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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]

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]

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]

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. [ABSTRACT FROM AUTHOR]

Background: FLI1 is an oncogenic transcription factor that promotes diverse malignancies through mechanisms that are not fully understood. Herein, FLI1 is shown to regulate the expression of Ubiquitin Associated and SH3 Domain Containing A/B (UBASH3A/B) genes. UBASH3B and UBASH3A are found to act as an oncogene and tumor suppressor, respectively, and their combined effect determines erythroleukemia progression downstream of FLI1. Methods: Promoter analysis combined with luciferase assays and chromatin immunoprecipitation (ChIP) analysis were applied on the UBASH3A/B promoters. RNAseq analysis combined with bioinformatic was used to determine the effect of knocking-down UBASH3A and UBASH3B in leukemic cells. Downstream targets of UBASH3A/B were inhibited in leukemic cells either via lentivirus-shRNAs or small molecule inhibitors. Western blotting and RT-qPCR were used to determine transcription levels, MTT assays to assess proliferation rate, and flow cytometry to examine apoptotic index. Results: Knockdown of FLI1 in erythroleukemic cells identified the UBASH3A/B genes as potential downstream targets. Herein, we show that FLI1 directly binds to the UBASH3B promoter, leading to its activation and leukemic cell proliferation. In contrast, FLI1 indirectly inhibits UBASH3A transcription via GATA2, thereby antagonizing leukemic growth. These results suggest oncogenic and tumor suppressor roles for UBASH3B and UBASH3A in erythroleukemia, respectively. Mechanistically, we show that UBASH3B indirectly inhibits AP1 (FOS and JUN) expression, and that its loss leads to inhibition of apoptosis and acceleration of proliferation. UBASH3B also positively regulates the SYK gene expression and its inhibition suppresses leukemia progression. High expression of UBASH3B in diverse tumors was associated with worse prognosis. In contrast, UBASH3A knockdown in erythroleukemic cells increased proliferation; and this was associated with a dramatic induction of the HSP70 gene, HSPA1B. Accordingly, knockdown of HSPA1B in erythroleukemia cells significantly accelerated leukemic cell proliferation. Accordingly, overexpression of UBASH3A in different cancers was predominantly associated with good prognosis. These results suggest for the first time that UBASH3A plays a tumor suppressor role in part through activation of HSPA1B. Conclusions: FLI1 promotes erythroleukemia progression in part by modulating expression of the oncogenic UBASH3B and tumor suppressor UBASH3A. [ABSTRACT FROM AUTHOR]

Background: The involvement of centromere protein M (CENPM) in various types of cancer has been established, however, its impact on breast cancer and immune infiltration remains unknown. Methods: We examined the expression of CENPM in different cancer types by utilizing the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression Pan-Cancer (GEO) databases. Using data from the TCGA, we examined the correlation between the expression of CENPM, the prognosis, and the clinicopathological features of individuals diagnosed with breast cancer. We conducted an enrichment analysis of CENPM using the clusterProfiler R software tool, utilizing data obtained from breast cancer patients and specimens at our institution. In addition to examining the correlation between CENPM expression and genes associated with immune checkpoints, the TIDE algorithm was employed to explore the potential of CENPM as a biomarker for immunotherapy in breast cancer. The impact of CENPM on the growth of breast cancer cells was evaluated through the utilization of the CCK8 test and the colony formation assay. The effect of CENPM on the migration of breast cancer cells was assessed using scratch and transwell assays. Results: Research findings indicate that elevated levels of CENPM are linked to patient outcomes in breast cancer and various clinicopathological features. Furthermore, elevated levels of CENPM expression correlated with decreased levels of CD8 + T cells and mast cells, increased levels of Tregs and Th2, and reduced levels of CD8 + T cells. Additionally, the coexpression of CENPM with the majority of genes related to immune checkpoints indicates its potential to forecast the effectiveness of treatment in breast cancer. Suppression of CENPM hampers the growth and movement of breast tumor cells. Conclusions: In summary, our study findings indicate that CENPM may serve as a cancer-causing gene in breast cancer and also as a biomarker for predicting the efficacy of immunotherapy. The oncogene CENPM is associated with breast cancer and is involved in cell proliferation and immune infiltration. [ABSTRACT FROM AUTHOR]

Background: Phosphoglycerate kinase 1 (PGK1) is a metabolic enzyme that participates in various biological and pathological processes. Dysregulated PGK1 has been observed in numerous malignancies. However, whether and how PGK1 affects non-small cell lung cancer (NSCLC) is not yet fully elucidated. Methods: Herein, the non-metabolic function of PGK1 in NSCLC was explored by integrating bioinformatics analyses, cellular experiments, and nude mouse xenograft models. The upstream regulators and downstream targets of PGK1 were examined using multiple techniques such as RNA sequencing, a dual-luciferase reporter assay, Co-immunoprecipitation, and Western blotting. Results: We confirmed that PGK1 was upregulated in NSCLC and this upregulation was associated with poor prognosis. Further in vitro and in vivo experiments demonstrated the promoting effects of PGK1 on NSCLC cell growth and metastasis. Additionally, we discovered that PGK1 interacted with and could be O-GlcNAcylated by OGT. The inhibition of PGK1 O-GlcNAcylation through OGT silencing or mutation at the T255 O-GlcNAcylation site could weaken PGK1-mediated NSCLC cell proliferation, colony formation, migration, and invasion. We also found that a low miR-24-3p level led to an increase in OGT expression. Additionally, PGK1 exerted its oncogenic properties by augmenting ERK phosphorylation and MCM4 expression. Conclusions: PGK1 acted as a crucial mediator in controlling NSCLC progression. The miR-24-3p/OGT axis was responsible for PGK1 O-GlcNAcylation, and ERK/MCM4 were the downstream effectors of PGK1. It appears that PGK1 might be an attractive therapeutic target for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Polyamines are essential for the growth and proliferation of mammalian cells and are intimately involved in biological mechanisms such as DNA replication, RNA transcription, protein synthesis, and post-translational modification. These mechanisms regulate cellular proliferation, differentiation, programmed cell death, and the formation of tumors. Several studies have confirmed the positive effect of polyamines on the maintenance of health, while others have demonstrated that their activity may promote the occurrence and progression of diseases. This review examines a variety of topics, such as polyamine source and metabolism, including metabolism, transport, and the potential impact of polyamines on health and disease. In addition, a brief summary of the effects of oncogenes and signaling pathways on tumor polyamine metabolism is provided. 5ikmGssBZD_e4xpSJscY2Y Video Abstract [ABSTRACT FROM AUTHOR]

Background: Ceramide, a bioactive signaling sphingolipid, has long been implicated in cancer. Members of the ceramide synthase (CerS) family determine the acyl chain lengths of ceramides, with ceramide synthase 4 (CerS4) primarily generating C18–C20-ceramide. Although CerS4 is known to be overexpressed in breast cancer, its role in breast cancer pathogenesis is not well established. Methods: To investigate the role of CerS4 in breast cancer, public datasets, including The Cancer Genome Atlas (TCGA) and two Gene Expression Omnibus (GEO) datasets (GSE115577 and GSE96058) were analyzed. Furthermore, MCF-7 cells stably overexpressing CerS4 (MCF-7/CerS4) as a model for luminal subtype A (LumA) breast cancer were produced, and doxorubicin (also known as Adriamycin [AD])-resistant MCF-7/ADR cells were generated after prolonged treatment of MCF-7 cells with doxorubicin. Kaplan–Meier survival analysis assessed the clinical significance of CERS4 expression, while Student's t-tests or Analysis of Variance (ANOVA) compared gene expression and cell viability in different MCF-7 cell lines. Results: Analysis of the public datasets revealed elevated CERS4 expression in breast cancer, especially in the most common breast cancer subtype, LumA. Persistent CerS4 overexpression in MCF-7 cells activated multiple cancer-associated pathways, including pathways involving sterol regulatory element–binding protein, nuclear factor kappa B (NF-κB), Akt/mammalian target of rapamycin (mTOR), and β-catenin. Furthermore, MCF-7/CerS4 cells acquired doxorubicin, paclitaxel, and tamoxifen resistance, with concomitant upregulation of ATP-binding cassette (ABC) transporter genes, such as ABCB1, ABCC1, ABCC2, ABCC4, and ABCG2. MCF-7/CerS4 cells were characterized by increased cell migration and epithelial–mesenchymal transition (EMT). Finally, CERS4 knockdown in doxorubicin-resistant MCF-7/ADR cells resulted in reduced activation of cancer-associated pathways (NF-κB, Akt/mTOR, β-catenin, and EMT) and diminished chemoresistance, accompanied by ABCB1 and ABCC1 downregulation. Conclusions: Chronic CerS4 overexpression may exert oncogenic effects in breast cancer via alterations in signaling, EMT, and chemoresistance. Therefore, CerS4 may represent an attractive target for anticancer therapy, especially in LumA breast cancer. [ABSTRACT FROM AUTHOR]

