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Abstract Long non-coding RNAs (lncRNAs) represent an important class of RNAs comprising more than 200 nucleotides, which are produced by RNA polymerase II. Although lacking an open reading framework and protein-encoding activity, lncRNAs can mediate endogenous gene expression by serving as chromatin remodeler, transcriptional or post-transcriptional modulator, and splicing regulator during gene modification. In recent years, increasing evidence shows the significance of lncRNAs in many malignancies, with vital roles in tumorigenesis and cancer progression. Moreover, lncRNAs were also considered potential diagnostic and prognostic markers in cancer. The lncRNA small nuclear RNA host gene 16 (SNHG16), found on chromosome 17q25.1, represents a novel tumor-associated lncRNA. SNHG16 was recently found to exhibit dysregulated expression in a variety of malignancies. There are growing evidence of SNHG16’s involvement in characteristics of cancer, including proliferation, apoptosis, together with its involvement in chemoresistance. In addition, SNHG16 has been described as a promising diagnostic and prognostic biomarker in cancer patients. The current review briefly summarizes recently reported findings about SNHG16 and discuss its expression, roles, mechanisms, and diagnostic and prognostic values in human cancers.

Abstract Genetic and epigenetic changes deregulate RNA and protein expression in cancer cells. In this regard, tumors exhibit an abnormal proteome in comparison to the corresponding normal tissues. Translation control is a crucial step in the regulation of gene expression regulation under normal and pathological conditions that ultimately determines cellular fate. In this context, evidence shows that transfer and ribosomal RNA (tRNA and rRNA) modifications affect the efficacy and fidelity of translation. The number of RNA modifications increases with the complexity of organisms, suggesting an evolutionary diversification of the possibilities for fine-tuning the functions of coding and non-coding RNAs. In this review, we focus on alterations of modifications of transfer and ribosomal RNA that affect translation in human cancer. This variation in the RNA modification status can be the result of altered modifier expression (writers, readers or erasers), but also due to components of the machineries (C/D or H/ACA boxes) or alterations of proteins involved in modifier expression. Broadening our understanding of the mechanisms by which site-specific modifications modulate ribosome activity in the context of tumorigenesis will enable us to enrich our knowledge about how ribosomes can influence cell fate and form the basis of new therapeutic opportunities.

Abstract Background DNA damage accumulates over the course of cancer development. The often-substantial amount of somatic mutations in cancer poses a challenge to traditional methods to characterize tumors based on driver mutations. However, advances in machine learning technology can take advantage of this substantial amount of data. Results We developed a command line interface python package, pyCancerSig, to perform sample profiling by integrating single nucleotide variation (SNV), structural variation (SV) and microsatellite instability (MSI) profiles into a unified profile. It also provides a command to decipher underlying cancer processes, employing an unsupervised learning technique, Non-negative Matrix Factorization, and a command to visualize the results. The package accepts common standard file formats (vcf, bam). The program was evaluated using a cohort of breast- and colorectal cancer from The Cancer Genome Atlas project (TCGA). The result showed that by integrating multiple mutations modes, the tool can correctly identify cases with known clear mutational signatures and can strengthen signatures in cases with unclear signal from an SNV-only profile. The software package is available at https://github.com/jessada/pyCancerSig. Conclusions pyCancerSig has demonstrated its capability in identifying known and unknown cancer processes, and at the same time, illuminates the association within and between the mutation modes.

Abstract NoncoRNA ( http://www.ncdtcdb.cn:8080/NoncoRNA/ ) is a manually curated database of experimentally supported non-coding RNAs (ncRNAs) and drug target associations that aim to potentially provide a high-quality data resource for exploring drug sensitivity/resistance-related ncRNAs in various human cancers. ncRNA are RNA molecular that do not encode proteins, but are involved in gene regulation and cellular functions in variety of human diseases, including neurodegenerative diseases and cancers. Here, we developed NoncoRNA which contained 8233 entries between 5568 ncRNAs and 154 drugs in 134 cancers. Each entry in the NoncoRNA contains detailed information on the ncRNAs, drugs, and cancers, the ncRNA expression pattern and experimental detection techniques, drug response and other targets, literature references, and other information. NoncoRNA offers a user-friendly, open access web interface to easily browse, search, and download data. NoncoRNA also provides a submission page for researchers to submit newly validated ncRNA-drug-cancer associations. NoncoRNA might serve as an immeasurable resource for understanding the roles of ncRNAs in cancer therapy.

