentage of F4/80hi CX3CR1lo Ki67lo MHCIIhi macrophages and decreases the percentage of F4/80lo CD64+ PD-L1lo macrophages. scRNA-seq analyses demonstrate that 3-HAA treatment is proved to regulate the function of M1 macrophages, M2 macrophages, and proliferating macrophages. Notably, 3-HAA inhibits the proinflammatory factors TNF and IL-6 in multiple cell subsets, including resident macrophages, proliferating macrophages, and pDCs. This study reveals the landscape of immune cell subsets in HCC in response to 3-HAA, indicating that 3-HAA may be a promising therapeutic target for HCC.

Current understanding of the intratumoral microbiome in various tumors.

It is estimated that in the future, the number of new cancer cases worldwide will exceed the 19.3 million recorded in 2020, and the number of deaths will exceed 10 million. Cancer remains the leading cause of human mortality and lagging socioeconomic development. Intratumoral microbes have been revealed to exist in many cancer types, including pancreatic, colorectal, liver, esophageal, breast, and lung cancers. Intratumoral microorganisms affect not only the host immune system, but also the effectiveness of tumor chemotherapy. This review concentrates on the characteristics and roles of intratumoral microbes in various tumors. In addition, the potential of therapies targeting intratumoral microbes, as well as the main challenges currently delaying these therapies, are explored. Furthermore, we briefly summarize existing technical methods used to characterize intratumoral microbes. We hope to provide ideas for exploring intratumoral microbes as potential biomarkers and targets for tumor diagnosis, treatment, and prognostication.

New insights into iNKT cells and their roles in liver diseases.

Natural killer T cells (NKTs) are an important part of the immune system. Since their discovery in the 1990s, researchers have gained deeper insights into the physiology and functions of these cells in many liver diseases. NKT cells are divided into two subsets, type I and type II. Type I NKT cells are also named iNKT cells as they express a semi-invariant T cell-receptor (TCR) α chain. As part of the innate immune system, hepatic iNKT cells interact with hepatocytes, macrophages (Kupffer cells), T cells, and dendritic cells through direct cell-to-cell contact and cytokine secretion, bridging the innate and adaptive immune systems. A better understanding of hepatic iNKT cells is necessary for finding new methods of treating liver disease including autoimmune liver diseases, alcoholic liver diseases (ALDs), non-alcoholic fatty liver diseases (NAFLDs), and liver tumors. Here we summarize how iNKT cells are activated, how they interact with other cells, and how they function in the presence of liver disease.

Role of main RNA modifications in cancer: N6-methyladenosine, 5-methylcytosine, and pseudouridine.

Cancer is one of the major diseases threatening human life and health worldwide. Epigenetic modification refers to heritable changes in the genetic material without any changes in the nucleic acid sequence and results in heritable phenotypic changes. Epigenetic modifications regulate many biological processes, such as growth, aging, and various diseases, including cancer. With the advancement of next-generation sequencing technology, the role of RNA modifications in cancer progression has become increasingly prominent and is a hot spot in scientific research. This review studied several common RNA modifications, such as N6-methyladenosine, 5-methylcytosine, and pseudouridine. The deposition and roles of these modifications in coding and noncoding RNAs are summarized in detail. Based on the RNA modification background, this review summarized the expression, function, and underlying molecular mechanism of these modifications and their regulators in cancer and further discussed the role of some existing small-molecule inhibitors. More in-depth studies on RNA modification and cancer are needed to broaden the understanding of epigenetics and cancer diagnosis, treatment, and prognosis.