Objective: Herein, we aimed at exploring the FAP expression in clear cell renal cell carcinoma (ccRCC) along with its clinical implication. Methods: Using computational tools analysis of different freely accessible gene databases, the expression pattern, clinical importance, co-expressed genes, and signaling pathways of FAP in ccRCC were thoroughly investigated. FAP expression was examined in clinical ccRCC specimens through qRT-PCR, western blotting and immunohistochemistry. Furthermore, in vitro and in vivo experiments were carried out using flow cytometry, CCK-8, wound-healing and Transwell assays, as well as xenograft tumor model, respectively. Results: FAP levels were found to be significantly elevated in ccRCC based on bioinformatic data from public databases. Patients who exhibited higher expression levels of FAP had poorer prognoses, according to Kaplan–Meier analysis of survival data. In addition, diagnostic and prognostic value of FAP in ccRCC was figured out by ROC curve and prognostic nomogram model. In vitro study revealed that the over-expression FAP accelerated cell proliferation, migration as well as invasion, and suppressed cell apoptosis, but silencing of FAP had the opposite effect. FAP suppression reduced the PI3K/AKT/mTOR pathway's stimulation, whereas FAP up-regulation increased the stimulation of the pathway. Blocking the PI3K/AKT/mTOR signaling pathway with the dual PI3K/mTOR inhibitor BEZ235 repressesed cancer-promoting effect of FAP. Additionally, we found that the downregulation of FAP was effective at slowing tumor progression in vivo. Conclusion: It is possible that FAP could be a reliable biomarker for the diagnosis and prognosis of ccRCC because of its role in the ccRCC progression via triggering the PI3K/AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Background: A number of human diseases have been associated with Centromere protein N (CENPN), but its role in breast cancer is unclear. Methods: A pan-cancer database of Genotype Tissue Expression (GTEx) and the Cancer Genome Atlas (TCGA) were used to examine the expression of CENPN. Using TCGA clinical survival data and breast cancer specimens from our center for validation, the relationship between CENPN expression, breast cancer prognosis, and clinicopathological characteristics of patients was examined. Bioinformatics was utilized to conduct an enrichment study of CENPN. Additionally, the potential of CENPN as a predictive biomarker for immunotherapy success was confirmed by analyzing the co-expression of CENPN with immune-checkpoint related genes, reviewing the TCGA database, and evaluating the correlation between CENPN expression and immune cell infiltration. Using the CCK8 test and colony formation assay, CENPN was evaluated for its ability to inhibit breast cancer cell proliferation. Transwell assays and scratch tests were used to assess the impact of CENPN on breast cancer cell migration. Results: CENPN is found in a wide range of tumors, including breast cancer. Additional investigation revealed that CENPN was co-expressed with the majority of immune checkpoint-related genes, had the potential to serve as a predictive biomarker for immunotherapy effectiveness, and that high CENPN expression was linked to high Tregs and low CD8 + T cells and NK cells. Breast cancer cells' malignant characteristics, such as migration and cell proliferation, were inhibited by CENPN knockdown. Conclusions: According to our findings, CENPN may be an oncogene in breast cancer, as well as a new therapeutic target for immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a dismal prognosis, and despite significant advances in our understanding of its genetic drivers, like KRAS, TP53, CDKN2A, and SMAD4, effective therapies remain limited. Here, we identified a new therapeutic target GRIN2D and then explored its functions and mechanisms in PDAC progression. Methods: We performed a genome-wide RNAi screen in a PDAC xenograft model and identified GRIN2D, which encodes the GluN2D subunit of N-methyl-D-aspartate receptors (NMDARs), as a potential oncogene. Western blot, immunohistochemistry, and analysis on Gene Expression Omnibus were used for detecting the expression of GRIN2D in PDAC. Cellular experiments were conducted for exploring the functions of GRIN2D in vitro while subcutaneous and orthotopic injections were used in in vivo study. To clarify the mechanism, we used RNA sequencing and cellular experiments to identify the related signaling pathway. Cellular assays, RT-qPCR, and western blot helped identify the impacts of the NMDAR antagonist memantine. Results: We demonstrated that GRIN2D was highly expressed in PDAC cells, and further promoted oncogenic functions. Mechanistically, transcriptome profiling identified GRIN2D-regulated genes in PDAC cells. We found that GRIN2D promoted PDAC progression by activating the p38 MAPK signaling pathway and transcription factor CREB, which in turn promoted the expression of HMGA2 and IL20RB. The upregulated GRIN2D could effectively promote tumor growth and liver metastasis in PDAC. We also investigated the therapeutic potential of NMDAR antagonism in PDAC and found that memantine reduced the expression of GRIN2D and inhibited PDAC progression. Conclusion: Our results suggested that NMDA receptor GRIN2D plays important oncogenic roles in PDAC and represents a novel therapeutic target. Significance: The study reveals a prominent role for GRIN2D in PDAC progression, suggesting that GRIN2D might be a novel therapeutic target for PDAC. [ABSTRACT FROM AUTHOR]

Malignant tumors have been one of the major reasons for deaths worldwide. Timely and accurate diagnosis as well as effective intervention of tumors play an essential role in the survival of patients. Genomic instability is the important foundation and feature of cancer, hence, in vivo oncogene imaging based on novel probes provides a valuable tool for the diagnosis of cancer at early-stage. However, the in vivo oncogene imaging is confronted with great challenge, due to the extremely low copies of oncogene in tumor cells. By combining with various novel activatable probes, the molecular imaging technologies provide a feasible approach to visualize oncogene in situ, and realize accurate treatment of tumor. This review aims to declare the design of nanoprobes responded to tumor associated DNA or RNA, and summarize their applications in detection and bioimaging for tumors. The significant challenges and prospective of oncogene-targeting nanoprobes towards tumors diagnosis are revealed as well. [ABSTRACT FROM AUTHOR]

Hippo signaling was first identified in Drosophila as a key controller of organ size by regulating cell proliferation and anti-apoptosis. Subsequent studies have shown that this pathway is highly conserved in mammals, and its dysregulation is implicated in multiple events of cancer development and progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) (hereafter YAP/TAZ) are the downstream effectors of the Hippo pathway. YAP/TAZ overexpression or activation is sufficient to induce tumor initiation and progression, as well as recurrence and therapeutic resistance. However, there is growing evidence that YAP/TAZ also exert a tumor-suppressive function in a context-dependent manner. Therefore, caution should be taken when targeting Hippo signaling in clinical trials in the future. In this review article, we will first give an overview of YAP/TAZ and their oncogenic roles in various cancers and then systematically summarize the tumor-suppressive functions of YAP/TAZ in different contexts. Based on these findings, we will further discuss the clinical implications of YAP/TAZ-based tumor targeted therapy and potential future directions. [ABSTRACT FROM AUTHOR]

