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Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of non‐Hodgkin lymphoma and is associated with a poor prognosis. Data from the Gene Expression Profiling Interactive Analysis (GEPIA) database revealed dysregulated expression of several ubiquitin‐specific proteases (USPs) in DLBCL tissues (DLBCL vs. non‐DLBCL = 47 vs. 337), including USP19 (log2fold change = 1.17, P < 0.05). USP19 is closely linked to tumorigenesis, but its role in DLBCL progression remains largely unknown. Here, we investigated the role of USP19 in DLBCL development. Genetic manipulation of USP19 using adenovirus‐based vectors was performed in two DLBCL cell lines, SUDHL4 and DB cells. The results showed that USP19 knockdown suppressed the proliferation, anchorage‐independent growth and xenograft tumor formation of DLBCL cells and arrested the cell cycle at the G1 stage. In parallel, DLBCL cells overexpressing USP19 acquired a more malignant phenotype. Next, to explore USP19 interactors, we performed co‐immunoprecipitation/liquid chromatography–mass spectrometry and identified potential interacting proteins. Among them, Parkinson disease protein 7 (PARK7), a member of the peptidase C56 family known to be involved in carcinogenesis, was further validated to bind with and be stabilized by USP19. Additionally, we found that USP19 induced PARK7 deubiquitylation in both DLBCL cell lines, and PARK7 acted as a downstream effector of USP19 in regulating the growth of DLBCL cells. Collectively, USP19 exerts a tumor‐promoting role in DLBCL through interacting with and stabilizing PARK7. [ABSTRACT FROM AUTHOR]

Breast cancer has become the malignant tumor with the first incidence and the second mortality among female cancers. Most female breast cancers belong to luminal-type breast cancer and HER2-positive breast cancer. These breast cancer cells all have different driving genes, which constantly promote the proliferation and metastasis of breast cancer cells. Signal transducer and activator of transcription 3 (STAT3) is an important breast cancer-related gene, which can promote the progress of breast cancer. It has been proved in clinical and basic research that over-expressed and constitutively activated STAT3 is involved in the progress, proliferation, metastasis and chemotherapy resistance of breast cancer. STAT3 is an important key target in luminal-type breast cancer and HER2-positive cancer, which has an important impact on the curative effect of related treatments. In breast cancer, the activation of STAT3 will change the spatial position of STAT3 protein and cause different phenotypic changes of breast cancer cells. In the current basic research and clinical research, small molecule inhibitors activated by targeting STAT3 can effectively treat breast cancer, and enhance the efficacy level of related treatment methods for luminal-type and HER2-positive breast cancers. [ABSTRACT FROM AUTHOR]

As an AAA + ATPase, thyroid hormone receptor interacting protein 13 (TRIP13) primarily functions in DNA double-strand break repair, chromosome recombination, and cell cycle checkpoint regulation; aberrant expression of TRIP13 can result in chromosomal instability (CIN). According to recent research, TRIP13 is aberrantly expressed in a variety of cancers, and a patient's poor prognosis and tumor stage are strongly correlated with high expression of TRIP13. Tumor cell and subcutaneous xenograft growth can be markedly inhibited by TRIP13 knockdown or TRIP13 inhibitor administration. In the initiation and advancement of human malignancies, TRIP13 seems to function as an oncogene. Based on available data, TRIP13 may function as a biological target and biomarker for cancer. The creation of inhibitors that specifically target TRIP13 may present novel approaches to treating cancer. [ABSTRACT FROM AUTHOR]

Integrin α7 (ITGA7) is an extracellular matrix‐binding protein. Integrins are the main type of cell adhesive molecules in mammals, playing a role in many biological pathways. Although various studies have shown correlations between ITGA7 and various types of cancer, a comprehensive study at a pan‐cancer level has not yet been conducted. In this study, we investigated the function of ITGA7 in distinct tumor types using the multi‐omics relevant information, then two CeRNA regulatory network was drawn to identify the ITGA7 hub regulatory RNAs. The results indicated that the expression of ITGA7 varies in different tumors. Overexpression of ITGA7 was correlated with a worse OS in BLCA, LGG, and UVM, and the downregulation of ITGA7 was related to a worse OS in PAAD. In addition, BLCA, and UVM showed poor PFS in association with ITGA7 overexpression, and PAAD, SARC, and THCA indicated poor PFS in correlation with ITGA7 under expression. Further analyses of ITGA7 gene alteration data showed that ITGA7 amplifications may have an impact on Kidney Chromophobe prognosis. In 20 types of tumors, ITGA7 expression was linked to cancer‐associated fibroblast infiltration. ITGA7 expression was linked to cancer‐associated fibroblast infiltration. ITGA7‐Related Gene Enrichment Analysis indicated that ITGA7 expression‐correlated and functional binding genes were enriched in homotypic cell–cell adhesion, focal adhesion, and ECM‐receptor interaction. This pan‐cancer study found that abnormal expression of ITGA7 was correlated with poor prognosis and metastasis in different types of tumors. Thus, the ITGA7 gene may prove to be a promising biomarker for the prognosis and complication prevention of different cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: When oncogenes, which are genes that can cause cancer, become active, they disrupt normal cell processes, especially DNA replication. This disruption is known as replication stress (RS), in which the DNA copying process is stalled or damaged. To prevent cancer, cells usually have a defense system called the DNA damage response (DDR), which can prevent damaged cells from turning into cancer. However, some cells manage to survive this stress by developing replication stress tolerance (RST). These cells can continue to grow, leading to genomic instability (GIN), which is a key feature of cancer. GIN causes various genetic changes that make cells more likely to become cancerous and more difficult to treat. This review explains how oncogenes cause RS and how cells cope with it, leading to the development of cancer. Understanding these processes can help in developing new cancer treatments. Activation of oncogenes disturbs a wide variety of cellular processes and induces physiological dysregulation of DNA replication, widely referred to as replication stress (RS). Oncogene-induced RS can cause replication forks to stall or collapse, thereby leading to DNA damage. While the DNA damage response (DDR) can provoke an anti-tumor barrier to prevent the development of cancer, a small subset of cells triggers replication stress tolerance (RST), allowing precancerous cells to survive, thereby promoting clonal expansion and genomic instability (GIN). Genomic instability (GIN) is a hallmark of cancer, driving genetic alterations ranging from nucleotide changes to aneuploidy. These alterations increase the probability of oncogenic events and create a heterogeneous cell population with an enhanced ability to evolve. This review explores how major oncogenes such as RAS, cyclin E, and MYC induce RS through diverse mechanisms. Additionally, we delve into the strategies employed by normal and cancer cells to tolerate RS and promote GIN. Understanding the intricate relationship between oncogene activation, RS, and GIN is crucial to better understand how cancer cells emerge and to develop potential cancer therapies that target these vulnerabilities. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most prevalent human cancers with a high lethality rate worldwide. In this study, we demonstrated that GSE1 (genetic suppressor element 1) expression is aberrantly upregulated in lung adenocarcinoma and that GSE1 depletion inhibits the proliferation and migration of both A549 and H1299 cells. Immunoprecipitation assays demonstrated that GSE1 interacts with histone deacetylase 1 (HDAC1) and other BRAF–HDAC complex (BHC) components in cells. The transcriptome of GSE1‐knockdown A549 cells indicated that 207 genes were upregulated and 159 were downregulated based on a p‐value <.05 and fold change ≥ 1.5. Bioinformatics analysis suggested that 140 differentially expressed genes harbor binding sites for HDAC1, including the tumor suppressor gene KLF6 (Kruppel‐like factor 6). Indeed, quantitative reverse‐transcription polymerase chain reaction and western blot analysis revealed that GSE1 could inhibit the transcription of KLF6 in lung cancer cells. In conclusion, GSE1 cooperates with HDAC1 to promote the proliferation and metastasis of non‐small cell lung cancer cells through the downregulation of KLF6 expression. [ABSTRACT FROM AUTHOR]