Kinase-targeted cancer therapy (KTCT) with ATP-competitive inhibitors has been widely applied in clinics. However, a number of kinase missense mutations were observed to confer acquired drug resistance during therapy, largely limiting the clinical application of kinase inhibitors in KTCT. Instead of directly influencing inhibitor binding, kinase mutations can also cause generic resistance to ATP-competitive inhibitors by increasing ATP affinity. Herein, the intermolecular interaction of the ATP molecule with clinically observed drug-resistant EGFR family kinase mutations involved in human cancer are systematically characterize. Rigorous quantum mechanics/molecular mechanics (QM/MM) calculation and empirical Poisson–Boltzmann/surface area (PB/SA) analysis as well as in vitro kinase assay and surface plasmon resonance analysis were integrated to explore the binding capability of ATP to mutant residues in the structural context of the kinase domain, which resulted in a comprehensive profile of ATP response to acquired drug-resistant mutations of four EGFR family kinases (EGFR/ErbB1, ErbB2, ErbB3 and ErbB4). From the profile, it was possible to identify those potent mutations that may influence ATP binding significantly; such mutations are potential candidates to cause generic resistance for ATP-competitive inhibitors. Consequently, the well documented generic drug-resistant mutation EGFR T790M and its counterpart ErbB2 T798M are found to increase ATP affinity by establishing an additional S–π interaction between the side-chain thioether group of the mutant Met residue and the aromatic adenine moiety of the ATP molecule, while EGFR D761Y is identified as a new generic drug-resistant mutation that can increase ATP affinity by eliminating unfavorable electrostatic repulsion. In contrast, ErbB2 K753E and T768I are considered to be two generic drug-sensitive mutations that can decrease ATP affinity by unfavorable charge reversal and by impairing favorable polar interaction, respectively. In addition, the EGFR L858R mutation is located at the kinase activation loop and nearby the kinase active site, thus largely complicating the multiply dependent relationship of kinase, ATP and inhibitor, which therefore exhibits divergent effects on different tested inhibitors.

Abstract Background While many studies have assessed the predictive value of secreted phosphoprotein (SPP) genes in cancer, the findings have been inconsistent. To resolve these inconsistencies, we systematically analyzed the available data to determine whether SPP1 and SPP2 are prognostic markers in the context of human cancer. Methods The expression of SPP1 and SPP2 was assessed by Oncomine analysis. The PrognoScan database was used to assess the prognostic value of SPP1 and SPP2, with cBioPortal used to assess copy number variations. The STRING database was used to generate a Protein - Protein Interaction (PPI) network for SPP genes. Results SPP1 was more likely to be over-expressed in breast, bladder, colorectal, head, neck, liver, lung, and esophageal cancers. SPP2 was expressed at lower levels in colorectal cancer, leukemia, liver cancer and pancreatic cancer. In addition, SPP1 and SPP2 mutations mainly occurred in cutaneous melanoma and endometrial cancer. Conclusions Our results suggest that SPP1 and SPP2 may be effective therapeutic or diagnostic targets in certain cancers. Further research is required to confirm these results and verify the value of SPP1 and SPP2 as clinical markers of cancer prognosis.

Abstract Background Most statistical methods used to identify cancer driver genes are either biased due to choice of assumed parametric models or insensitive to directional relationships important for causal inference. To overcome modeling biases and directional insensitivity, a recent statistical functional chi-squared test (FunChisq) detects directional association via model-free functional dependency. FunChisq examines patterns pointing from independent to dependent variables arising from linear, non-linear, or many-to-one functional relationships. Meanwhile, the Functional Annotation of Mammalian Genome 5 (FANTOM5) project surveyed gene expression at over 200,000 transcription start sites (TSSs) in nearly all human tissue types, primary cell types, and cancer cell lines. The data cover TSSs originated from both coding and noncoding genes. For the vast uncharacterized human TSSs that may exhibit complex patterns in cancer versus normal tissues, the model-free property of FunChisq provides us an unprecedented opportunity to assess the evidence for a gene’s directional effect on human cancer. Results We first evaluated FunChisq and six other methods using 719 curated cancer genes on the FANTOM5 data. FunChisq performed best in detecting known cancer driver genes from non-cancer genes. We also show the capacity of FunChisq to reveal non-monotonic patterns of functional association, to which typical differential analysis methods such as t-test are insensitive. Further applying FunChisq to screen unannotated TSSs in FANTOM5, we predicted 1108 putative cancer driver noncoding RNAs, stronger than 90% of curated cancer driver genes. Next, we compared leukemia samples against other samples in FANTOM5 and FunChisq predicted 332/79 potential biomarkers for lymphoid/myeloid leukemia, stronger than the TSSs of all 87/100 known driver genes in lymphoid/myeloid leukemia. Conclusions This study demonstrated the advantage of FunChisq in revealing directional association, especially in detecting non-monotonic patterns. Here, we also provide the most comprehensive catalog of high-quality biomarkers that may play a causative role in human cancers, including putative cancer driver noncoding RNAs and lymphoid/myeloid leukemia specific biomarkers.