Prostaglandin E2 and Receptors: Insight Into Tumorigenesis, Tumor Progression, and Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common primary liver cancer with ∼750,000 annual incidence rates globally. PGE2, usually known as a pro-inflammatory cytokine, is over-expressed in various human malignancies including HCC. PGE2 binds to EP receptors in HCC cells to influence tumorigenesis or enhance tumor progression through multiple pathways such as EP1-PKC-MAPK, EP2-PKA-GSK3ß, and EP4-PKA-CREB. In the progression of hepatocellular carcinoma, PGE2 can promote the proliferation and migration of liver cancer cells by affecting hepatocytes directly and the tumor microenvironment (TME) through ERK/COX-2/PGE2 signal pathway in hepatic stellate cells (HSC). For the treatment of hepatocellular carcinoma, there are drugs such as T7 peptide and EP1 antagonist ONO-8711 targeting Cox-2/PGE2 axis to inhibit tumor progression. In conclusion, PGE2 has been shown to be a traditional target with pleiotropic effects in tumorigenesis and progression of HCC that could be used to develop a new potential clinical impact. For the treatment study focusing on the COX-PGE2 axis, the exclusive usage of non-steroidal anti-inflammatory agents (NSAIDs) or COX-2-inhibitors may be replaced by a combination of selective EP antagonists and traditional anti-tumoral drugs to alleviate severe side effects and achieve better outcomes.

Regulatory mechanism of HIF-1α and its role in liver diseases: a narrative review.

Objective: To summarize the structure, regulatory mechanism, and target genes of hypoxia-inducible factor-1 alpha (HIF-1α) and to comprehensively expound its role in various chronic liver diseases, thus providing a new perspective on the treatment of various liver diseases. Background: Liver disease, especially chronic liver disease, is a long-standing public health problem; the mortality rate due to end-stage cirrhosis and liver cancer is high worldwide and continues to grow. Moreover, there is a lack of effective targeted therapy for most liver diseases, such as fatty liver, alcoholic liver disease (ALD), and advanced liver cancer, for which drug treatment approaches are extremely limited. As the liver is a highly aerobic organ, an insufficient oxygen supply can induce a series of diseases, and HIF proteins play an important role in these processes. Methods: Literature on HIF-1α and its effects on various liver diseases were extensively searched, and the feasibility and challenges of targeting HIF-1α to treat various chronic liver diseases were analyzed. Conclusions: HIF-1α is widely involved in the occurrence, development, and prognosis of ALD, nonalcoholic fatty liver disease (NAFLD), acetaminophen (APAP)-induced liver injury (AILI), viral hepatitis, hepatocellular carcinoma (HCC), and other liver diseases. HIF-1α participates in complex signaling pathways, and its expression is regulated in many liver diseases. These results suggest the feasibility and clinical significance of targeting HIF-1α to treat liver diseases.

Phosphoribosyl Pyrophosphate Amido Transferase: A New Prognostic Biomarker for Hepatocellular Carcinoma.

BACKGROUND: PPAT (phosphoribosyl pyrophosphate amido transferase) catalyzes the first committed step of de novo purine biosynthesis and is a key regulatory point in the biosynthesis of nascent purine nucleotides. However, the clinical significance and biologic role of PPAT in hepatocellular carcinoma (HCC) remain unknown. METHODS: We compared the expression of PPAT in carcinomatous and precancerous hepatocellular carcinoma tissues by immunohistochemistry in 90 cases of HCC. Correlation analysis was also made on clinical data, survival, classification, and staging. RESULTS: The expression of PPAT in HCC tumor tissues is significantly higher than that in adjacent normal tissues. The results of the Kaplan-Meier analysis showed that HCC patients with high PPAT expression survived shorter than those with low PPAT expression. Moreover, the expression of PPAT was significantly associated with the tumor grade (P=0.014), PD-L1 (P<0.001), and CTLA4 (P=0.003). The later grade of the tumor, the higher the expression of PPAT. In the PD-L1 high expression group, PPAT is also highly expressed. CONCLUSION: Our study demonstrated that PPAT expression might be included in the process of carcinogenesis and prognosis. Hence, PPAT could be served as a new prognostic biomarker for patients of HCC.

Long noncoding RNA SNHG4: a novel target in human diseases.