This review concerns nc886, a 101-nucleotide non-coding RNA (ncRNA). Because nc886 is transcribed by RNA polymerase III (Pol III) and contains a CpG island in its promoter region, its expression is regulated by several transcription factors and the DNA methylation status. These features drive nc886 expression in two opposing directions during tumorigenesis. The known function of nc886 is to bind to and modulate the activity of target proteins such as PKR, Dicer, and OAS1. By being differentially expressed during tumorigenesis and interacting with these proteins, nc886 plays a role in tumor surveillance, promotes or suppresses tumorigenesis, and influences the efficacy of cancer therapy. The multiple roles of nc886 have been well-documented in the literature. In this review, we have summarized this literature and critically discussed the roles and mechanisms of action of nc886 in various cancers. [ABSTRACT FROM AUTHOR]

Background: Cholangiocarcinoma is a malignancy with high aggressiveness, and extrahepatic cholangiocarcinoma (ECCA) represents the predominant subtype. However, the molecular architecture and underlying pathogenic mechanisms of ECCA remain poorly understood. The objective of this study is to elucidate the molecular markers and biological pathways associated with ECCA. Methods: In order to identify the factors influencing ECCA, we conducted transcriptome sequencing on a cohort of 8 surgically resected ECCA specimens. To validate our findings, we integrated data from The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases using batch integration analysis. Finally, we confirmed our results using clinical samples. Results: The findings of this study reveal that through the analysis of sequencing data, we have successfully identified the genes that are differentially expressed and have a significant role in the development of ECCA. Utilizing the Weighted Gene Co- expression Network Analysis approach, we have integrated these identified gene modules with the GEO dataset, leading to the identification offour key genes (PTGDS, ITIH2, LSAMP, HBB) that are strongly associated with the progression-free survival of ECCA. We screened a key gene LSAMP from four genes using immunohistochemistry. The gene primarily participate in crucial biological processes such as the ECCA cell cycle and DNA replication. The qRT-PCR reaction and Western Blot conducted on the tissues provided confirmation of the expression levels of the gene, which exhibited consistency with the outcomes of our analysis. Conclusions: Our study has successfully identified potential biomarkers LSAMP for ECCA, which can serve as valuable tools for early detection and targeted therapeutic interventions in clinical settings. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of malignancies with worst outcomes among digestive system tumors. Identification of novel biomarkers is of great significance for treatment researches and prognosis prediction of pancreatic cancer patients. Due to OSBPL10 known involvement in oncogenic activity in other tumors, we elucidated the mechanism underlying its contribution to pancreatic cancer progression. We employed data from the Gene Expression Omnibus database to detect the expression of OSBPL10 in normal and pancreatic cancer tissues. A series of assays were conducted to assess the impact of OSBPL10 on the proliferation and metastatic capacities of pancreatic cancer cells and the influence of OSBPL10 on macrophages were evaluated by Flow cytometry. In addition, Co‐immunoprecipitation, mass spectrometry, and western blot assays were utilized to investigate the potential mechanisms of OSBPL10 activity. From our study, OSBPL10 is revealed to be upregulated in pancreatic cancer, with poor prognosis. The overexpression promotes malignant behaviors of pancreatic cancer cells and has an impact on tumor immune microenvironment by stimulating the transformation M1 macrophages into M2 macrophages. Mechanistically, hypoxia induces the expression of OSBPL10 through interaction between hypoxia‐inducible factor 1‐α and the promoter region of OSBPL10. Additionally, OSBPL10 directly bound to CNBP, mediating CNBP expression and ultimately regulating the proliferation and metastasis capacity of pancreatic cancer cells, as well as influencing macrophage polarization. The research emphasized the oncogenic role of OSBPL10 in pancreatic cancer, uncovering key mechanisms involving hypoxia, HIF‐1α, and CNBP. The finding suggests that OSBPL10 is a novel biomarker in pancreatic cancer, making it a potential therapeutic target for intervention in this malignancy. [ABSTRACT FROM AUTHOR]

Alpha beta hydrolase domain containing 5 (ABHD5) is an essential coactivator of adipose triglyceride lipase (ATGL), a rate-limiting enzyme in various cell types that promotes the hydrolysis of triacylglycerol (TG) into diacylglycerol (DG) and fatty acid (FA). It acts as a critical regulatory factor in cellular lipid metabolism. The reprogramming of lipid metabolism is one of the hallmarks of cancer, suggesting that altering lipid metabolism could become a new strategy for tumor treatment. Research has revealed a close association between ABHD5 and the development and progression of malignancies. This review summarizes the role of ABHD5 in various malignant tumors and explores the different signaling pathways and metabolic routes that may be involved, providing a comprehensive mechanistic understanding of ABHD5. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the role of Actin like 6 A (ACTL6A) in cancer and explore the potential mechanism of its function. Methods: Differential expression of ACTL6A was analyzed using Oncomine and TIMER database. Then, we downloaded data sets from TCGA database. The correlation between ACTL6A expression and survival in pan-cancer were analyzed by "survival", "survminer" R package and PrognoScan database. STRING (v 11.0) and stringAPP for Cytoscape v3.7.2 were used to predict ACTL6A associated genes. Copy number and methylation alterations of ACTL6A were analyzed using cBioPortal and GSCALite. Transcription factors were downloaded from The Human Transcription Factors Database and analyzed using "limma" R package, JASPAR and PROMO database. Correlations analysis between ACTL6A and immune cells were performed using TIMER and GEPIA database. Results: In our studies, we found that ACTL6A was widely upregulated in cancers, which might be attributed to its gene amplifications. Moreover, ACTL6A might regulated by transcription factors (TFs), including E2F1, YY1, CDX2 and HOXD10. In addition, high ACTL6A expression was associated with poor prognosis in most cancers. Meanwhile, ACTL6A was associated with the infiltration of immune cells, especially in liver hepatocellular carcinoma and brain lower grade glioma. Conclusion: Amplification of ACTL6A is correlated with poor prognosis and contribute to immune cells infiltration in LIHC and LGG, which may provide immune-related therapeutic targets to guide clinical strategies. [ABSTRACT FROM AUTHOR]

Tazarotene-induced gene 1 (TIG1) is induced by a derivative of vitamin A and is known to regulate many important biological processes and control the development of cancer. TIG1 is widely expressed in various tissues; yet in many cancer tissues, it is not expressed because of the methylation of its promoter. Additionally, the expression of TIG1 in cancer cells inhibits their growth and invasion, suggesting that TIG1 acts as a tumor suppressor gene. However, in some cancers, poor prognosis is associated with TIG1 expression, indicating its protumor growth characteristics, especially in promoting the invasion of inflammatory breast cancer cells. This review comprehensively summarizes the roles of the TIG1 gene in cancer development and details the mechanisms through which TIG1 regulates cancer development, with the aim of understanding its various roles in cancer development. [ABSTRACT FROM AUTHOR]

Tumor suppressor genes and proto-oncogenes comprise most of the complex genomic landscape associated with cancer, with a minimal number of genes exhibiting dual-context-dependent functions. The transcription factor cellular promoter 2 (TFCP2), a pivotal transcription factor encoded by the alpha globin transcription factor CP2 gene, is a constituent of the TFCP2/grainyhead family of transcription factors. While grainyhead members have been extensively studied for their crucial roles in developmental processes, embryogenesis, and multiple cancers, the TFCP2 subfamily has been relatively less explored. The molecular mechanisms underlying TFCP2's involvement in carcinogenesis are still unclear even though it is a desirable target for cancer treatment and a therapeutic marker. This comprehensive literature review summarizes the molecular functions of TFCP2, emphasizing its involvement in cancer pathophysiology, particularly in the epithelial-mesenchymal transition and metastasis. It highlights TFCP2's critical function as a regulatory target and explores its potential as a prognostic marker for survival and inflammation in carcinomas. Its ambiguous association with carcinomas underlines the urgent need for an in-depth understanding to facilitate the development of more efficacious targeted therapeutic modality and diagnostic tools. This study aims to elucidate the multifaceted effects of TFCP2 regulation, through a comprehensive integration of the existing knowledge in cancer therapeutics. Furthermore, the clinical relevance and the inherent challenges encountered in investigating its intricate role in cancer pathogenesis have been discussed in this review. [ABSTRACT FROM AUTHOR]

Abstract Breast cancer has become the malignant tumor with the first incidence and the second mortality among female cancers. Most female breast cancers belong to luminal-type breast cancer and HER2-positive breast cancer. These breast cancer cells all have different driving genes, which constantly promote the proliferation and metastasis of breast cancer cells. Signal transducer and activator of transcription 3 (STAT3) is an important breast cancer-related gene, which can promote the progress of breast cancer. It has been proved in clinical and basic research that over-expressed and constitutively activated STAT3 is involved in the progress, proliferation, metastasis and chemotherapy resistance of breast cancer. STAT3 is an important key target in luminal-type breast cancer and HER2-positive cancer, which has an important impact on the curative effect of related treatments. In breast cancer, the activation of STAT3 will change the spatial position of STAT3 protein and cause different phenotypic changes of breast cancer cells. In the current basic research and clinical research, small molecule inhibitors activated by targeting STAT3 can effectively treat breast cancer, and enhance the efficacy level of related treatment methods for luminal-type and HER2-positive breast cancers.