The dysregulation of transfer RNA (tRNA) expression contributes to the diversity of proteomics, heterogeneity of cell populations, and instability of the genome, which may be related to human cancer susceptibility. However, the relationship between tRNA dysregulation and cancer susceptibility remains elusive because the landscape of cancer-associated tRNAs has not been portrayed yet. Furthermore, the molecular mechanisms of tRNAs involved in tumorigenesis and cancer progression have not been systematically understood. In this review, we detail current knowledge of cancer-related tRNAs and comprehensively summarize the basic characteristics and functions of these tRNAs, with a special focus on their role and involvement in human cancer. This review bridges the gap between tRNAs and cancer and broadens our understanding of their relationship, thus providing new insights and strategies to improve the potential clinical applications of tRNAs for cancer diagnosis and therapy.

The dysregulation of mRNA translation is common in malignancies and may lead to tumorigenesis and progression. Eukaryotic initiation factor 4A (eIF4A) proteins are essential for translation, exhibit bidirectional RNA helicase function, and act as RNA-dependent ATPases. In this review, we explored the predicted structures of the three eIF4A isoforms (eIF4A1, eIF4A2, and eIF4A3), and discussed possible explanations for which function during different translation stages (initiation, mRNA localization, export, and mRNA splicing). These proteins also frequently served as targets of microRNAs (miRNAs) or long noncoding RNAs (lncRNAs) to mediate epithelial-mesenchymal transition (EMT), which was associated with tumor cell invasion and metastasis. To define the differential expression of eIF4A family members, we applied the Tumor Immune Estimation Resource website. We figured out that the eIF4A family genes were differently expressed in specific cancer types. We also found that the level of the eIF4A family genes were associated with abundant immune cells infiltration and tumor purity. The associations between eIF4A proteins and cancer patient clinicopathological features suggested that eIF4A proteins might serve as biomarkers for early tumor diagnosis, histological classification, and clinical grading/staging, providing new tools for precise and individualized cancer treatment.

The vital tissue homeostasis regulator p53 forms a tetramer when it binds to DNA and regulates the genes that mediate essential biological processes such as cell-cycle arrest, senescence, DNA repair, and apoptosis. Missense mutations in the core DNA-binding domain (109–292) simultaneously cause the loss of p53 tumor suppressor function and accumulation of the mutant p53 proteins that are carcinogenic. The most common p53 hotspot mutation at codon 248 in the DNA-binding region, where arginine (R) is substituted by tryptophan (W), glycine (G), leucine (L), proline (P), and glutamine (Q), is reported in various cancers. However, it is unclear how the p53 Arg248 mutation with distinct amino acid substitution affects the structure, function, and DNA binding affinity. Here, we characterized the pathogenicity and protein stability of p53 hotspot mutations at codon 248 using computational tools PredictSNP, Align GVGD, HOPE, ConSurf, and iStable. We found R248W, R248G, and R248P mutations highly deleterious and destabilizing. Further, we subjected all five R248 mutant-p53–DNA and wt-p53–DNA complexes to molecular dynamics simulation to investigate the structural stability and DNA binding affinity. From the MD simulation analysis, we observed increased RMSD, RMSF, and Rg values and decreased protein–DNA intermolecular hydrogen bonds in the R248-p53–DNA than the wt-p53–DNA complexes. Likewise, due to high SASA values, we observed the shrinkage of proteins in R248W, R248G, and R248P mutant-p53–DNA complexes. Compared to other mutant p53–DNA complexes, the R248W, R248G, and R248P mutant-p53–DNA complexes showed more structural alteration. MM-PBSA analysis showed decreased binding energies with DNA in all five R248-p53–DNA mutants than the wt-p53–DNA complexes. Henceforth, we conclude that the amino acid substitution of Arginine with the other five amino acids at codon 248 reduces the p53 protein’s affinity for DNA and may disrupt cell division, resulting in a gain of p53 function. The proposed study influences the development of rationally designed molecular-targeted treatments that improve p53-based therapeutic outcomes in cancer.