Background: IDH1/2 hotspot mutations are well known to drive oncogenic mutations in gliomas and are well-defined in the WHO 2021 classification of central nervous system tumors. Specifically, IDH mutations lead to aberrant hypermethylation of under-methylated regions (UMRs) in normal tissues through the disruption of TET enzymes. However, the chromatin reprogramming and transcriptional changes induced by IDH-related hypermethylation in gliomas remain unclear. Results: Here, we have developed a precise computational framework based on Hidden Markov Model to identify altered methylation states of UMRs at single-base resolution. By applying this framework to whole-genome bisulfite sequencing data from 75 normal brain tissues and 15 IDH mutant glioma tissues, we identified two distinct types of hypermethylated UMRs in IDH mutant gliomas. We named them partially hypermethylated UMRs (phUMRs) and fully hypermethylated UMRs (fhUMRs), respectively. We found that the phUMRs and fhUMRs exhibit distinct genomic features and chromatin states. Genes related to fhUMRs were more likely to be repressed in IDH mutant gliomas. In contrast, genes related to phUMRs were prone to be up-regulated in IDH mutant gliomas. Such activation of phUMR genes is associated with the accumulation of active H3K4me3 and the loss of H3K27me3, as well as H3K36me3 accumulation in gene bodies to maintain gene expression stability. In summary, partial erosion on UMRs was accompanied by locus-specific changes in key chromatin marks, which may contribute to oncogene activation. Conclusions: Our study provides a computational strategy for precise decoding of methylation encroachment patterns in IDH mutant gliomas, revealing potential mechanistic insights into chromatin reprogramming that contribute to oncogenesis. [ABSTRACT FROM AUTHOR]

Background: Disco-interaction protein 2 homologue B (DIP2B) plays an important role in DNA methylation. There have been many reports on DIP2B in various diseases, but neither the diagnostic value nor the prognostic value of DIP2B across cancer types has been deeply explored. Methods: The expression levels of DIP2B in 33 cancer types were analysed based on data sets from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database. The relationships of DIP2B expression with immune cell infiltration and immune-related gene expression were studied via the CIBERSORT, ESTIMATE and TISIDB tools. Gene set variation analysis (GSVA) was performed to identify pathways related to DIP2B. DIP2B knockdown by siRNA was performed in breast cancer cell lines to investigate the effect on proliferation, apoptosis and migration. The relationships of DIP2B expression with clinicopathological features and prognosis were analysed based on immunohistochemistry. Results: DIP2B was highly expressed in 26 of 33 cancer types and was significantly associated with poor overall survival (OS) in breast invasive carcinoma (BRCA), mesothelioma and chromophobe renal cell carcinoma (each P < 0.05). DIP2B showed a negative correlation with the immune score, the infiltration levels of key immune killer cells (CD8 + T cells, activated NK cells and plasma cells), and the expression of major histocompatibility complex–related genes and chemokine-related genes in BRCA. Subtype analysis showed that DIP2B expression was associated with poor OS in Her-2 + BRCA patients (P < 0.05). DIP2B showed a negative correlation with immune killer cell infiltration and immune regulatory genes in BRCA subtypes. In BRCA, the GSVA results revealed that genes correlating positively with DIP2B were enriched in cancer-related pathways (PI3K-AKT) and cell-cycle-related pathways (MITOTIC_SPINDLE, G2M_CHECKPOINT and E2F_TARGETS), while genes correlating negatively with DIP2B were enriched in DNA_REPAIR. Knockdown of the DIP2B gene induced a reduction in proliferation and migration and an increase in apoptosis in breast cancer cell lines. DIP2B expression was associated with lymph node metastasis and poor histological grade in BRCA according to immunohistochemistry (each P < 0.05). DIP2B expression predicted reduced disease-free survival and OS in BRCA patients (each P < 0.05), especially those with the Her-2 + subtype (P = 0.023 and P = 0.069). Conclusions: DIP2B may be a prognostic biomarker for BRCA, especially for the Her-2 + subtype. DIP2B is associated with a "cold" tumour immune microenvironment in BRCA and might serve as a future target for immunotherapy. [ABSTRACT FROM AUTHOR]

The acquisition of genetic abnormalities engendering oncogene dysregulation underpins cancer development. Certain proto-oncogenes possess several dysregulation mechanisms, yet how each mechanism impacts clinical outcome is unclear. Using T-cell acute lymphoblastic leukemia (T-ALL) as an example, we show that patients harboring 5'super-enhancer (5'SE) mutations of the TAL1 oncogene identifies a specific patient subgroup with poor prognosis irrespective of the level of oncogene dysregulation. Remarkably, the MYB dependent oncogenic 5'SE can be targeted using Mebendazole to induce MYB protein degradation and T-ALL cell death. Of note Mebendazole treatment demonstrated efficacy in vivo in T-ALL preclinical models. Our work provides proof of concept that within a specific oncogene driven cancer, the mechanism of oncogene dysregulation rather than the oncogene itself can identify clinically distinct patient subgroups and pave the way for future super-enhancer targeting therapy. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs are involved in epigenetic gene modification, including binding to the chromatin rearrangement complex in pre-transcriptional regulation and to gene promoters in gene expression regulation, as well as acting as microRNA sponges to control messenger RNA levels in post-transcriptional regulation. An increasing number of studies have found that long noncoding RNA plasmacytoma variant translocation 1 (PVT1) plays an important role in cancer development. In this review of a large number of studies on PVT1, we found that PVT1 is closely related to tumor onset, proliferation, invasion, epithelial–mesenchymal transformation, and apoptosis, as well as poor prognosis and radiotherapy and chemotherapy resistance in some cancers. This review comprehensively describes PVT1 expression in various cancers and presents novel approaches to the diagnosis and treatment of cancer. [ABSTRACT FROM AUTHOR]

Background: N-Acetylgalactosaminyltransferases (GALNTs), the enzymes that initiate mucin-type O-glycosylation, are closely associated with tumor occurrence and progression. However, a comprehensive analysis of GALNTs in non-small cell lung cancer (NSCLC) is lacking. Methods: The expression profiles and prognostic values of the GALNT family members in NSCLC were analyzed using publicly available databases. Gain- and loss-of-function experiments were applied to assess the biological function of GALNT2 in NSCLC. High-throughput sequencing and bioinformatics approaches were employed to uncover the regulatory mechanism of GALNT2. Results: Among the family members of GALNTs, only GALNT2 was frequently overexpressed in NSCLC tissues and was positively correlated with poor prognosis. In vitro assays showed that GALNT2 knockdown repressed NSCLC cell proliferation, migration, and invasion, but induced apoptosis and cell cycle arrest. Correspondently, GALNT2 overexpression exerted the opposite effects. In vivo experiments demonstrated that knockdown of GALNT2 restrained tumor formation in nude mice. Mechanistic investigations revealed that GALNT2 modified the O-glycosylation of ITGA5 and affected the activation of the PI3K/Akt and MAPK/ERK pathways. Further studies showed that miR-30d was a negative regulator of GALNT2. Conclusions: These findings suggest that GALNT2 is an oncogene in NSCLC and has the potential as a target for NSCLC therapy. [ABSTRACT FROM AUTHOR]

ING genes belong to family of tumor suppressor genes with regulatory functions on cell proliferation, apoptosis, and cellular senescence. These include a family of proteins with 5 members (ING1-5), which are downregulated in human malignancies and/or affected by pathogenic mutations. ING proteins are highly evolutionarily conserved proteins containing several domains through which bind to chromatin structures by exerting their effects as readers of histone modification marks, and also binding to proteins like p53 involved in biological processes such as cell cycle regulation. Further, they are known as subunits of histone acetylation as well as deacetylation complexes and so exert their regulatory roles through epigenetic mechanisms. Playing role in restriction of proliferative but also invasive potentials of normal cells, INGs are particularly involved in cancer development and progression. However, additional studies and experimental confirmation are required for these models. This paper highlights the potential impact that INGs may have on the development of human cancer and explores what new information has recently arise on the functions of ING genes. [ABSTRACT FROM AUTHOR]