Abstract Purpose To investigate the role of Actin like 6 A (ACTL6A) in cancer and explore the potential mechanism of its function. Methods Differential expression of ACTL6A was analyzed using Oncomine and TIMER database. Then, we downloaded data sets from TCGA database. The correlation between ACTL6A expression and survival in pan-cancer were analyzed by “survival”, “survminer” R package and PrognoScan database. STRING (v 11.0) and stringAPP for Cytoscape v3.7.2 were used to predict ACTL6A associated genes. Copy number and methylation alterations of ACTL6A were analyzed using cBioPortal and GSCALite. Transcription factors were downloaded from The Human Transcription Factors Database and analyzed using “limma” R package, JASPAR and PROMO database. Correlations analysis between ACTL6A and immune cells were performed using TIMER and GEPIA database. Results In our studies, we found that ACTL6A was widely upregulated in cancers, which might be attributed to its gene amplifications. Moreover, ACTL6A might regulated by transcription factors (TFs), including E2F1, YY1, CDX2 and HOXD10. In addition, high ACTL6A expression was associated with poor prognosis in most cancers. Meanwhile, ACTL6A was associated with the infiltration of immune cells, especially in liver hepatocellular carcinoma and brain lower grade glioma. Conclusion Amplification of ACTL6A is correlated with poor prognosis and contribute to immune cells infiltration in LIHC and LGG, which may provide immune-related therapeutic targets to guide clinical strategies.

Background and Aim: Canine transmissible venereal tumor (CTVT), a unique transmissible cancer in dogs, affects the external genitalia and potentially spreads to other parts of the body. While somatic mutations in oncogenic and tumor-suppressing genes are linked to CTVT development, the impact of DNA methylation, which affects gene expression, remains unclear. This study explored whether DNA methylation in the promoter regions of the MYC oncogene and CDKN2B tumor suppressor genes in CTVTs is associated with their expression, both at the gene and protein levels. Materials and Methods: To investigate promoter DNA methylation of MYC and CDKN2B in CTVTs, we analyzed frozen tissue samples from genital CTVT (GTVTs) and extragenital CTVT (ETVTs). Genomic DNA was extracted, bisulfite-treated, and analyzed using bisulfite polymerase chain reaction (PCR) and sequencing. The messenger RNA and protein of MYC and CDKN2B were also extracted and assessed by real-time PCR and Western blotting. Matching formalin-fixed, paraffin-embedded blocks were used for immunohistochemical staining to visualize protein distribution in GTVT and ETVT tissues. Results: Although both GTVT and ETVT samples showed MYC promoter methylation, the extent of methylation differed significantly. GTVTs displayed a much higher degree of methylation, potentially explaining the more pronounced downregulation of MYC gene expression and reduction in c-MYC protein levels observed in GTVTs compared with ETVTs. Our data revealed a prevalent hypermethylation pattern in the CDKN2B promoter across both sample types. However, DNA methylation, which was expected to have a suppressive effect, did not correlate with gene/protein expression. GTVTs displayed high protein levels despite significantly reduced CDKN2B expression. Conversely, ETVTs maintained regular CDKN2B expression but exhibited reduced protein production, suggesting a complex interplay between methylation and expression in these tumors. Conclusion: MYC demonstrated a clear association between its promoter methylation status, gene expression, and protein levels; however, CDKN2B lacked this correlation, implying the involvement of methylation-independent regulatory mechanisms and highlighting the need for further investigation.

The effect of grainyhead‐like transcription factor 3 (GRHL3) on cancer development depends on the cancer subtypes as shown in tumor entities such as colorectal or oral squamous cell carcinomas. Here, we analyzed the subtype‐specific role of GRHL3 in bladder carcinogenesis, comparing common urothelial carcinoma (UC) with squamous bladder cancer (sq‐BLCA). We examined GRHL3 mRNA and protein expression in cohorts of patient samples, its prognostic role and its functional impact on tumorigeneses in different molecular and histopathological subtypes of bladder cancer. We showed for GRHL3 a reverse expression in squamous and urothelial bladder cancer subtypes. Stably GRHL3‐overexpressing EJ28, J82, and SCaBER in vitro models revealed a tumor‐suppressive function in squamous and an oncogenic role in the urothelial cancer cells affecting cell and colony growth, and migratory and invasive capacities. Transcriptomic profiling demonstrated highly subtype‐specific GRHL3‐regulated expression networks coined by the enrichment of genes involved in integrin‐mediated pathways. In SCaBER, loss of ras homolog family member A (RHOA) GTPase activity was demonstrated to be associated with co‐regulation of eukaryotic translation initiation factor 4E family member 3 (EIF4E3), a potential tumor suppressor gene. Thus, our data provide for the first time a detailed insight into the role of the transcription factor GRHL3 in different histopathological subtypes of bladder cancer.

Serine/threonine‐protein kinase B‐raf (BRAF) mutations are found in 8–15% of colorectal cancer patients and identify a subset of tumors with poor outcome in the metastatic setting. We have previously reported that BRAF‐mutant human cells display a high rate of protein production, causing proteotoxic stress, and are selectively sensitive to the proteasome inhibitors bortezomib and carfilzomib. In this work, we tested whether carfilzomib could restrain the growth of BRAF‐mutant colorectal tumors not only by targeting cancer cells directly, but also by promoting an immune‐mediated antitumor response. In human and mouse colorectal cancer cells, carfilzomib triggered robust endoplasmic reticulum stress and autophagy, followed by the emission of immunogenic‐damage‐associated molecules. Intravenous administration of carfilzomib delayed the growth of BRAF‐mutant murine tumors and mobilized the danger‐signal proteins calreticulin and high mobility group box 1 (HMGB1). Analyses of drug‐treated samples revealed increased intratumor recruitment of activated cytotoxic T cells and natural killers, concomitant with the downregulation of forkhead box protein P3 (Foxp3)+ T‐cell surface glycoprotein CD4 (CD4)+ T cells, indicating that carfilzomib promotes reshaping of the immune microenvironment of BRAF‐mutant murine colorectal tumors. These results will inform the design of clinical trials in BRAF‐mutant colorectal cancer patients.

Abnormalities of several oncogenes and tumor suppressor genes have been identified in carcinomas during the last decade and of pathological warfare and physiological traits, and multiple genetic changes have been demonstrated in individual carcinomas. We conducted a systematic review of studies enrolling adolescents and adults with Carcinoma, every type in which a cancer intervention was randomized, or all study designs in which there was a primary or secondary outcome. We searched Ovid MEDLINE, EMBASE, and Evidence-Based Medicine Reviews from 1990 to June 2015. Two reviewers evaluated study eligibility and abstracted data. In total, 67 studies were included and consisted of 62 randomized trials, reviews, and 5 studies. None of the studies (0/81) provided a definition. Only one randomized trial provided a definition. We were unable to identify any definitions used in studies of adolescents and adults with Carcinoma. Given that a proportion of this population may receive intensive treatment, there is an urgent need for consensus-based definitions of use across trials and review systematic & and meta-analysis.