Aging and circadian rhythms have been connected for decades, but their molecular interaction has remained unknown, especially for cancers. In this situation, we summarized the current research actuality and problems in this field using the bibliometric analysis. Publications in the PubMed and Web of Science databases were retrieved. Overall, there is a rising trend in the publication volume regarding aging and circadian rhythms in the field of cancer. Researchers from USA, Germany, Italy, China and England have greater studies than others. Top three publication institutions are University of California System, UDICE-French Research Universities and University of Texas System. Current research hotspots include oxidative stress, breast cancer, melatonin, cell cycle, calorie restriction, prostate cancer and NF-KB. In conclusion, results generated by bibliometric analysis indicate that many approaches involve in the complex interactions between aging and circadian rhythm in cancer. These established and emerging research directions guide our exploration of the regulatory mechanisms of aging and circadian rhythms in cancer and provide a reference for developing new research avenues., (Copyright ©2024 Chinese Journal of Cancer Research. All rights reserved.)

BackgroundYTH N6-methyladenosine RNA binding protein 1 (YTHDF1) has been indicated proven to participate in the cross-presentation of tumor antigens in dendritic cells and the cross-priming of CD8+ T cells. However, the role of YTHDF1 in prognosis and immunology in human cancers remains largely unknown.MethodsAll original data were downloaded from TCGA and GEO databases and integrated via R 3.2.2. YTHDF1 expression was explored with the Oncomine, TIMER, GEPIA, and BioGPS databases. The effect of YTHDF1 on prognosis was analyzed via GEPIA, Kaplan-Meier plotter, and the PrognoScan database. The TISIDB database was used to determine YTHDF1 expression in different immune and molecular subtypes of human cancers. The correlations between YTHDF1 expression and immune checkpoints (ICP), tumor mutational burden (TMB), microsatellite instability (MSI), and neoantigens in human cancers were analyzed via the SangerBox database. The relationships between YTHDF1 expression and tumor-infiltrated immune cells were analyzed via the TIMER and GEPIA databases. The relationships between YTHDF1 and marker genes of tumor-infiltrated immune cells in urogenital cancers were analyzed for confirmation. The genomic alterations of YTHDF1 were investigated with the c-BioPortal database. The differential expression of YTHDF1 in urogenital cancers with different clinical characteristics was analyzed with the UALCAN database. YTHDF1 coexpression networks were studied by the LinkedOmics database.ResultsIn general, YTHDF1 expression was higher in tumors than in paired normal tissue in human cancers. YTHDF1 expression had strong relationships with prognosis, ICP, TMB, MSI, and neoantigens. YTHDF1 plays an essential role in the tumor microenvironment (TME) and participates in immune regulation. Furthermore, significant strong correlations between YTHDF1 expression and tumor immune-infiltrated cells (TILs) existed in human cancers, and marker genes of TILs were significantly related to YTHDF expression in urogenital cancers. TYHDF1 coexpression networks mostly participated in the regulation of immune response and antigen processing and presentation.ConclusionYTHDF1 may serve as a potential prognostic and immunological pan-cancer biomarker. Moreover, YTHDF1 could be a novel target for tumor immunotherapy.