The full-length BRCA1-associated RING domain 1 (BARD1) gene encodes a 777-aa protein. BARD1 displays a dual role in cancer development and progression as it acts as a tumor suppressor and an oncogene. Structurally, BARD1 has homologous domains to BRCA1 that aid their heterodimer interaction to inhibit the progression of different cancers such as breast and ovarian cancers following the BRCA1-dependant pathway. In addition, BARD1 was shown to be involved in other pathways that are involved in tumor suppression (BRCA1-independent pathway) such as the TP53-dependent apoptotic signaling pathway. However, there are abundant BARD1 isoforms exist that are different from the full-length BARD1 due to nonsense and frameshift mutations, or deletions were found to be associated with susceptibility to various cancers including neuroblastoma, lung, breast, and cervical cancers. This article reviews the spectrum of BARD1 full-length genes and its different isoforms and their anticipated associated risk. Additionally, the study also highlights the role of BARD1 as an oncogene in breast cancer patients and its potential uses as a prognostic/diagnostic biomarker and as a therapeutic target for cancer susceptibility testing and treatment. [ABSTRACT FROM AUTHOR]

Cancer can be induced by a variety of possible causes, including tumor suppressor gene failure and proto-oncogene hyperactivation. Tumor-associated extrachromosomal circular DNA has been proposed to endanger human health and speed up the progression of cancer. The amplification of ecDNA has raised the oncogene copy number in numerous malignancies according to whole-genome sequencing on distinct cancer types. The unusual structure and function of ecDNA, and its potential role in understanding current cancer genome maps, make it a hotspot to study tumor pathogenesis and evolution. The discovery of the basic mechanisms of ecDNA in the emergence and growth of malignancies could lead researchers to develop new cancer therapies. Despite recent progress, different aspects of ecDNA require more investigation. We focused on the features, and analyzed the bio-genesis, and origin of ecDNA in this review, as well as its functions in neuroblastoma and glioma cancers. [ABSTRACT FROM AUTHOR]

Background: Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis, is up-regulated in several cancers, including metastatic melanoma (MM). The BRAF oncogene is mutated in different cancer types, among which MM and thyroid carcinoma (THCA) are prominent. Drugs targeting mutant BRAF are effective, especially in MM patients, even though resistance rapidly develops. Previous data have linked NAMPT over-expression to the acquisition of BRAF resistance, paving the way for therapeutic strategies targeting the two pathways.Methods: Exploiting the TCGA database and a collection of MM and THCA tissue microarrays we studied the association between BRAF mutations and NAMPT expression. BRAF wild-type (wt) cell lines were genetically engineered to over-express the BRAF V600E construct to demonstrate a direct relationship between over-activation of the BRAF pathway and NAMPT expression. Responses of different cell line models to NAMPT (i)nhibitors were studied using dose-response proliferation assays. Analysis of NAMPT copy number variation was performed in the TCGA dataset. Lastly, growth and colony forming assays were used to study the tumorigenic functions of NAMPT itself.Results: The first finding of this work is that tumor samples carrying BRAF-mutations over-express NAMPT, as demonstrated by analyzing the TCGA dataset, and MM and THC tissue microarrays. Importantly, BRAF wt MM and THCA cell lines modified to over-express the BRAF V600E construct up-regulated NAMPT, confirming a transcriptional regulation of NAMPT following BRAF oncogenic signaling activation. Treatment of BRAF-mutated cell lines with two different NAMPTi was followed by significant reduction of tumor growth, indicating NAMPT addiction in these cells. Lastly, we found that several tumors over-expressing the enzyme, display NAMPT gene amplification. Over-expression of NAMPT in BRAF wt MM cell line and in fibroblasts resulted in increased growth capacity, arguing in favor of oncogenic properties of NAMPT.Conclusions: Overall, the association between BRAF mutations and NAMPT expression identifies a subset of tumors more sensitive to NAMPT inhibition opening the way for novel combination therapies including NAMPTi with BRAFi/MEKi, to postpone and/or overcome drug resistance. Lastly, the over-expression of NAMPT in several tumors could be a key and broad event in tumorigenesis, substantiated by the finding of NAMPT gene amplification. [ABSTRACT FROM AUTHOR]

The Kirsten ras oncogene KRAS is a member of the small GTPase superfamily participating in the RAS/MAPK pathway. A single amino acid substitution in KRAS gene has been shown to activate the encoded protein resulting in cell transformation. This oncogene is involved in the malignant transformation in several tissues. Notably, numerous non-coding RNAs have been found to interact with KRAS protein. Such interaction results in a wide array of human disorders, particularly cancers. Orilnc1, KIMAT1, SLCO4A1-AS1, LINC01420, KRAS1P, YWHAE, PART1, MALAT1, PCAT-1, lncRNA-NUTF2P3-001 and TP53TG1 are long non-coding RNAs (lncRNAs) whose interactions with KRAS have been verified in the context of cancer. miR-143, miR-96, miR-134 and miR-126 have also been shown to interact with KRAS in different tissues. Finally, circITGA7, circ_GLG1, circFNTA and circ-MEMO1 are examples of circular RNAs (circRNAs) that interact with KRAS. In this review, we describe the interaction between KRAS and lncRNAs, miRNAs and circRNAs, particularly in the context of cancer. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) has become the second deadliest cancer in the world and severely threatens human health. An increasing number of studies have focused on the role of the RNA helicase DEAD-box (DDX) family in CRC. However, the mechanism of DDX10 in CRC has not been elucidated. Methods: In our study, we analysed the expression data of CRC samples from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Subsequently, we performed cytological experiments and animal experiments to explore the role of DDX10 in CRC cells. Furthermore, we performed Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein–protein interaction (PPI) network analyses. Finally, we predicted the interacting protein of DDX10 by LC–MS/MS and verified it by coimmunoprecipitation (Co-IP) and qPCR. Results: In the present study, we identified that DDX10 mRNA was extremely highly expressed in CRC tissues compared with normal colon tissues in the TCGA and GEO databases. The protein expression of DDX10 was measured by immunochemistry (IHC) in 17 CRC patients. The biological roles of DDX10 were explored via cell and molecular biology experiments in vitro and in vivo and cell cycle assays. We found that DDX10 knockdown markedly reduced CRC cell proliferation, migration and invasion. Then, we constructed a PPI network with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). GO and KEGG enrichment analysis and gene set enrichment analysis (GSEA) showed that DDX10 was closely related to RNA splicing and E2F targets. Using LC–MS/MS and Co-IP assays, we discovered that RPL35 is the interacting protein of DDX10. In addition, we hypothesize that RPL35 is related to the E2F pathway and the immune response in CRC. Conclusions: In conclusion, provides a better understanding of the molecular mechanisms of DDX10 in CRC and provides a potential biomarker for the diagnosis and treatment of CRC. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the malignant tumor with the highest incidence in women. DNA methylation has an important effect on breast cancer, but the effect of abnormal DNA methylation on gene expression in breast cancer is still unclear. Therefore, it is very important to find therapeutic targets related to DNA methylation. Results: In this work, we calculated the DNA methylation distribution and gene expression level in cancer and para-cancerous tissues for breast cancer samples. We found that DNA methylation in key regions is closely related to gene expression by analyzing the relationship between the distribution characteristics of DNA methylation in different regions and the change of gene expression level. Finally, the 18 key genes (17 tumor suppressor genes and 1 oncogene) related to prognosis were confirmed by the survival analysis of clinical data. Some important DNA methylation regions in these genes that result in breast cancer were found. Conclusions: We believe that 17 TSGs and 1 oncogene may be breast cancer biomarkers regulated by DNA methylation in key regions. These results will help to explore DNA methylation biomarkers as potential therapeutic targets for breast cancer. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer is the most aggressive gynecological malignancy. Transcriptional regulators impact the tumor phenotype and, consequently, clinical progression and response to therapy. PHD finger protein 20-like protein 1 (PHF20L1) is a transcriptional regulator with several isoforms, and studies on its role in ovarian cancer are limited. We previously reported that PHF20L1 is expressed as a fucosylated protein in SKOV-3 cells stimulated with ascites from patients with ovarian cancer. Methods: We decided to analyze the expression of PHF20L1 in ovarian cancer tissues, determine whether a correlation exists between PHF20L1 expression and patient clinical data, and analyze whether ascites can modulate the different isoforms of this protein. Ovarian cancer biopsies from 29 different patients were analyzed by immunohistochemistry, and the expression of the isoforms in ovarian cancer cells with or without exposure to the tumor microenvironment, i.e., the ascitic fluid, was determined by western blotting assays. Results: Immunohistochemical results suggest that PHF20L1 exhibits increased expression in sections of tumor tissues from patients with ovarian cancer and that higher PHF20L1 expression correlates with shorter progression-free survival and shorter overall survival. Furthermore, western blotting assays determined that protein isoforms are differentially regulated in SKOV-3 cells in response to stimulation with ascites from patients with epithelial ovarian cancer. Conclusion: The results suggest that PHF20L1 could play a relevant role in ovarian cancer given that higher PHF20L1 protein expression is associated with lower overall patient survival. [ABSTRACT FROM AUTHOR]

Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is an important lncRNA derived from the XIST gene in mammals. XIST is abnormally expressed in numerous tumors, in most of which XIST functions as an oncogene. XIST is involved in multiple aspects of carcinogenesis, including tumor onset, progression, and prognosis. In our review, we collected and analyzed the recent studies on the impact of XIST in human tumor development. The multilevel molecular functions of XIST in human tumors are comprehensively reviewed to clarify the pathologic mechanisms and to offer a novel direction for further study. [ABSTRACT FROM AUTHOR]

Background: Ten–eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in DNA demethylation and transcriptional regulation, plays a key role in the maintenance of stem cell pluripotency, and is dysregulated in malignant cells. The identification of cancer stem cells (CSCs) driving tumor growth and metastasis is the primary objective of biomarker discovery in aggressive prostate cancer (PCa). In this context, we analyzed TET1 expression in PCa. Methods: A large-scale immunohistochemical analysis of TET1 was performed in normal prostate (NOR) and PCa using conventional slides (50 PCa specimens) and tissue microarrays (669 NOR and 1371 PCa tissue cores from 371 PCa specimens). Western blotting, RT-qPCR, and 450 K methylation array analyses were performed on PCa cell lines. Genome-wide correlation, gene regulatory network, and functional genomics studies were performed using publicly available data sources and bioinformatics tools. Results: In NOR, TET1 was exclusively expressed in normal cytokeratin 903 (CK903)–positive basal cells. In PCa, TET1 was frequently detected in alpha-methylacyl-CoA racemase (AMACR)–positive tumor cell clusters and was detectable at all tumor stages and Gleason scores. Pearson's correlation analyses of PCa revealed 626 TET1-coactivated genes (r > 0.5) primarily encoding chromatin remodeling and mitotic factors. Moreover, signaling pathways regulating antiviral processes (62 zinc finger, ZNF, antiviral proteins) and the pluripotency of stem cells were activated. A significant proportion of detected genes exhibited TET1-correlated promoter hypomethylation. There were 161 genes encoding transcription factors (TFs), of which 133 were ZNF-TFs with promoter binding sites in TET1 and in the vast majority of TET1-coactivated genes. Conclusions: TET1-expressing cells are an integral part of PCa and may represent CSCs with oncogenic potential. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer. Approximately 80% of patients initially diagnosed with locally advanced or metastatic disease survive only 4–11 months after diagnosis. Tremendous efforts have been made toward understanding the biology of PDAC. Results: In this study, we first utilized next-generation sequencing technique and existing microarray datasets to identify significant differentially expressed genes between PDAC and non-tumor adjacent tissue. By comparing top significant survival genes in PDAC Gene Expression Profiling Interactive Analysis database and PDAC transcriptome data from patients, our integrated analysis discovered five potential central genes (i.e., MYEOV, KCNN4, FAM83A, S100A16, and DDX60L). Subsequently, we analyzed the cellular functions of the potential novel oncogenes MYEOV and DDX60L, which are highly expressed in PDAC cells. Notably, the knockdown of MYEOV and DDX60L significantly inhibited the metastasis of cancer cells and induced apoptosis. Further RNA sequencing analyses showed that massive signaling pathways, particularly the TNF signaling pathway and nuclear factor-kappa B (NF-κB) signaling pathway, were affected in siRNA-treated cancer cells. The siDDX60L and siMYEOV significantly inhibited the expression of chemokine CXCL2, which may potentially affect the tumor microenvironment in PDAC tissues. Conclusions: The present findings identified the novel oncogene DDX60L, which was highly expressed in PDAC. Transcriptome profiling through siRNA knockdown of DDX60L uncovered its functional roles in the PDAC in humans. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is a common cancer among women in the world. However, its pathogenesis is still to be determined. The role and molecular mechanism of Nucleosome Assembly Protein 1 Like 1 (NAP1L1) in breast cancer have not been reported. Elucidation of molecular mechanism might provide a novel therapeutic target for breast cancer treatment. Methods: A bioinformatics analysis was conducted to determine the differential expression of NAP1L1 in breast cancer and find the potential biomarker that interacts with NAP1L1 and hepatoma-derived growth factor (HDGF). The expression of NAP1L1 in tissues was detected by using immunohistochemistry. Breast cancer cells were transfected with the corresponding lentiviral particles and siRNA. The efficiency of transfection was measured by RT-qPCR and western blotting. Then, MTT, Edu, plate clone formation, and subcutaneous tumorigenesis in nude mice were used to detect the cell proliferation in breast cancer. Furthermore, coimmunoprecipitation (Co-IP) assay and confocal microscopy were performed to explore the detailed molecular mechanism of NAP1L1 in breast cancer. Results: In this study, NAP1L1 protein was upregulated based on the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Consistent with the prediction, immunohistochemistry staining showed that NAP1L1 protein expression was significantly increased in breast cancer tissues. Its elevated expression was an unfavorable factor for breast cancer clinical progression and poor prognosis. Stably or transiently knocking down NAP1L1 reduced the cell growth in vivo and in vitro via repressing the cell cycle signal in breast cancer. Furthermore, the molecular basis of NAP1L1-induced cell cycle signal was further studied. NAP1L1 interacted with the HDGF, an oncogenic factor for tumors, and the latter subsequently recruited the key oncogenic transcription factor c-Jun, which finally induced the expression of cell cycle promoter Cyclin D1(CCND1) and thus the cell growth of breast cancer. Conclusions: Our data demonstrated that NAP1L1 functions as a potential oncogene via interacting with HDGF to recruit c-Jun in breast cancer. [ABSTRACT FROM AUTHOR]

In light of the overexpression of STK3 in GC patients, we finally investigated the clinical associations of STK3 in GC by TCGA cohort ( I n i = 375) and our in-house Hong Kong cohort ( I n i = 263). 2 STK3 promotes GC by activating the Ras-MAPK signaling pathway (*, P < 0.05; **, P < 0.01; ***, P < 0.001). a The heatmap of STK family members in nine GC cell lines. Keywords: STK3; Gastric cancer; Oncogene; Ras-MAPK signaling EN STK3 Gastric cancer Oncogene Ras-MAPK signaling 1 8 8 11/16/21 20211112 NES 211112 Bonan Chen, Wai Nok Chan and Chun Wai Mui contributed equally to this work. [Extracted from the article]