The incidence of cancer is increasing worldwide and is the most common cause of death. Identification of novel cancer diagnostic and prognostic biomarkers is important for developing cancer treatment strategies and reducing mortality. Cyclin-dependent kinase subunit 2 (CKS2) is involved in cell cycle and proliferation processes, and based on these processes, CKS2 was identified as a cancer gene. CKS2 is expressed in a variety of tissues in the human body, but its abnormal expression is associated with cancer in a variety of systems. CKS2 is generally elevated in cancer, plays a role in almost all aspects of cancer biology (such as cell proliferation, invasion, metastasis, and drug resistance) through multiple mechanisms regulating certain important genes, and is associated with clinicopathological features of patients. In addition, CKS2 expression patterns are closely related to cancer type, stage and other clinical variables. Therefore, CKS2 is considered as a tool for cancer diagnosis and prognosis and may be a promising tumor biomarker and therapeutic target. This article reviews the biological function, mechanism of action and potential clinical significance of CKS2 in cancer, in order to provide a new theoretical basis for clinical molecular diagnosis, molecular targeted therapy and scientific research of cancer. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to detect candidate oncogenes of rhabdoid tumor of the kidney (RTK) and evaluate their roles in RTK in vitro. Methods: An integrated analysis of messenger RNA (mRNA) and microRNA (miRNA) sequencing was performed to determine the expression profile of exosome-derived miRNAs and mRNAs in human RTK-derived cell lines and a human embryonic renal cell line. A Gene Ontology enrichment analysis was performed to analyze the functional characteristics of differentially expressed mRNAs in RTK cells. Matrigel invasion and wound-healing assays were performed to evaluate the cell invasion and migration abilities. Results: Forty mRNAs were highly expressed in RTK cells targeted by exosomal miRNAs, the expression of which was lower in RTK cells than in the controls. These mRNAs were primarily related to cell adhesion. Of these mRNAs, we selected neuropilin 1 (NRP1) as a candidate oncogene because its upregulated expression is associated with a poor prognosis of several types of tumors. RTK cells in which NRP1 had been knocked down exhibited decreased invasive and migratory abilities. Conclusion: Our study indicates that NRP1 acts as an oncogene by promoting the invasion and migration of RTK cells and that it could serve as a therapeutic target. [ABSTRACT FROM AUTHOR]

The myeloma overexpressed gene (MYEOV) has been proposed to be a protooncogene due to high RNA transcript levels found in multiple cancers, including myeloma, breast, lung, pancreas and esophageal cancer. The presence of an open reading frame (ORF) in humans and other primates suggests protein-coding potential. Yet, we still lack evidence of a functional MYEOV protein. It remains undetermined how MYEOV overexpression affects cancerous tissues. In this work, we show that MYEOV has likely originated and may still function as an enhancer, regulating CCND1 and LTO1. Firstly, MYEOV 3' enhancer activity was confirmed in humans using publicly available ATAC-STARR-seq data, performed on B-cell-derived GM12878 cells. We detected enhancer histone marks H3K4me1 and H3K27ac overlapping MYEOV in multiple healthy human tissues, which include B cells, liver and lung tissue. The analysis of 3D genome datasets revealed chromatin interactions between a MYEOV-3'-putative enhancer and the proto-oncogene CCND1. BLAST searches and multi-sequence alignment results showed that DNA sequence from this human enhancer element is conserved from the amphibians/amniotes divergence, with a 273 bp conserved region also found in all mammals, and even in chickens, where it is consistently located near the corresponding CCND1 orthologues. Furthermore, we observed conservation of an active enhancer state in the MYEOV orthologues of four non-human primates, dogs, rats, and mice. When studying this homologous region in mice, where the ORF of MYEOV is absent, we not only observed an enhancer chromatin state but also found interactions between the mouse enhancer homolog and Ccnd1 using 3D-genome interaction data. This is similar to the interaction observed in humans and, interestingly, coincides with CTCF binding sites in both species. Taken together, this suggests that MYEOV is a primatespecific gene with a de novo ORF that originated at an evolutionarily older enhancer region. This deeply conserved putative enhancer element could regulate CCND1 in both humans and mice, opening the possibility of studying MYEOV regulatory functions in cancer using non-primate animal models. [ABSTRACT FROM AUTHOR]

Introduction: Local Australian guidelines for the optimal management of stage III unresectable non-small cell lung cancer (NSCLC) are lacking. The American Society of Clinical Oncology (ASCO) guidelines recommend consolidation durvalumab for all patients with unresectable stage III NSCLC, irrespective of their PD-L1 expression or driver mutation status. The European Society of Medical Oncology (ESMO) differs, with consolidation durvalumab only recommended in those patients whose tumours express PD-L1. Methods: Due to differing global guidelines, we conducted an Australia and New Zealand wide survey of medical oncologists specialising in thoracic cancer to determine the variations in patterns of prescribing durvalumab in stage III unresectable NSCLC. This survey was done electronically and sponsored by the Thoracic Oncology Group of Australia (TOGA). Results: Thirty-two medical oncologists completed the survey. In patients with EGFR-mutated stage III unresectable NSCLC, 6% of respondents stated that they prescribed durvalumab for all patients, while an additional 6% strongly recommended treatment. Forty-four percent suggested little benefit of consolidation durvalumab in this cohort, with an additional 19% advocating for observation only. In patients with PD-L1 negative (0%) stage III unresectable NSCLC, 13% of respondents prescribed durvalumab for all patients, while an additional 56% strongly recommended treatment. Interestingly, 18%, 10%, and 10% of prescribers discussed self-funded oral tyrosine kinase inhibitor therapy in patients with EGFR, ALK, or ROS-1-mutated NSCLC respectively as a substitute for consolidation durvalumab. Conclusion: Overall, the clinical practice of Australian and New Zealand Medical Oncologists is variable, but remains consistent with either the ASCO or ESMO guidelines. Local practice guidelines are required to ensure consistency in prescribing patterns across Australia, as well as providing evidence for self-funded treatments outside standard of care. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) are well known for their oncogenic or anti-oncogenic roles in cancer development. AGAP2-AS1, a new lncRNA, has been extensively demonstrated as an oncogenic lncRNA in various cancers. Abundant experimental results have proved the aberrantly high level of AGAP2-AS1 in a great number of malignancies, such as glioma, colorectal, lung, ovarian, prostate, breast, cholangiocarcinoma, bladder, colon and pancreatic cancers. Importantly, the biological functions of AGAP2-AS1 have been extensively demonstrated. It could promote the proliferation, migration and invasion of cancer cells. Simultaneously, the clinical significances of AGAP2-AS1 were also illustrated. AGAP2-AS1 was exceptionally overexpressed in various cancer tissues. Clinical studies disclosed that the abnormal overexpression of AGAP2-AS1 was tightly connected with overall survival (OS), lymph nodes metastasis (LNM), clinical stage, tumor infiltration, high histological grade (HG), serous subtype and PFI times. However, to date, the biological actions and clinical significances of AGAP2-AS1 have not been systematically reviewed in human cancers. In the present review, the authors overviewed the biological actions, potential mechanisms and clinical features of AGAP2-AS1 according to the previous studies. In summary, AGAP2-AS1, as a vital oncogenic gene, is a promising biomarker and potential target for carcinoma prognosis and therapy. [ABSTRACT FROM AUTHOR]

ErbB3‐binding protein 1(Ebp1) has two isoforms, p42 Ebp1 and p48 Ebp1, both of which can regulate cell growth and differentiation. But these isoforms often have opposite effects, including contradictory roles in regulation of cell growth in different tissues and cells. P48 Ebp1 belongs to the full‐length sequence, while conformational changes in the crystal structure of p42 Ebp1 reveals a lack of an α helix at the amino terminus. Due to the differences in the structures of these two isoforms, they have different binding partners and protein modifications. Ebp1 can function as both an oncogene and a tumor suppressor factor. However, the underlying mechanisms by which these two isoforms exert opposite functions are still not fully understood. In this review, we summarize the genes and the structures of protein of these two isoforms, protein modifications, binding partners and the association of different isoforms with diseases. [ABSTRACT FROM AUTHOR]

Multiple studies indicate that iron chelators enhance their anti-cancer properties by inducing NDRG1, a known tumor and metastasis suppressor. However, the exact role of NDRG1 remains controversial, as newer studies have shown that NDRG1 can also act as an oncogene. Our group recently introduced mitochondrially targeted iron chelators deferoxamine (mitoDFO) and deferasirox (mitoDFX) as effective anti-cancer agents. In this study, we evaluated the ability of these modified chelators to induce NDRG1 and the role of NDRG1 in breast cancer. We demonstrated that both compounds specifically increase NDRG1 without inducing other NDRG family members. We have documented that the effect of mitochondrially targeted chelators is at least partially mediated by GSK3α/β, leading to phosphorylation of NDRG1 at Thr346 and to a lesser extent on Ser330. Loss of NDRG1 increases cell death induced by mitoDFX. Notably, MDA-MB-231 cells lacking NDRG1 exhibit reduced extracellular acidification rate and grow slower than parental cells, while the opposite is true for ER+ MCF7 cells. Moreover, overexpression of full-length NDRG1 and the N-terminally truncated isoform (59112) significantly reduced sensitivity towards mitoDFX in ER+ cells. Furthermore, cells overexpressing full-length NDRG1 exhibited a significantly accelerated tumor formation, while its N-terminally truncated isoforms showed significantly impaired capacity to form tumors. Thus, overexpression of full-length NDRG1 promotes tumor growth in highly aggressive triple-negative breast cancer. [ABSTRACT FROM AUTHOR]