Circular RNAs (circRNAs) are RNAs that have an important role in various pathological processes, including cancer. After the usage of high-throughput RNA sequencing, many circRNAs were found to be differentially expressed in various cancer cell lines and regulate cell signaling pathways by modulating particular gene expressions. Understanding their role in these pathways and what cancers they are found in can set the stage for identifying diagnostic and prognostic biomarkers and therapeutic targets of cancer. This paper will discuss which circRNAs are found in different cancers and what mechanisms they use to upregulate or downregulate certain cellular components. [ABSTRACT FROM AUTHOR]

Background: YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) has been indicated proven to participate in the cross-presentation of tumor antigens in dendritic cells and the cross-priming of CD8+ T cells. However, the role of YTHDF1 in prognosis and immunology in human cancers remains largely unknown. Methods: All original data were downloaded from TCGA and GEO databases and integrated via R 3.2.2. YTHDF1 expression was explored with the Oncomine, TIMER, GEPIA, and BioGPS databases. The effect of YTHDF1 on prognosis was analyzed via GEPIA, Kaplan-Meier plotter, and the PrognoScan database. The TISIDB database was used to determine YTHDF1 expression in different immune and molecular subtypes of human cancers. The correlations between YTHDF1 expression and immune checkpoints (ICP), tumor mutational burden (TMB), microsatellite instability (MSI), and neoantigens in human cancers were analyzed via the SangerBox database. The relationships between YTHDF1 expression and tumor-infiltrated immune cells were analyzed via the TIMER and GEPIA databases. The relationships between YTHDF1 and marker genes of tumor-infiltrated immune cells in urogenital cancers were analyzed for confirmation. The genomic alterations of YTHDF1 were investigated with the c-BioPortal database. The differential expression of YTHDF1 in urogenital cancers with different clinical characteristics was analyzed with the UALCAN database. YTHDF1 coexpression networks were studied by the LinkedOmics database. Results: In general, YTHDF1 expression was higher in tumors than in paired normal tissue in human cancers. YTHDF1 expression had strong relationships with prognosis, ICP, TMB, MSI, and neoantigens. YTHDF1 plays an essential role in the tumor microenvironment (TME) and participates in immune regulation. Furthermore, significant strong correlations between YTHDF1 expression and tumor immune-infiltrated cells (TILs) existed in human cancers, and marker genes of TILs were significantly related to YTHDF expression in urogenital cancers. TYHDF1 coexpression networks mostly participated in the regulation of immune response and antigen processing and presentation. Conclusion: YTHDF1 may serve as a potential prognostic and immunological pan-cancer biomarker. Moreover, YTHDF1 could be a novel target for tumor immunotherapy. [ABSTRACT FROM AUTHOR]

The zinc finger and BTB (broad-complex, tramtrack and bric a brac) domain containing protein 7A (ZBTB7A) is a pleiotropic transcription factor that plays an important role in various stages of cell proliferation, differentiation, and other developmental processes. ZBTB7A is a member of the POK family that directly and specifically binds to short DNA recognition sites located near their target genes thereby acting as transcriptional activator or repressor. ZBTB7A overexpression has been associated with tumorigenesis and metastasis in various human cancer types, including breast, prostate, lung, ovarian, and colon cancer. However in some instances downregulation of ZBTB7A results in tumor progression, suggesting its role as a tumor suppressor. ZBTB7A is involved with complicated regulatory networks which include protein–protein and protein-nucleic acid interactions. ZBTB7A involvement in cancer progression and metastasis is perhaps enabled through the regulation of various signaling pathways depending on the type and genetic context of cancer. The association of ZBTB7A with other proteins affects cancer aggressiveness, therapeutic resistance and clinical outcome. This review focuses on the involvement of ZBTB7A in various signaling pathways and its role in cancer progression. We will also review the literature on ZBTB7A and cancer which could be potentially explored for its therapeutic implications. [ABSTRACT FROM AUTHOR]

Bisphenol A [BPA; (CH3)2C(C6H4OH)2] is a synthetic chemical used as a precursor material for the manufacturing of plastics and resins. It gained attention due to its high chances of human exposure and predisposing individuals at extremely low doses to diseases, including cancer. It enters the human body via oral, inhaled, and dermal routes as leach-out products. BPA may be anticipated as a probable human carcinogen. Studies using in vitro cell lines, rodent models, and epidemiological analysis have convincingly shown the increasing susceptibility to cancer at doses below the oral reference dose set by the Environmental Protection Agency for BPA. Furthermore, BPA exerts its toxicological effects at the genetic and epigenetic levels, influencing various cell signaling pathways. The present review summarizes the available data on BPA and its potential impact on cancer and its clinical outcome. [ABSTRACT FROM AUTHOR]