Protein ubiquitination is one of the most crucial posttranslational modifications responsible for regulating the stability and activity of proteins involved in homeostatic cellular function. Inconsistencies in the ubiquitination process may lead to tumorigenesis. Ubiquitin-specific peptidases are attractive therapeutic targets in different cancers and are being evaluated for clinical development. Ubiquitin-specific peptidase 37 (USP37) is one of the least studied members of the USP family. USP37 controls numerous aspects of oncogenesis, including stabilizing many different oncoproteins. Recent work highlights the role of USP37 in stimulating the epithelial-mesenchymal transition and metastasis in lung and breast cancer by stabilizing SNAI1 and stimulating the sonic hedgehog pathway, respectively. Several aspects of USP37 biology in cancer cells are yet unclear and are an active area of research. This review emphasizes the importance of USP37 in cancer and how identifying its molecular targets and signalling networks in various cancer types can help advance cancer therapeutics. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Its therapy has not significantly improved during the past four decades despite intense research efforts. New molecularly targeted therapies are in great need. The proto-oncogene c-Myc (MYC) is an attractive target due to its transactivation role in multiple signaling cascades. Deregulation of the MYC is considered one of a series of oncogenic events required for tumorigenesis. However, limited knowledge is available on which mechanism underlie MYC dysregulation and how long non-coding RNAs (lncRNAs) are involved in MYC dysregulation in AML. Methods: AML microarray chips and public datasets were screened to identify novel lncRNA GAS6-AS1 was dysregulated in AML. Gain or loss of functional leukemia cell models were produced, and in vitro and in vivo experiments were applied to demonstrate its leukemogenic phenotypes. Interactive network analyses were performed to define intrinsic mechanism. Results: We identified GAS6-AS1 was overexpressed in AML, and its aberrant function lead to more aggressive leukemia phenotypes and poorer survival outcomes. We revealed that GAS6-AS1 directly binds Y-box binding protein 1 (YBX1) to facilitate its interaction with MYC, leading to MYC transactivation and upregulation of IL1R1, RAB27B and other MYC target genes associated with leukemia progression. Further, lentiviral-based GAS6-AS1 silencing inhibited leukemia progression in vivo. Conclusions: Our findings revealed a previously unappreciated role of GAS6-AS1 as an oncogenic lncRNA in AML progression and prognostic prediction. Importantly, we demonstrated that therapeutic targeting of the GAS6-AS1/YBX1/MYC axis inhibits AML cellular propagation and disease progression. Our insight in lncRNA associated MYC-driven leukemogenesis may contribute to develop new anti-leukemia treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is one of the most common and fatal cancers worldwide. Effective biomarkers to aid the early diagnosis of GC, as well as predict the course of disease, are urgently needed. Hence, we explored the role and function of cadherin-6 (CDH6) in the diagnosis and prognosis of gastric cancer. Methods: The expression levels of CDH6 in cancerous and normal gastric tissue were analyzed using multiple public databases. Gene set enrichment analysis (GSEA) was performed using The Cancer Genome Atlas (TCGA) dataset. The diagnostic efficiency of CDH6 expression in GC patients was determined through receiver operating characteristic (ROC) curve analysis. The associations between clinical variables and CDH6 expression were evaluated statistically, and the prognostic factors for overall survival were analyzed by univariate and multivariate Cox regression. 44 GC tissue samples, 20 donor-matched adjacent normal tissue samples, and associated detailed clinical information, were collected from the Tianjin Medical University General Hospital. CDH6 expression levels were determined for further validation. Results: CDH6 was upregulated in GC samples compared to normal gastric tissue. Furthermore, GSEA identified the tricarboxylic acid (TCA) cycle, extracellular matrix (ECM) receptor interaction, glyoxylate and dicarboxylate metabolism, oxidative phosphorylation, and the pentose phosphate pathway as differentially enriched in GC tissue samples. According to the area under the ROC curve (AUC) values (AUC = 0.829 in the TCGA and 0.966 in the GSE54129 dataset), CDH6 expression was associated with high diagnostic efficacy. Patients with high CDH6 levels in their GC tissues had a higher T number (according to the TNM classification) and a worse prognosis than those with low CDH6 expression. Univariate and multivariate Cox regression analysis showed that CDH6 was an independent risk factor for overall survival (univariate: HR = 1.305, P = 0.002, multivariate: HR = 1.481, P < 0.001). Conclusion: CDH6 was upregulated in GC, and high CDH6 expression was indicative of a higher T number and a worse prognosis. Therefore, CDH6 represents a potentially independent molecular biomarker for the diagnostic and prognostic prediction of GC. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is still a serious male malignant disease across the world. However, no exact pathogenesis had been explained. Although adenylosuccinate lyase (ADSL) gene was identified to be important in PCa early in 1987, its comprehensive functions for PCa have not been presented. Methods: The cBioPortal for Cancer Genomics, Oncomine and GEO database were retrieved to investigate the associations between of the ADSL gene and PCa. Then, the PC-3, DU145 and C4-2B cell lines were applied in vitro experiments. RNA sequencing and further western blot (WB) were applied to explore the potential mechanisms of ADSL gene in PCa. Results: Based on PCa clinical datasets, we firstly found ADSL gene highly expressed in PCa tissues. Moreover, its transcript level increased in the metastatic PCa further. Elevated ADSL gene expression indicated a poor prognosis of PCa. While inhibiting the expression of ADSL with siRNA, the ability of cell proliferation and migration all declined markedly, with increased cell apoptosis inversely. Most of cells were blocked in the G0/G1 phase. Additionally, RNA sequencing also discovered the inactivity of cell cycle pathway after ADSL knockdown, which had also confirmed on the proteins levels. Conclusions: Our study identified the ADSL as an oncogene of PCa through regulating the cell cycle pathway firstly, with explicit cell and clinical phenotypes. Further mechanisms were needed to confirm its carcinogenic effect. [ABSTRACT FROM AUTHOR]

MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and hematopoiesis. Due to the multi-functionality of MYC, its expression is regulated at multiple levels. Deregulation of this oncogene can give rise to a variety of cancers. In this review, MYC regulation and the mechanisms by which MYC adjusts cellular functions and its implication in hematologic malignancies are summarized. Further, we also discuss potential inhibitors of MYC that could be beneficial for treating hematologic malignancies. [ABSTRACT FROM AUTHOR]

Background: Particular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor-stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs.Methods: MS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue samples and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival.Results: Phosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated 'omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 amplification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and amplification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target.Conclusions: This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment. [ABSTRACT FROM AUTHOR]

Background: The homeobox gene Homeobox B7 (HOXB7) is overexpressed across a range of cancers and promotes tumorigenesis through varying effects on proliferation, survival, migration and invasion. However, its expression pattern and oncogenic role of HOXB7 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. Here, we aimed to explore the expression pattern of HOXB7, its clinical significance as well as functional roles in HNSCC. Methods: HOXB7 mRNA expression in HNSCC was determined by data mining and analyses from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) datasets. The protein abundance of HOXB7 was measured by immunohistochemistry in 119 primary HNSCC samples and associations between its expression and clinicopathological parameters and patient survival were evaluated. The pro-tumorigenic roles of HOXB7 in HNSCC were further delineated in vitro by loss-of-function assay. And a xenograft tumor model was established in nude mice to assess the role of HOXB7 in tumor growth. Connectivity Map (CMap) analysis was performed to identify bioactive small molecules which might be potential inhibitors for HOXB7. Results: Bioinformatics analyses showed that HOXB7 mRNA was significantly overexpressed in 8 independent HNSCC datasets from TCGA and GEO databases. HOXB7 protein was markedly upregulated in HNSCC samples as compared to normal counterparts and its overexpression significantly associated with high pathological grade, advanced clinical stage, cervical node metastasis (P = 0.0195, 0.0152, 0.0300) and reduced overall and disease-free survival (P = 0.0014, 0.0007). Univariate and multivariate Cox regression analyses further revealed HOXB7 as an independent prognostic factor for patients' overall survival. Moreover, HOXB7 knockdown significantly inhibited cell proliferation, migration and invasion and induced cell apoptosis in HNSCC cells, and resulted in compromised tumour growth in vivo. Furthermore, CMap (Connectivity map) analysis has identified three potential bioactive small molecule inhibitors (NU-1025, thiamine, vinburnine) for HOXB7 targeted therapy in HNSCC. Conclusions: Our findings revealed that overexpression of HOXB7 was associates with tumour aggressiveness and unfavourable prognosis by serving a novel prognostic biomarker in HNSCC. Moreover, HOXB7 might be involved in the development and progression of HNSCC as an oncogene, and thereby might be a potential therapeutic target for HNSCC. [ABSTRACT FROM AUTHOR]