Cancer research is linked to modern life-sciences, encompassing achievements in virology, yeast-biology, molecular-biology, genetics, systems-biology, bioinformatics, and so on. With these fascinating developments, it's easy to overlook that the fundamental theories and treatment strategies were established in the early 20th century and have remained valid ever since. Therefore, tribute must be paid to the founders of the field. The main hypotheses on carcinogenesis, the genetic model and the metabolic model, and the concept of cancer-treatment with cytotoxic, targeted or metabolic drugs were proposed more than 100 years ago by great minds such as T. Boveri, O. Warburg, and P. Ehrlich. Hence nothing about these cancer concepts is really new. Through development of powerful new technologies, we have been able to decipher the mechanisms of malignant transformation, thus significantly advancing the field. Our own studies have been focused on the cross-talk between cell-growth-signaling and lipid-metabolism in ovarian cancer to find crossover-points for co-targeting in order to achieve synergistic treatment effects. Notably, a side-effect of the application of current methods of molecularcell-biology is a deeper knowledge of the laws of normal cell-biology and cell-life. Thus we anticipate the field will advance rapidly in the near future. [ABSTRACT FROM AUTHOR]

Extrachromosomal DNA (ecDNA) are circular regions of DNA that are found in many cancers. They are an important means of oncogene amplification, and correlate with treatment resistance and poor prognosis. Consequently, there is great interest in exploring and targeting ecDNA vulnerabilities as potential new therapeutic targets for cancer treatment. However, the biological significance of ecDNA and their associated regulatory control remains unclear. Light microscopy has been a central tool in the identification and characterisation of ecDNA. In this review we describe the different cellular models available to study ecDNA, and the imaging tools used to characterise ecDNA and their regulation. The insights gained from quantitative imaging are discussed in comparison with genome sequencing and computational approaches. We suggest that there is a crucial need for ongoing innovation using imaging if we are to achieve a full understanding of the dynamic regulation and organisation of ecDNA and their role in tumourigenesis. [ABSTRACT FROM AUTHOR]

Major facilitator superfamily domain containing 12 (MFSD12) regulates lysosomal cysteine import and promotes the proliferation and survival of melanoma cells. However, the expression and function of MFSD12 in other cancers, particularly in lung cancer, remain unclear. The expression of MFSD12 across various types of cancers and corresponding control tissues was examined using TIMER. MFSD12 expression in lung adenocarcinoma (LUAD) and its correlation with distinct clinicopathological features of LUAD patients were analyzed with UALCAN. The correlation between MFSD12 expression and survival of LUAD patients was assessed using the R package, survival, and the relationship between MFSD12 expression and immune infiltration status in LUAD was investigated using CIBERSORT. In addition, MFSD12 expression was knocked down in PC9 LUAD cells and their proliferation, capacity for expansion, cell cycle, apoptosis, and migration/invasion were evaluated through CCK-8 assays, colony formation assays, 7-AAD staining, Annexin V/PI staining, and Transwell assays, respectively. The stemness of these PC9 cells was determined through Western blotting, flow cytometry, and tumor sphere formation assays. MFSD12 mRNA levels were significantly elevated in multiple types of cancers, including LUAD. MFSD12 expression was also positively correlated with cancer stage, nodal metastasis, and infiltration of various immune cells in LUAD, and high MFSD12 levels predicted poor survival among LUAD patients. Knockdown of MFSD12 in PC9 cells resulted in decreased proliferation, attenuated colony formation capacity, cell cycle arrest, elevated apoptosis, impaired migration/invasion, and reduced stemness in PC9 cells. MFSD12 is an oncogene in LUAD. [ABSTRACT FROM AUTHOR]

Background: B-cell acute lymphoblastic leukemia (B-ALL) is a complex disorder that includes multiple genetic changes, one of the main causes of which is rare and common chromosomal translocations that lead to abnormal gene fusions. This abnormal fusion produces a new protein that causes the leukemia cells. These types of rearrangements usually occur in lymphoma and result in the movement of genetic material between different chromosomes or within chromosomes. This systematic review aims to evaluate published studies and investigate the role and importance of common and rare chromosomal translocations in the occurrence of BALL. Material and Methods: This systematic review investigated and evaluated the evidence regarding the effect of chromosomal translocations in adults and pediatrics with B-ALL. This review was based on the preferred reporting items for systematic reviews and meta-analysis checklists. A literature search was conducted using international databases (such as PubMed, Web of Science, Scopus, Research Gate, Google Scholar, and Cochrane Systematic Reviews database). Only English-language articles published between January 2010 and January 2023 including MESH terms such as ALL, B-ALL, and chromosomal translocations were selected. Seventy-five related studies had the necessary criteria to be examined in the present study. Results: A total of 237 articles were retrieved in the online search. The excluded articles included research on other types of leukemia in adults and children, descriptive studies, case studies, studies related to animal models of leukemogenesis, and comparisons of common treatment methods of leukemia grouping cancers. Finally, seventy-five studies were identified as eligible for inclusion in this systematic review. Conclusion: This review provides a comprehensive assessment of common and rare chromosomal translocations that can lead to the development of cancer cells. Chromosomal translocations play a role as diagnostic markers and important prognostic indicators and help specialists adjust treatment approaches according to their occurrence. [ABSTRACT FROM AUTHOR]

Introduction: The members retinoic acid receptors (RARs) (α, β, and γ) and retinoid X receptors (RXRs) (α, β, and γ) belong to the retinoid receptor family. They regulate the biological action of classical retinoids through nuclear retinoid receptors, a transcription factor that is regulated by ligands. Through the binding of particular retinoic acid-responsive elements (RAREs) located in target gene promoters, RARs and members of the RXRs form heterodimers. By binding to its nuclear receptors and triggering the transcription of the target genes downstream, retinoic acid (RA) mediates the expression of certain genes. Retinoids so mainly control gene expression to carry out their biological actions. RARs are essential for many biological processes, such as development, immunity, reproduction, organogenesis, and homeostasis. Apart from their physiological functions, RARs are also linked to pathologies and tumors due to mutations, protein fusions, changes in expression levels, or abnormal post-translational changes that lead to aberrant functions and homeostasis breakdown. The oncogenic development of animal tissues or cultured cells is linked to altered expression of retinoid receptors. The RAR-α is over-expressed in several malignancies. Increased invasion and migration in several cancer forms, including HNSC carcinoma, pediatric low-grade gliomas, lung adenocarcinoma, and breast cancer, have been linked to its upregulated expression. Numerous approved therapeutic regimens targeting RAR-α have been developed, improving patient survival rates. Objective: This study’s main objective was to identify novel RAR-α-targeting drugs and evaluate the expression patterns of RAR-α in breast cancer patients. Methodology: In-silico investigation using a variety of bioinformatics tools like UALCAN, TISCH, TIMER 2.0, ENRICHR, and others were employed to examine the expression of RAR-α. Further we evaluated in-silico inhibition of RAR-α with trifarotene and also tested the cytotoxicity of trifarotene in breast cancer cells. Results: Our research indicates that RAR-α is upregulated in several malignancies including Breast Cancer. It regulates granulocyte differentiation and has an association with the retinoic acid receptor signaling pathway and cellular response to estrogen stimulus. Furthermore, trifarotene was found as a potential synthetic compound that targets RAR-α through in silico and invitro study. Discussion: Overall, this research indicates that elevated expression of RAR-α enhances the onset of breast cancer. Using trifarotene medication to target RAR-α will significantly boost the response of breast cancer individuals to treatment and delay the development of resistance to drugs. [ABSTRACT FROM AUTHOR]