Trop-2 is a transmembrane signal transducer that can induce cancer growth. Using antibody targeting and N-terminal Edman degradation, we show here that Trop-2 undergoes cleavage in the first thyroglobulin domain loop of its extracellular region, between residues R87 and T88. Molecular modeling indicated that this cleavage induces a profound rearrangement of the Trop-2 structure, which suggested a deep impact on its biological function. No Trop-2 cleavage was detected in normal human tissues, whereas most tumors showed Trop-2 cleavage, including skin, ovary, colon, and breast cancers. Coimmunoprecipitation and mass spectrometry analysis revealed that ADAM10 physically interacts with Trop-2. Immunofluorescence/confocal time-lapse microscopy revealed that the two molecules broadly colocalize at the cell membrane. We show that ADAM10 inhibitors, siRNAs and shRNAs abolish the processing of Trop-2, which indicates that ADAM10 is an effector protease. Proteolysis of Trop-2 at R87-T88 triggered cancer cell growth both in vitro and in vivo. A corresponding role was shown for metastatic spreading of colon cancer, as the R87A-T88A Trop-2 mutant abolished xenotransplant metastatic dissemination. Activatory proteolysis of Trop-2 was recapitulated in primary human breast cancers. Together with the prognostic impact of Trop-2 and ADAM10 on cancers of the skin, ovary, colon, lung, and pancreas, these data indicate a driving role of this activatory cleavage of Trop-2 on malignant progression of tumors. [ABSTRACT FROM AUTHOR]

Monoubiquitination of FANCD2 is a central step in the activation of the Fanconi anemia (FA) pathway after DNA damage. Defects in the FA pathway centered around FANCD2 not only lead to genomic instability but also induce tumorigenesis. At present, few studies have investigated FANCD2 in tumors, and no pan-cancer research on FANCD2 has been conducted. We conducted a comprehensive analysis of the role of FANCD2 in cancer using public databases and other published studies. Moreover, we evaluated the role of FANCD2 in the proliferation, migration and invasion of lung adenocarcinoma cells through in vitro and in vivo experiments, and explored the role of FANCD2 in cisplatin chemoresistance. We investigated the regulatory effect of FANCD2 on the cell cycle of lung adenocarcinoma cells by flow cytometry, and verified this effect by western blotting. FANCD2 expression is elevated in most TCGA tumors and shows a strong positive correlation with poor prognosis in tumor patients. In addition, FANCD2 expression shows strong correlations with immune infiltration, immune checkpoints, the tumor mutation burden (TMB), and microsatellite instability (MSI), which are immune-related features, suggesting that it may be a potential target of tumor immunotherapy. We further found that FANCD2 significantly promotes the proliferation, invasion, and migration abilities of lung adenocarcinoma cells and that its ability to promote cancer cell proliferation may be achieved by modulating the cell cycle. The findings indicate that FANCD2 is a potential biomarker and therapeutic target in cancer treatment by analyzing the oncogenic role of FANCD2 in different tumors. • This study provides the first pan-cancer analysis of FANCD2 using data from public databases. • FANCD2 is upregulated and has poor prognosis in most cancers and plays a potential role in regulating tumor immunity. • We further validated FANCD2 as an important oncogenic gene and promotes tumor progression by regulating cell cycle. [ABSTRACT FROM AUTHOR]

Abstract Background The selection of reference genes is essential for quantifying gene expression. Theoretically they should be expressed stably and not regulated by experimental or pathological conditions. However, identification and validation of reference genes for human cancer research are still being regarded as a critical point, because cancerous tissues often represent genetic instability and heterogeneity. Recent pan-cancer studies have demonstrated the importance of the appropriate selection of reference genes for use as internal controls for the normalization of gene expression; however, no stably expressed, consensus reference genes valid for a range of different human cancers have yet been identified. Results In the present study, we used large-scale cancer gene expression datasets from The Cancer Genome Atlas (TCGA) database, which contains 10,028 (9,364 cancerous and 664 normal) samples from 32 different cancer types, to confirm that the expression of the most commonly used reference genes is not consistent across a range of cancer types. Furthermore, we identified 38 novel candidate reference genes for the normalization of gene expression, independent of cancer type. These genes were found to be highly expressed and highly connected to relevant gene networks, and to be enriched in transcription-translation regulation processes. The expression stability of the newly identified reference genes across 29 cancerous and matched normal tissues were validated via quantitative reverse transcription PCR (RT-qPCR). Conclusions We reveal that most commonly used reference genes in current cancer studies cannot be appropriate to serve as representative control genes for quantifying cancer-related gene expression levels, and propose in this study three potential reference genes (HNRNPL, PCBP1, and RER1) to be the most stably expressed across various cancerous and normal human tissues.