Background: Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. GNG5, which is part of the G-protein family, has been associated with different malignant tumors, though the role of GNG5 in glioma has not been studied. Therefore, we aimed to identify the relationship between GNG5 and glioma prognosis and identify a new biomarker for the diagnosis and treatment of gliomas. Methods: We used data on more than a thousand gliomas from multiple databases and clinical data to determine the expression of GNG5 in glioma. Based on clinical data and CGGA database, we identified the correlation between GNG5 and multiple molecular and clinical features and prognosis using various analytical methods. Co-expression analysis and GSEA were performed to detect GNG5-related genes in glioma and possible signaling pathways involved. ESTIMATE, ssGSEA, and TIMER were used to detect the relationship between GNG5 and the immune microenvironment. Functional experiments were performed to explore the function of GNG5 in glioma cells. Results: GNG5 is highly expressed in gliomas, and its expression level is positively correlated with pathological grade, histological type, age, and tumor recurrence and negatively correlated with isocitrate dehydrogenase mutation, 1p/19 co-deletion, and chemotherapy. Moreover, GNG5 as an independent risk factor was negatively correlated with the overall survival time. GSEA revealed the potential signaling pathways involved in GNG5 function in gliomas, including cell adhesion molecules signaling pathway. The ssGSEA, ESTIMATE, and TIMER based analysis indicated a correlation between GNG5 expression and various immune cells in glioma. In vivo and in vitro experiments showed that GNG5 could participate in glioma cell proliferation and migration. Conclusions: Based on the large data platform and the use of different databases to corroborate results obtained using various datasets, as well as in vitro and in vivo experiments, our study reveals for the first time that GNG5, as an oncogene, is overexpressed in gliomas and can inhibit the proliferation and migration of glioma cells and lead to poor prognosis of patients. Thus, GNG5 is a potential novel biomarker for the clinical diagnosis and treatment of gliomas. [ABSTRACT FROM AUTHOR]

Background: XRCC2, a homologous recombination-related gene, has been reported to be associated with a variety of cancers. However, its role in glioma has not been reported. This study aimed to find out the role of XRCC2 in glioma and reveal in which glioma-specific biological processes is XRCC2 involved based on thousands of glioma samples, thereby, providing a new perspective in the treatment and prognostic evaluation of glioma. Methods: The expression characteristics of XRCC2 in thousands of glioma samples from CGGA and TCGA databases were comprehensively analyzed. Wilcox or Kruskal test was used to analyze the expression pattern of XRCC2 in gliomas with different clinical and molecular features. The effect of XRCC2 on the prognosis of glioma patients was explored by Kaplan–Meier and Cox regression. Gene set enrichment analysis (GSEA) revealed the possible cellular mechanisms involved in XRCC2 in glioma. Connectivity map (CMap) was used to screen small molecule drugs targeting XRCC2 and the expression levels of XRCC2 were verified in glioma cells and tissues by RT-qPCR and immunohistochemical staining. Results: We found the overexpression of XRCC2 in glioma. Moreover, the overexpressed XRCC2 was associated with a variety of clinical features related to prognosis. Cox and meta-analyses showed that XRCC2 is an independent risk factor for the poor prognosis of glioma. Furthermore, the results of GSEA indicated that overexpressed XRCC2 could promote malignant progression through involved signaling pathways, such as in the cell cycle. Finally, doxazosin, quinostatin, canavanine, and chrysin were identified to exert anti-glioma effects by targeting XRCC2. Conclusions: This study analyzed the expression pattern of XRCC2 in gliomas and its relationship with prognosis using multiple datasets. This is the first study to show that XRCC2, a novel oncogene, is significantly overexpressed in glioma and can lead to poor prognosis in glioma patients. XRCC2 could serve as a new biomarker for glioma diagnosis, treatment, and prognosis evaluation, thus bringing new insight into the management of glioma. [ABSTRACT FROM AUTHOR]

The human family of Potassium (K+) Channel Tetramerization Domain (KCTD) proteins counts 25 members, and a significant number of them are still only partially characterized. While some of the KCTDs have been linked to neurological disorders or obesity, a growing tally of KCTDs are being associated with cancer hallmarks or involved in the modulation of specific oncogenic pathways. Indeed, the potential relevance of the variegate KCTD family in cancer warrants an updated picture of the current knowledge and highlights the need for further research on KCTD members as either putative therapeutic targets, or diagnostic/prognostic markers. Homology between family members, capability to participate in ubiquitination and degradation of different protein targets, ability to heterodimerize between members, role played in the main signalling pathways involved in development and cancer, are all factors that need to be considered in the search for new key players in tumorigenesis. In this review we summarize the recent published evidence on KCTD members' involvement in cancer. Furthermore, by integrating this information with data extrapolated from public databases that suggest new potential associations with cancers, we hypothesize that the number of KCTD family members involved in tumorigenesis (either as positive or negative modulator) may be bigger than so far demonstrated. -fFEfNtUXdeWcKncW3NUpD Video abstract [ABSTRACT FROM AUTHOR]

Background: Fatty acid oxidation (FAO) provides an important source of energy to promote the growth of leukemia cells. Carnitine palmitoyltransferase 1a(CPT1a), a rate-limiting enzyme of the essential step of FAO, can facilitate cancer metabolic adaptation. Previous reports demonstrated that CPT1a acts as a potential molecular target in solid tumors and hematologic disease. However, no systematic study was conducted to explore the prognostic value of CPT1a expression and possible treatment strategies with CPT1a inhibitor on acute myeloid leukemia (AML).Methods: The expression of CPT1a in 325 cytogenetically normal AML (CN-AML) patients was evaluated using RT-PCR. The combination effects of ST1326 and ABT199 were studied in AML cells and primary patients. MTS was used to measure the cell proliferation rate. Annexin V/propidium iodide staining and flow cytometry analysis was used to measure the apoptosis rate. Western blot was used to measure the expression of Mcl-1. RNAseq and GC-TOFMS were used for genomic and metabolic analysis.Results: In this study, we found AML patients with high CPT1a expression (n = 245) had a relatively short overall survival (P = 0.01) compared to patients in low expression group (n = 80). In parallel, downregulation of CPT1a inhibits proliferation of AML cells. We also conducted genomic and metabolic interactive analysis in AML patients, and found several essential genes and pathways related to aberrant expression of CPT1a. Moreover, we found downregulation of CPT1a sentitized BCL-2 inhibitor ABT199 and CPT1a-selective inhibitor ST1326 combined with ABT199 had a strong synergistic effect to induce apoptosis in AML cells and primary patient blasts for the first time. The underlying synergistic mechanism might be that ST1326 inhibits pGSK3β and pERK expression, leading to downregulation of Mcl-1.Conclusion: Our study indicates that overexpression of CPT1a predicts poor clinical outcome in AML. CPT1a-selective inhibitor ST1326 combined with Bcl-2 inhibitor ABT199 showed strong synergistic inhibitory effects on AML. [ABSTRACT FROM AUTHOR]

Nonsense-mediated decay (NMD) was first described as a quality-control mechanism that targets and rapidly degrades aberrant mRNAs carrying premature termination codons (PTCs). However, it was found that NMD also degrades a significant number of normal transcripts, thus arising as a mechanism of gene expression regulation. Based on these important functions, NMD regulates several biological processes and is involved in the pathophysiology of a plethora of human genetic diseases, including cancer. The present review aims to discuss the paradoxical, pro- and anti-tumorigenic roles of NMD, and how cancer cells have exploited both functions to potentiate the disease. Considering recent genetic and bioinformatic studies, we also provide a comprehensive overview of the present knowledge of the advantages and disadvantages of different NMD modulation-based approaches in cancer therapy, reflecting on the challenges imposed by the complexity of this disease. Furthermore, we discuss significant advances in the recent years providing new perspectives on the implications of aberrant NMD-escaping frameshifted transcripts in personalized immunotherapy design and predictive biomarker optimization. A better understanding of how NMD differentially impacts tumor cells according to their own genetic identity will certainly allow for the application of novel and more effective personalized treatments in the near future. [ABSTRACT FROM AUTHOR]