The 10th International MDM2 Workshop was held at the National Cancer Center Research Institute (NCCRI) in Tokyo, Japan, from October 15 to 18, 2023. It attracted 166 participants from 12 countries. The meeting featured 52 talks and 41 poster presentations. In the first special session, six invited speakers gave educational and outstanding talks on breakthroughs in MDM2 research. Three keynote speakers presented emerging p53‐independent functions of MDM2/MDM4, functional association of MDM2/p53 with cancer immunity, and drug discovery targeting the MDM2/MDM4‐p53 pathway. Additionally, 19 invited speakers introduced their new findings. Twenty‐one presenters, many of whom were young investigators, postdocs, and students, were selected from submitted abstracts and reported their exciting and unpublished results. For poster presenters, outstanding poster awards were given to the best presenters. There were many inspiring questions and discussions throughout the meeting. Social events like a welcome party, a workshop dinner, and an optional tour enabled further scientific interactions among the participants. The meeting successfully provided an exciting platform for scientific exchange. The experience gained from organizing this meeting will be handed over to the next organizers of the 11th International MDM2 Workshop. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most common malignancies worldwide. Hypoxia‐inducible domain (HIGD) family members (e.g., HIGD1A) have been linked to tumor progression. However, the role of HIGD1B (another HIGD family member) in GC has yet to be fully understood. Based on data from TCGA_GC, GSE65801, and GSE65801 data sets, HIGD1B levels were evaluated in normal and GC tissues. Next, HIGD1B levels were validated by reverse transcription‐quantitative PCR and western blot analysis analyses. Meanwhile, patients with GC in the TCGA_GC cohort were grouped into high‐ and low‐HIGD1B level groups, and overall survival, functional enrichment, and immune infiltration were analyzed. Additionally, gain‐ and loss‐of‐function experiments were performed to determine the function of HIGD1B in GC cells. Compared to normal controls, HIGD1B mRNA levels were significantly elevated in GC tissues. Moreover, high HIGD1B levels may be an independent indicator of poor prognosis in patients with GC. Additionally, high HIGD1B levels were correlated with high stromal and ESTIMATE scores and elevated expression of immune checkpoints in patients with GC. Functional analyses showed that HIGD1B deficiency notably suppressed GC cell proliferation, migration, and invasion. Moreover, HIGD1B deficiency significantly induced mitochondria‐mediated apoptosis in GC cells by inactivating Akt and ERK pathways. Collectively, HIGD1B may predict the prognosis of patients with GC and may function as an oncogene in GC. These findings suggest that HIGD1B may serve as a prognostic biomarker and potential therapeutic target in GC. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common type of primary malignant bone tumor. Due to the lack of selectivity and sensitivity of chemotherapy drugs to tumor cells, coupled with the use of large doses, chemotherapy drugs often have systemic toxicity. The use of modern sequencing technology to screen tumor markers in a large number of tumor samples is a common method for screening highly specific and selective anti-tumor drugs. This study aims to identify potential biomarkers using the latest reported gene expression signatures of oncogene-induced replication stress (ORS) in aggressive cancers, and potential anti-osteosarcoma drugs were screened in different drug databases. In this study, we obtained 89 osteosarcoma-related samples in the TARGET database, all of which included survival information. According to the median expression of each of six reported ORS gene markers (NAT10/DDX27/ZNF48/C8ORF33/MOCS3/MPP6), we divided 89 osteosarcoma gene expression datasets into a high expression group and a low expression group and then performed a differentially expressed gene (DEG) analysis. The coexisting genes of 6 groups of DEGs were used as replication stress-related genes (RSGs) of osteosarcoma. Then, key RSGs were screened using LASSO regression, a Cox risk proportional regression prognostic model and a tenfold cross-validation test. GSE21257 datasets collected from the Gene Expression Omnibus (GEO) database were used to verify the prognostic model. The final key RSGs selected were used in the L1000PWD and DGIdb databases to mine potential drugs. After further validation by the prognostic model, we identified seven genes associated with ORS in osteosarcoma as key RSGs, including transcription factor 7 like 2 (TCF7L2), solute carrier family 27 member 4 (SLC27A4), proprotein convertase subtilisin/kexin type 5 (PCSK5), nucleolar protein 6 (NOL6), coiled-coil-coil-coil-coil-helix domain containing 4 (CHCHD4), eukaryotic translation initiation factor 3 subunit B (EIF3B), and synthesis of cytochrome C oxidase 1 (SCO1). Then, we screened the seven key RSGs in two drug databases and found six potential anti-osteosarcoma drugs (D GIdb database: repaglinide, tacrolimus, sirolimus, cyclosporine, and hydrochlorothiazide; L1000PWD database: the small molecule VU-0365117-1). Seven RSGs (TCF7L2, SLC27A4, PCSK5, NOL6, CHCHD4, EIF3B, and SCO1) may be associated with the ORS gene signatures in osteosarcoma. Repaglinide, tacrolimus, sirolimus, cyclosporine, hydrochlorothiazide and the small molecule VU-0365117-1 are potential therapeutic drugs for osteosarcoma. [ABSTRACT FROM AUTHOR]

The effect of grainyhead‐like transcription factor 3 (GRHL3) on cancer development depends on the cancer subtypes as shown in tumor entities such as colorectal or oral squamous cell carcinomas. Here, we analyzed the subtype‐specific role of GRHL3 in bladder carcinogenesis, comparing common urothelial carcinoma (UC) with squamous bladder cancer (sq‐BLCA). We examined GRHL3 mRNA and protein expression in cohorts of patient samples, its prognostic role and its functional impact on tumorigeneses in different molecular and histopathological subtypes of bladder cancer. We showed for GRHL3 a reverse expression in squamous and urothelial bladder cancer subtypes. Stably GRHL3‐overexpressing EJ28, J82, and SCaBER in vitro models revealed a tumor‐suppressive function in squamous and an oncogenic role in the urothelial cancer cells affecting cell and colony growth, and migratory and invasive capacities. Transcriptomic profiling demonstrated highly subtype‐specific GRHL3‐regulated expression networks coined by the enrichment of genes involved in integrin‐mediated pathways. In SCaBER, loss of ras homolog family member A (RHOA) GTPase activity was demonstrated to be associated with co‐regulation of eukaryotic translation initiation factor 4E family member 3 (EIF4E3), a potential tumor suppressor gene. Thus, our data provide for the first time a detailed insight into the role of the transcription factor GRHL3 in different histopathological subtypes of bladder cancer. [ABSTRACT FROM AUTHOR]

Serine/threonine‐protein kinase B‐raf (BRAF) mutations are found in 8–15% of colorectal cancer patients and identify a subset of tumors with poor outcome in the metastatic setting. We have previously reported that BRAF‐mutant human cells display a high rate of protein production, causing proteotoxic stress, and are selectively sensitive to the proteasome inhibitors bortezomib and carfilzomib. In this work, we tested whether carfilzomib could restrain the growth of BRAF‐mutant colorectal tumors not only by targeting cancer cells directly, but also by promoting an immune‐mediated antitumor response. In human and mouse colorectal cancer cells, carfilzomib triggered robust endoplasmic reticulum stress and autophagy, followed by the emission of immunogenic‐damage‐associated molecules. Intravenous administration of carfilzomib delayed the growth of BRAF‐mutant murine tumors and mobilized the danger‐signal proteins calreticulin and high mobility group box 1 (HMGB1). Analyses of drug‐treated samples revealed increased intratumor recruitment of activated cytotoxic T cells and natural killers, concomitant with the downregulation of forkhead box protein P3 (Foxp3)+ T‐cell surface glycoprotein CD4 (CD4)+ T cells, indicating that carfilzomib promotes reshaping of the immune microenvironment of BRAF‐mutant murine colorectal tumors. These results will inform the design of clinical trials in BRAF‐mutant colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Cancer is a heavy human burden worldwide, with high morbidity and mortality. Identification of novel cancer diagnostic and prognostic biomarkers is important for developing cancer treatment strategies and reducing mortality. Transcription factors, including SRY associated high mobility group box (SOX) proteins, are thought to be involved in the regulation of specific biological processes. There is growing evidence that SOX transcription factors play an important role in cancer progression, including tumorigenesis, changes in the tumor microenvironment, and metastasis. SOX5 is a member of SOX Group D of Sox family. SOX5 is expressed in various tissues of human body and participates in various physiological and pathological processes and various cellular processes. However, the abnormal expression of SOX5 is associated with cancer of various systems, and the abnormal expression of SOX5 acts as a tumor promoter to promote cancer cell viability, proliferation, invasion, migration and EMT through multiple mechanisms. In addition, the expression pattern of SOX5 is closely related to cancer type, stage and adverse clinical outcome. Therefore, SOX5 is considered as a potential biomarker for cancer diagnosis and prognosis. In this review, the expression of SOX5 in various human cancers, the mechanism of action and potential clinical significance of SOX5 in tumor, and the therapeutic significance of Sox5 targeting in cancer were reviewed. In order to provide a new theoretical basis for cancer clinical molecular diagnosis, molecular targeted therapy and scientific research. [ABSTRACT FROM AUTHOR]