Background: Solute carrier family 31 (copper transporter), member 1 ( SLC31A1 ) is a key factor in maintaining intracellular copper concentration and an important factor affecting cancer energy metabolism. Therefore, exploring the potential biological function and value of SLC31A1 could provide a new direction for the targeted therapy of tumors., Methods: This study assessed gene expression levels, survival, clinicopathology, gene mutations, methylation levels, the tumor mutational burden (TMB), microsatellite instability (MSI), and the immune cell infiltration of SLC31A1 in pan-cancer using the Tumor Immune Estimation Resource 2.0 (TIMER2.0), Gene Expression Profiling Interactive Analysis (GEPIA), University of Alabama at Birmingham CANcer (UALCAN) data analysis portal, and cBioPortal databases. To further understand the potential biological mechanisms of SLC31A1 in different cancers, single-cell level sequencing and a Gene Ontology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) enrichment analysis of SLC31A1 were also performed. Finally, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) were used to validate the expression of SLC31A1 in cancers, such as gastric cancer., Results: SLC31A1 was expressed in most cancer tissues. In kidney renal clear cell carcinoma (KIRC), the high expression of SLC31A1 was associated with good overall survival (OS), while in adrenocortical carcinoma (ACC), breast invasive carcinoma (BRCA), lower grade glioma (LGG), mesothelioma (MESO), and skin cutaneous melanoma (SKCM), the low expression of SLC31A1 was associated with good OS. The highest frequency of SLC31A1 amplification was observed in ACC. In addition, missense mutations accounted for a major portion of the mutation types. The truncation mutation S105Y may be a putative cancer driver. SLC31A1 affected methylation levels in cancer and was associated with the TMB, MSI, and the level of infiltration of various immune cells. Additionally, the single-cell sequencing results showed that SLC31A1 was associated with multiple biological functions in cancer. Finally, the SLC31A1 enrichment analysis revealed that the SLC31A1 -related genes were mainly enriched in the mitochondrial matrix and envelope vesicles. The RT-qPCR and WB results were consistent with the predicted results., Conclusions: SLC31A1 may be a potential target related to cancer energy metabolism and may have prognostic value., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1308/coif). The authors have no conflicts of interest to declare., (2024 Translational Cancer Research. All rights reserved.)

Kinase-targeted cancer therapy (KTCT) with ATP-competitive inhibitors has been widely applied in clinics. However, a number of kinase missense mutations were observed to confer acquired drug resistance during therapy, largely limiting the clinical application of kinase inhibitors in KTCT. Instead of directly influencing inhibitor binding, kinase mutations can also cause generic resistance to ATP-competitive inhibitors by increasing ATP affinity. Herein, the intermolecular interaction of the ATP molecule with clinically observed drug-resistant EGFR family kinase mutations involved in human cancer are systematically characterize. Rigorous quantum mechanics/molecular mechanics (QM/MM) calculation and empirical Poisson-Boltzmann/surface area (PB/SA) analysis as well as in vitro kinase assay and surface plasmon resonance analysis were integrated to explore the binding capability of ATP to mutant residues in the structural context of the kinase domain, which resulted in a comprehensive profile of ATP response to acquired drug-resistant mutations of four EGFR family kinases (EGFR/ErbB1, ErbB2, ErbB3 and ErbB4). From the profile, it was possible to identify those potent mutations that may influence ATP binding significantly; such mutations are potential candidates to cause generic resistance for ATP-competitive inhibitors. Consequently, the well documented generic drug-resistant mutation EGFR T790M and its counterpart ErbB2 T798M are found to increase ATP affinity by establishing an additional S-π interaction between the side-chain thioether group of the mutant Met residue and the aromatic adenine moiety of the ATP molecule, while EGFR D761Y is identified as a new generic drug-resistant mutation that can increase ATP affinity by eliminating unfavorable electrostatic repulsion. In contrast, ErbB2 K753E and T768I are considered to be two generic drug-sensitive mutations that can decrease ATP affinity by unfavorable charge reversal and by impairing favorable polar interaction, respectively. In addition, the EGFR L858R mutation is located at the kinase activation loop and nearby the kinase active site, thus largely complicating the multiply dependent relation-ship of kinase, ATP and inhibitor, which therefore exhibits divergent effects on different tested inhibitors. [ABSTRACT FROM AUTHOR]