Recently, long noncoding RNAs (lncRNAs) have attracted great attention from researchers. LncRNAs are non-protein-coding RNAs of more than 200 nucleotides in length. Multiple studies have been published on the relationship between lncRNA expression and the progression of human diseases. LncRNA small nucleolar RNA host gene 4 (SNHG4), a member of the lncRNA SNHG family, is abnormally expressed in a variety of human diseases, including gastric cancer, renal cell carcinoma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, osteosarcoma, cervical cancer, liver cancer, lung cancer, non-small-cell lung cancer, neonatal pneumonia, diabetic retinopathy, neuropathic pain, acute cerebral infarction, acute myeloid leukaemia, and endometriosis. In this paper, the structure of SNHG4 is first introduced, and then studies in humans, animal models and cells are summarized to highlight the expression and function of SNHG4 in the above diseases. In addition, the specific mechanism of SNHG4 as a competing endogenous RNA (ceRNA) is discussed. The findings indicate that SNHG4 can be used as a biomarker for disease prognosis evaluation and as a potential target for disease diagnosis and treatment.

Uncovering the Association Between m5C Regulator-Mediated Methylation Modification Patterns and Tumour Microenvironment Infiltration Characteristics in Hepatocellular Carcinoma.

Background: 5-Methylcytosine (m5C) plays essential roles in hepatocellular carcinoma (HCC), but the association between m5C regulation and immune cell infiltration in HCC has not yet been clarified. Methods: In this study, we analysed 371 patients with HCC from The Cancer Genome Atlas (TCGA) database, and the expression of 13 m5C regulators was investigated. Additionally, gene set variation analysis (GSVA), unsupervised clustering analysis, single-sample gene set enrichment analysis (ssGSEA), correlation analysis, and immunohistochemical (IHC) staining were performed. Results: Among the 371 patients, 41 had mutations in m5C regulators, the frequency of which was 11.26%. Compared with normal hepatic tissues, the expression of m5C regulators with copy number variations (CNVs) expansion was significantly higher than that in HCC tissues. Then, we identified three m5C modification patterns that had obvious tumour microenvironment (TME) cell infiltration characteristics. The prognostic analysis of the three major m5C modification subtypes showed that Cluster-2 had a clear survival advantage over the others. In addition, we found that DNMT1 was highly expressed in tumour tissues compared with normal tissues in a tissue microarray (TMA) and that it was positively correlated with many TME-infiltrating immune cells. High expression of the m5C regulator DNMT1 was related to a poor prognosis in patients with HCC. Furthermore, we developed three distinct Immu-clusters. Importantly, mRNAs related to the transcription of growth factor ß (TGF-ß)/EMT pathway were significantly up-regulated in Immu-cluster 2, indicating that this cluster is considered to be the immune rejection phenotype. Immu-cluster 3 showed elevated expression of mRNAs related to immune checkpoint genes. Conclusion: Our work revealed the association between m5C modification and immune regulators in the TME. These findings also suggest that DNMT1 has great potential as a prognostic biomarker and therapeutic target for HCC.

The Emerging Role of Thymopoietin-Antisense RNA 1 as Long Noncoding RNA in the Pathogenesis of Human Cancers.

Long noncoding RNAs (lncRNAs) play essential roles in the occurrence and development of multiple human cancers. An accumulating body of researches have investigated thymopoietin antisense RNA 1 (TMPO-AS1) as a newly discovered lncRNA, which functions as an oncogenic lncRNA that is upregulated in various human malignancies and associated with poor prognosis. Many studies have detected abnormally high expression levels of TMPO-AS1 in multiple cancers, such as lung cancer, breast cancer, colorectal cancer (CRC), hepatocellular carcinoma, CRC, gastric cancer, ovarian cancer, thyroid cancer, esophageal cancer, Wilms tumor, cervical cancer, retinoblastoma, bladder cancer, osteosarcoma, and prostate cancer. TMPO-AS1 has been subsequently demonstrated to play a pivotal role in tumorigenesis and progression. The aberrantly expressed TMPO-AS1 acts as a competing endogenous RNA (ceRNA) that inhibits miRNA expression, thus activating the expression of downstream oncogenes. This study comprehensively summarizes the aberrant expressions of TMPO-AS1 as reported in the current literature and explains the relevant biological regulation mechanisms in carcinogenesis and tumor progression. Corresponding studies have indicated that TMPO-AS1 has a potential value as a promising biomarker or a target for cancer therapy.