NCYM is a cis-antisense gene of MYCN oncogene and encodes an oncogenic protein that stabilizes MYCN via inhibition of GSK3b. High NCYM expression levels are associated with poor clinical outcomes in human neuroblastomas, and NCYM overexpression promotes distant metastasis in animal models of neuroblastoma. Using vacuum-ultraviolet circular dichroism and small-angle X-ray scattering, we previously showed that NCYM has high flexibility with partially folded structures; however, further structural characterization is required for the design of anti-cancer agents targeting NCYM. Here we report the 1H, 15N and 13C nuclear magnetic resonance assignments of NCYM. Secondary structure prediction using Secondary Chemical Shifts and TALOS-N analysis demonstrates that the structure of NCYM is essentially disordered, even though residues in the central region of the peptide clearly present a propensity to adopt a dynamic helical structure. This preliminary study provides foundations for further analysis of interaction between NCYM and potential partners. [ABSTRACT FROM AUTHOR]

Background & Aims: Transforming growth factor β (TGF-β) plays an oncogenic role in advanced cancer by promoting cell proliferation, metastasis and immunosuppression. PMEPA1 (prostate transmembrane protein androgen induced 1) has been shown to promote TGF-β oncogenic effects in other tumour types. Thus, we aimed to explore the role of PMEPA1 in hepatocellular carcinoma (HCC). Methods: We analysed 1,097 tumours from patients with HCC, including discovery (n = 228) and validation (n = 361) cohorts with genomic and clinicopathological data. PMEPA1 levels were assessed by qPCR (n = 228), gene expression data (n = 869) and at the single-cell level (n = 54). Genetically engineered mouse models overexpressing MYC+PMEPA1 compared to MYC were generated and molecular analyses were performed on the HCCs obtained. Results: PMEPA1 was overexpressed in 18% of HCC samples (fold-change >2; n = 201/1,097), a feature associated with TGF-β signalling activation (p

Abstract In cancer treatment, therapeutic strategies that integrate tumor-specific characteristics (i.e., precision oncology) are widely implemented to provide clinical benefits for cancer patients. Here, through in-depth integration of tumor transcriptome and patients’ prognoses across cancers, we investigated dysregulated and prognosis-associated genes and catalogued such important genes in a cancer type-dependent manner. Utilizing the expression matrices of these genes, we built models to quantitatively evaluate the malignant levels of tumors across cancers, which could add value to the clinical staging system for improved prediction of patients’ survival. Furthermore, we performed a transcriptome-based molecular subtyping on hepatocellular carcinoma, which revealed three subtypes with significantly diversified clinical outcomes, mutation landscapes, immune microenvironment, and dysregulated pathways. As tumor transcriptome was commonly profiled in clinical practice with low experimental complexity and cost, this work proposed easy-to-perform approaches for practical clinical promotion towards better healthcare and precision oncology of cancer patients.

Abstract Background Studies evaluating the effectiveness of immune checkpoint inhibitors (ICI) for endometrial cancer (EC) are limited. This study aimed to assess the efficacy of PD-1/PD-L1 inhibitors as monotherapy for EC by conducting a meta-analysis. The predictive significance of MMR status, a biomarker for ICI response, also required further investigation. Methods A systematic literature search was conducted in English databases until September 2023. The analysis included objective response rate (ORR), disease control rate (DCR), adverse events (AEs), and odds ratios (OR), along with their corresponding 95% confidence intervals (CI). Results There were twelve trials totaling 685 individuals. PD-1/PD-L1 inhibitor monotherapy resulted in an ORR for 34% (95% CI = 24–44%) of the pooled EC patients. Subgroup analysis revealed a significantly higher ORR in dMMR EC (45%) compared to pMMR EC (8%), with an OR of 6.36 (95% CI = 3.64–11.13). The overall DCR was 42%, with dMMR EC at 51% and pMMR EC at 30% (OR = 2.61, 95% CI = 1.69–4.05). Grade three or higher adverse events (AEs) occurred in 15% of cases (95% CI = 9–24%) of the pooled incidence of AEs, which was 68% (95% CI = 65–72%). Conclusions This meta-analysis provides significant evidence for the effectiveness of PD-1/PD-L1 inhibitors as monotherapy for EC. Notably, dMMR EC patients demonstrated superior treatment efficacy with PD-1/PD-L1 inhibitor immunotherapy. Further research is required to explore subclassifications of EC based on dMMR molecular subtypes, enabling improved treatment strategies and outcomes for EC patients.

Abstract Esophageal squamous cell carcinoma (ESCC) is one of most prevalent cancers worldwide, especially in China. Lacking in depth mechanism study, effective targets and therapeutics are desperately needed in the clinic. RNA-binding proteins (RBPs) mediate the localization, stability, and translation of the target transcripts and fine-tune the physiological functions of the proteins encoded. Bioinformatics analysis revealed that IGF2BPs were highly expressed in ESCC tissues and at least participated in the regulation of cell proliferation of ESCC cells. Biological researches demonstrated that IGF2BP2 promoted the cell proliferation, migration and invasion of ESCC KYSE30 and KYSE450 cells. IGF2BP2 could bind to EIF4A1 mRNA by recognition of m6A sites and enhanced translation of EIF4A1. IGF2BPs, as m6A reader, IGF2BPs were oncogenic genes in ESCC by regulating the expression of EIF4A1 through m6A sites. IGF2BP2, EIF4A1 and their targets could serve as potential biomarkers and therapeutic targets for ESCC, offering promising novel approaches for the diagnosis and treatment of ESCC.

KRAS is a small GTPase that is among the most commonly mutated oncogenes in cancer. Here, we discuss KRAS biology, therapeutic avenues to target it, and mechanisms of resistance that tumors employ in response to KRAS inhibition. Several strategies are under investigation for inhibiting oncogenic KRAS, including small molecule compounds targeting specific KRAS mutations, pan-KRAS inhibitors, PROTACs, siRNAs, PNAs, and mutant KRAS-specific immunostimulatory strategies. A central challenge to therapeutic effectiveness is the frequent development of resistance to these treatments. Direct resistance mechanisms can involve KRAS mutations that reduce drug efficacy or copy number alterations that increase the expression of mutant KRAS. Indirect resistance mechanisms arise from mutations that can rescue mutant KRAS-dependent cells either by reactivating the same signaling or via alternative pathways. Further, non-mutational forms of resistance can take the form of epigenetic marks, transcriptional reprogramming, or alterations within the tumor microenvironment. As the possible strategies to inhibit KRAS expand, understanding the nuances of resistance mechanisms is paramount to the development of both enhanced therapeutics and innovative drug combinations.