Background: Inositol polyphosphate 4-phosphatase type II (INPP4B) is a negative regulator of the PI3K-Akt signalling pathway and plays a contradictory role in different types of cancers. However, the its biological role played by INPP4B in human gallbladder cancer (GBC) has not been elucidated. In this study, we investigated the expression, clinical significance and biological function of INPP4B in GBC patients and cell lines.Methods: The INPP4B protein expression levels in gallbladder cancer tissues and normal gallbladder tissues were detected by immunohistochemistry, and the clinical significance of INPP4B was analysed. Knockdown and overexpression of INPP4B in GBC-SD and SGC-996 cells followed by cell proliferation, clonogenic, apoptosis detection, scratch wound-healing and transwell assays were used to identify INPP4B function in vitro.Results: INPP4B was up-regulated in human GBC tissues compared with normal gallbladder tissues and was related to histopathological differentiation (p = 0.026). Here, we observed that INPP4B was highly expressed in high-moderately differentiated tumours compared with low-undifferentiated tumours (p = 0.022). Additionally, we found that INPP4B expression was not associated with overall survival of GBC patients (p = 0.071) and was not an independent prognostic factor. Furthermore, when we stratified the relationship between INPP4B expression and the prognosis of GBC based on histopathological differentiation, we found that INPP4B played a contradictory role in GBC progression depending on the degree of differentiation. In addition, INPP4B knockdown inhibited the proliferation, colony formation, migration and invasion in GBC cells, while INPP4B overexpression had the opposite effects in vitro, which indicates its role as an oncoprotein.Conclusions: These findings suggested that INPP4B may play a dual role in the prognosis of GBC depending on the degree of differentiation and that INPP4B might act as an oncogene in gallbladder cancer cells. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the malignant tumor with the highest incidence in women. DNA methylation has an important effect on breast cancer, but the effect of abnormal DNA methylation on gene expression in breast cancer is still unclear. Therefore, it is very important to find therapeutic targets related to DNA methylation. Results: In this work, we calculated the DNA methylation distribution and gene expression level in cancer and para-cancerous tissues for breast cancer samples. We found that DNA methylation in key regions is closely related to gene expression by analyzing the relationship between the distribution characteristics of DNA methylation in different regions and the change of gene expression level. Finally, the 18 key genes (17 tumor suppressor genes and 1 oncogene) related to prognosis were confirmed by the survival analysis of clinical data. Some important DNA methylation regions in these genes that result in breast cancer were found. Conclusions: We believe that 17 TSGs and 1 oncogene may be breast cancer biomarkers regulated by DNA methylation in key regions. These results will help to explore DNA methylation biomarkers as potential therapeutic targets for breast cancer. [ABSTRACT FROM AUTHOR]

c-Myc is a transcription factor that is constitutively and aberrantly expressed in over 70% of human cancers. Its direct inhibition has been shown to trigger rapid tumor regression in mice with only mild and fully reversible side effects, suggesting this to be a viable therapeutic strategy. Here we reassess the challenges of directly targeting c-Myc, evaluate lessons learned from current inhibitors, and explore how future strategies such as miniaturisation of Omomyc and targeting E-box binding could facilitate translation of c-Myc inhibitors into the clinic. [ABSTRACT FROM AUTHOR]

Background: In spite of great progress in the surgical and clinical management, until now no significant improvement in overall survival of High-Grade Serous Ovarian Cancer (HGSOC) patients has been achieved. Important aspects for disease control remain unresolved, including unclear pathogenesis, high heterogeneity and relapse resistance after chemotherapy. Therefore, further research on molecular mechanisms involved in cancer progression are needed to find new targets for disease management. The Krüppel-like factors (KLFs) are a family of transcriptional regulators controlling several basic cellular processes, including proliferation, differentiation and migration. They have been shown to play a role in various cancer-relevant processes, in a context-dependent way. Methods: To investigate a possible role of KLF family members as prognostic biomarkers, we carried out a bioinformatic meta-analysis of ovarian transcriptome datasets in different cohorts of late-stage HGSOC patients. In vitro cellular models of HGSOC were used for functional studies exploring the role of KLF7 in disease development and progression. Finally, molecular modelling and virtual screening were performed to identify putative KLF7 inhibitors. Results: Bioinformatic analysis highlighted KLF7 as the most significant prognostic gene, among the 17 family members. Univariate and multivariate analyses identified KLF7 as an unfavourable prognostic marker for overall survival in late-stage TCGA-OV and GSE26712 HGSOC cohorts. Functional in vitro studies demonstrated that KLF7 can play a role as oncogene, driving tumour growth and dissemination. Mechanistic targets of KLF7 included genes involved in epithelial to mesenchymal transition, and in maintaining pluripotency and self-renewal characteristics of cancer stem cells. Finally, in silico analysis provided reliable information for drug-target interaction prediction. Conclusions: Results from the present study provide the first evidence for an oncogenic role of KLF7 in HGSOC, suggesting it as a promising prognostic marker and therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Fusion transcripts are involved in tumourigenesis and play a crucial role in tumour heterogeneity, tumour evolution and cancer treatment resistance. However, fusion transcripts have not been studied at high spatial resolution in tissue sections due to the lack of full-length transcripts with spatial information. New highthroughput technologies like spatial transcriptomics measure the transcriptome of tissue sections on almost singlecell level. While this technique does not allow for direct detection of fusion transcripts, we show that they can be inferred using the relative poly(A) tail abundance of the involved parental genes. Method: We present a new method STfusion, which uses spatial transcriptomics to infer the presence and absence of poly(A) tails. A fusion transcript lacks a poly(A) tail for the 5' gene and has an elevated number of poly(A) tails for the 3' gene. Its expression level is defined by the upstream promoter of the 5' gene. STfusion measures the difference between the observed and expected number of poly(A) tails with a novel C-score. Results: We verified the STfusion ability to predict fusion transcripts on HeLa cells with known fusions. STfusion and C-score applied to clinical prostate cancer data revealed the spatial distribution of the cis-SAGe SLC45A3-ELK4 in 12 tissue sections with almost single-cell resolution. The cis-SAGe occurred in disease areas, e.g. inflamed, prostatic intraepithelial neoplastic, or cancerous areas, and occasionally in normal glands. Conclusions: STfusion detects fusion transcripts in cancer cell line and clinical tissue data, and distinguishes chimeric transcripts from chimeras caused by trans-splicing events. With STfusion and the use of C-scores, fusion transcripts can be spatially localised in clinical tissue sections on almost single cell level. [ABSTRACT FROM AUTHOR]

Background: anaplastic thyroid cancer (ATC) is one of the most lethal and aggressive cancers. Evidence has shown that the tumorigenesis of ATC is a multistep process involving the accumulation of genetic and epigenetic changes. Several studies have suggested that long non-coding RNAs (lncRNAs) may play an important role in the development and progression of ATC. In this article, we have collected the published reports about the role of lncRNAs in ATC. Methods: "Scopus", "Web of Science", "PubMed", "Embase", etc. were systematically searched for articles published since 1990 to 2020 in English language, using the predefined keywords. Results: 961 papers were reviewed and finally 33 papers which fulfilled the inclusion and exclusion criteria were selected. Based on this systematic review, among a lot of evidences on examining the function of lncRNAs in thyroid cancer, there are only a small number of studies about the role of lncRNAs and their molecular mechanisms in the pathogenesis of ATC. Conclusions: lncRNAs play a crucial role in regulation of different processes involved in the development and progression of ATC. Currently, just a few lncRNAs have been identified in ATC that may serve as prognosis markers such as GAS5, MIR22HG, and CASC2. Also, because of the dysregulation of Klhl14-AS, HOTAIRM1, and PCA3 during ATC development and progression, they may act as therapeutic targets. However, for most lncRNAs, only a single experiment has evaluated the expression profile in ATC tissues/cells. Therefore, further functional studies and expression profiling is needed to resolve this limitation and identify novel and valid biomarkers. [ABSTRACT FROM AUTHOR]