HAND2-AS1: A functional cancer-related long non-coding RNA.

Long non-coding RNAs (lncRNAs) regulate gene expression and carcinogenesis. The lncRNA heart and neural crest derivatives expressed transcript 2 antisense RNA 1 (HAND2­AS1) suppresses tumor growth, and its expression level was lower in tumor tissues than in adjacent normal tissues of most types of human cancers, including non-small cell lung cancer, ovarian cancer, breast cancer, gastric cancer, colorectal cancer, cervical cancer, endometrial cancer, prostate cancer, and esophagus squamous cell carcinoma. However, one study reported that the HAND2­AS1 expression was upregulated in hepatocellular carcinoma tissues comparing with non-tumor tissues and it promoted tumor development. The aberrant expression of HAND2-AS1 was strongly linked to tumor progression and prognosis. Moreover, HAND2-AS1 was involved in tumor cell proliferation, differentiation, apoptosis, and cellular glucose metabolism. This review summarizes data on the expression profile, functions, underlying mechanism, and clinical value of HAND2-AS1 in cancer. The expression profile of HAND2-AS1 in 33 tumors was evaluated by bioinformatics analysis of The Cancer Genome Atlas.

DLX6-AS1 is a potential biomarker and therapeutic target in cancer initiation and progression.

Long noncoding RNAs (lncRNAs) are involved in multiple functions such as the regulation of cellular homeostasis. They play prominent roles in the pathogenesis of human cancer, and contribute to every hallmark of cancer. The novel cancer-related lncRNA DLX6 antisense RNA 1 (DLX6-AS1) plays an essential regulatory role in enhancing and initiating carcinogenesis and tumor progression. This progression is due to the aberrant regulation of downstream factors in vitro as well as in vivo. DLX6-AS1 is significantly dysregulated in various cancers. DLX6-AS1 functions in tumor initiation and progression are regulated at the epigenetic, transcription, and posttranscriptional regulation levels. DLX6-AS1 functions as an oncogene, binding to miRNA targeting sites competing endogenous RNAs and causing the upregulation of downstream tumor-related genes and carcinogenesis. The regulation and detailed molecular mechanisms of DLX6-AS1 and its potential role in malignancies are comprehensively described in this paper. DLX6-AS1 has the potential to become a novel biomarker and therapeutic target for cancer.

The dual functions of the long noncoding RNA CASC15 in malignancy.

Emerging evidence has demonstrated that long noncoding RNAs (lncRNAs) play vital roles in tumorigenesis and progression. LncRNAs can participate in various biological processes, such as cell growth, anti-apoptosis functions, migration, and invasion. Cancer susceptibility candidate 15 (CASC15) is a cancer-related lncRNA that has been reported to play opposite roles in the pathogenesis of different types of cancers. Studies have shown that CASC15 is downregulated in ovarian cancer and neuroblastoma, acting mainly as a tumour suppressor, while it is highly expressed and carcinogenic in hepatocellular carcinoma (HCC), lung cancer, tongue squamous cell carcinoma, gastric cancer, colorectal cancer, cervical cancer, and breast cancer. Furthermore, aberrant CASC15 expression is associated with tumorigenesis, progression, and patient outcomes via regulation of target genes and signalling pathways. In this review, we summarize current data concerning the regulatory functions and underlying mechanisms of CASC15 in tumour development. We also highlight its potential clinical utility as a biomarker for early detection or as a therapeutic target in human cancers.