Abstract Background Although oncogenic RAS mutants are thought to exert mutagenic effects upon blood cells, it remains uncertain how a single oncogenic RAS impacts non-transformed multipotent hematopoietic stem or progenitor cells (HPCs). Such potential pre-malignant status may characterize HPCs in patients with RAS-associated autoimmune lymphoproliferative syndrome-like disease (RALD). This study sought to elucidate the biological and molecular alterations in human HPCs carrying monoallelic mutant KRAS (G13C) with no other oncogene mutations. Methods We utilized induced pluripotent stem cells (iPSCs) derived from two unrelated RALD patients. Isogenic HPC pairs harboring either wild-type KRAS or monoallelic KRAS (G13C) alone obtained following differentiation enabled reliable comparative analyses. The compound screening was conducted with an established platform using KRAS (G13C) iPSCs and differentiated HPCs. Results Cell culture assays revealed that monoallelic KRAS (G13C) impacted both myeloid differentiation and expansion characteristics of iPSC-derived HPCs. Comprehensive RNA-sequencing analysis depicted close clustering of HPC samples within the isogenic group, warranting that comparative studies should be performed within the same genetic background. When compared with no stimulation, iPSC-derived KRAS (G13C)-HPCs showed marked similarity with the wild-type isogenic control in transcriptomic profiles. After stimulation with cytokines, however, KRAS (G13C)-HPCs exhibited obvious aberrant cell-cycle and apoptosis responses, compatible with "dysregulated expansion," demonstrated by molecular and biological assessment. Increased BCL-xL expression was identified amongst other molecular changes unique to mutant HPCs. With screening platforms established for therapeutic intervention, we observed selective activity against KRAS (G13C)-HPC expansion in several candidate compounds, most notably in a MEK- and a BCL-2/BCL-xL-inhibitor. These two compounds demonstrated selective inhibitory effects on KRAS (G13C)-HPCs even with primary patient samples when combined. Conclusions Our findings indicate that a monoallelic oncogenic KRAS can confer dysregulated expansion characteristics to non-transformed HPCs, which may constitute a pathological condition in RALD hematopoiesis. The use of iPSC-based screening platforms will lead to discovering treatments that enable selective inhibition of RAS-mutated HPC clones.

ABSTRACTMany biological processes related to cell function and fate begin with chromatin alterations, and many factors associated with the efficacy of immune checkpoint inhibitors (ICIs) are actually downstream events of chromatin alterations, such as genome changes, neoantigen production, and immune checkpoint expression. However, the influence of genes as chromatin regulators on the efficacy of ICIs remains elusive, especially in gastric cancer (GC). In this study, thirty out of 1593 genes regulating chromatin associated with a favorable prognosis were selected for GC. CHAF1A, a well-defined oncogene, was identified as the highest linkage hub gene. High CHAF1A expression were associated with microsatellite instability (MSI), high tumor mutation burden (TMB), high tumor neoantigen burden (TNB), high expressions of PD-L1 and immune effector genes, and live infiltration of immune cells. High CHAF1A expression indicated a favorable response and prognosis in immunotherapy of several cohorts, which was independent of MSI, TMB, TNB, PD-L1 expression, immune phenotype and transcriptome scoring, and improved patient selection based on these classic biomarkers. In vivo, CHAF1A knockdown alone inhibited tumor growth but it impaired the effect of an anti-PD-1 antibody by increasing the relative tumor proliferation rate and decreasing the survival benefit, potentially through the activation of TGF-β signaling. In conclusion, CHAF1A may be a novel biomarker for improving patient selection in immunotherapy.

In cancer treatment, therapeutic strategies that integrate tumor-specific characteristics (i.e., precision oncology) are widely implemented to provide clinical benefits for cancer patients. Here, through in-depth integration of tumor transcriptome and patients' prognoses across cancers, we investigated dysregulated and prognosis-associated genes and catalogued such important genes in a cancer type-dependent manner. Utilizing the expression matrices of these genes, we built models to quantitatively evaluate the malignant levels of tumors across cancers, which could add value to the clinical staging system for improved prediction of patients' survival. Furthermore, we performed a transcriptome-based molecular subtyping on hepatocellular carcinoma, which revealed three subtypes with significantly diversified clinical outcomes, mutation landscapes, immune microenvironment, and dysregulated pathways. As tumor transcriptome was commonly profiled in clinical practice with low experimental complexity and cost, this work proposed easy-to-perform approaches for practical clinical promotion towards better healthcare and precision oncology of cancer patients. [ABSTRACT FROM AUTHOR]

Background: Studies evaluating the effectiveness of immune checkpoint inhibitors (ICI) for endometrial cancer (EC) are limited. This study aimed to assess the efficacy of PD-1/PD-L1 inhibitors as monotherapy for EC by conducting a meta-analysis. The predictive significance of MMR status, a biomarker for ICI response, also required further investigation. Methods: A systematic literature search was conducted in English databases until September 2023. The analysis included objective response rate (ORR), disease control rate (DCR), adverse events (AEs), and odds ratios (OR), along with their corresponding 95% confidence intervals (CI). Results: There were twelve trials totaling 685 individuals. PD-1/PD-L1 inhibitor monotherapy resulted in an ORR for 34% (95% CI = 24–44%) of the pooled EC patients. Subgroup analysis revealed a significantly higher ORR in dMMR EC (45%) compared to pMMR EC (8%), with an OR of 6.36 (95% CI = 3.64–11.13). The overall DCR was 42%, with dMMR EC at 51% and pMMR EC at 30% (OR = 2.61, 95% CI = 1.69–4.05). Grade three or higher adverse events (AEs) occurred in 15% of cases (95% CI = 9–24%) of the pooled incidence of AEs, which was 68% (95% CI = 65–72%). Conclusions: This meta-analysis provides significant evidence for the effectiveness of PD-1/PD-L1 inhibitors as monotherapy for EC. Notably, dMMR EC patients demonstrated superior treatment efficacy with PD-1/PD-L1 inhibitor immunotherapy. Further research is required to explore subclassifications of EC based on dMMR molecular subtypes, enabling improved treatment strategies and outcomes for EC patients. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is one of most prevalent cancers worldwide, especially in China. Lacking in depth mechanism study, effective targets and therapeutics are desperately needed in the clinic. RNA-binding proteins (RBPs) mediate the localization, stability, and translation of the target transcripts and fine-tune the physiological functions of the proteins encoded. Bioinformatics analysis revealed that IGF2BPs were highly expressed in ESCC tissues and at least participated in the regulation of cell proliferation of ESCC cells. Biological researches demonstrated that IGF2BP2 promoted the cell proliferation, migration and invasion of ESCC KYSE30 and KYSE450 cells. IGF2BP2 could bind to EIF4A1 mRNA by recognition of m6A sites and enhanced translation of EIF4A1. IGF2BPs, as m6A reader, IGF2BPs were oncogenic genes in ESCC by regulating the expression of EIF4A1 through m6A sites. IGF2BP2, EIF4A1 and their targets could serve as potential biomarkers and therapeutic targets for ESCC, offering promising novel approaches for the diagnosis and treatment of ESCC. [ABSTRACT FROM AUTHOR]

Among women, breast cancer ranks as the most prevalent form of cancer, and the presence of metastases significantly reduces prognosis and diminishes overall survival rates. Gaining insights into the biological mechanisms governing the conversion of cancer cells, their subsequent spread to other areas of the body, and the immune system's monitoring of tumor growth will contribute to the advancement of more efficient and targeted therapies. MicroRNAs (miRNAs) play a critical role in the interaction between tumor cells and immune cells, facilitating tumor cells' evasion of the immune system and promoting cancer progression. Additionally, miRNAs also influence metastasis formation, including the establishment of metastatic sites and the transformation of tumor cells into migratory phenotypes. Specifically, dysregulated expression of these genes has been associated with abnormal expression of oncogenes and tumor suppressor genes, thereby facilitating tumor development. This study aims to provide a concise overview of the significance and function of miRNAs in breast cancer, focusing on their involvement as tumor suppressors in the antitumor immune response and as oncogenes in metastasis formation. Furthermore, miRNAs hold tremendous potential as targets for gene therapy due to their ability to modulate specific pathways that can either promote or suppress carcinogenesis. This perspective highlights the latest strategies developed for miRNA-based therapies. [ABSTRACT FROM AUTHOR]

Melanocytic nevi (skin moles) have been regarded as a valuable example of cell senescence occurring in vivo. However, a study of induced nevi in a mouse model reported that the nevi were arrested by cell interactions rather than a cell‐autonomous process like senescence, and that size distributions of cell nests within nevi could not be accounted for by a stochastic model of oncogene‐induced senescence. Moreover, others reported that some molecular markers used to identify cell senescence in human nevi are also found in melanoma cells—not senescent. It has thus been questioned whether nevi really are senescent, with potential implications for melanoma diagnosis and therapy. Here I review these areas, along with the genetic, biological, and molecular evidence supporting senescence in nevi. In conclusion, there is strong evidence that cells of acquired human benign (banal) nevi are very largely senescent, though some must contain a minor non‐senescent cell subpopulation. There is also persuasive evidence that this senescence is primarily induced by dysfunctional telomeres rather than directly oncogene‐induced. [ABSTRACT FROM AUTHOR]