RAS mutation is the most frequent oncogenic alteration in human cancers. KRAS is the most frequently mutated followed by NRAS. The emblematic KRAS mutant cancers are pancreatic, colorectal, lung adenocarcinomas and urogenital cancers. KRAS mutation frequencies are relatively stable worldwide in various cancer types with the one exception of lung adenocarcinoma. The frequencies of KRAS variant alleles appears cancer type specific, reflecting the various carcinogenic processes. In addition to point mutation KRAS, allelic imbalances are also frequent in human cancers leading to the predominance of a mutant allele. KRAS mutant cancers are characterized by typical, cancer-type-specific co-occurring mutations and distinct gene expression signatures. The heterogeneity of KRAS mutant primary cancers is significant, affecting the variant allele frequency, which could lead to unpredictable branching development in metastases. Selection of minute mutant subclones in the primary tumors or metastases during target therapies can also occur frequently in lung or colorectal cancers leading to acquired resistance. Ultrahigh sensitivity techniques are now routinely available for diagnostic purposes, but the proper determination of mutant allele frequency of KRAS in the primary or metastatic tissues may have larger clinical significance. [ABSTRACT FROM AUTHOR]

N6-Methyladenosine (m6A), a pervasive posttranscriptional modification which is reversible, has been among hotspot issues in the past several years. The balance of intracellular m6A levels is dynamically maintained by methyltransferase complex and demethylases. Meanwhile, m6A reader proteins specifically recognize modified residues and convey messages so as to set up an efficient and orderly network of m6A regulation. The m6A mark has proved to affect every step of RNA life cycle, from processing in nucleus to translation or degradation in cytoplasm. Subsequently, disorders in m6A methylation are directly related to aberrant RNA metabolism, which results in tumorigenesis and altered drug response. Therefore, uncovering the underlying mechanism of m6A in oncogenic transformation and tumor progression seeks opportunities for novel targets in cancer therapy. In this review, we conclude the extensive impact of m6A on RNA metabolism and highlight its relevance with human cancer, implicating the far-reaching value in clinical application.

Qian Hao,1,* Cong Dai,1,* Yujiao Deng,1,* Peng Xu,1 Tian Tian,1 Shuai Lin,1 Meng Wang,1 Kang Liu,1 Dingli Song,1 Ying Wu,1 Yan Guo,2 Zhijun Dai1 1Department of Oncology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, People’s Republic of China *These authors contributed equally to this work Background: Various studies have evaluated the significance of phospho-histone-H3 (PHH3) expression in cancer patients, but controversy over its reliability remains. We conducted a meta-analysis to summarize the prognostic relevance of PHH3 expression in cancer patients. Patients and methods: Nineteen studies, including 4803 patients, were identified by searching PubMed, Web of Science, Embase, and Cochrane Library. The correlation of PHH3 expression level with overall survival (OS), disease-free survival, and recurrence-free survival was analyzed. Results: Overall, the results suggest that high expression of PHH3 can predict a poor OS (HR=2.66, 95% CI=1.74–4.08, P

EGFR and HER2 receptors are crucial signaling molecules tyrosine kinase involved in human cancer. Aberrant signaling is associated with a variety of cancers, frequently with poor prognosis. Currently, EGFR and HER2 receptors are being targeted by small molecules, which offer a huge benefit to those patients afflicted by aggressive forms of cancer, improving their prognosis. Both human and canine cancers share molecular, biological, histopathological and clinical similarities, including EGFR and HER2 expression in some forms of cancer. However, despite the use of one tyrosine kinase inhibitor approved to treat canine mastocytoma, canine cancers overexpressed EGFR and HER2 do not yet have targeted therapy, leading to high morbidity and mortality. Targeting EGFR and HER2 receptors in canine cancers using comparative approaches in human cancer could lead to better outcomes. [ABSTRACT FROM AUTHOR]

Background: DNA damage accumulates over the course of cancer development. The often-substantial amount of somatic mutations in cancer poses a challenge to traditional methods to characterize tumors based on driver mutations. However, advances in machine learning technology can take advantage of this substantial amount of data. Results: We developed a command line interface python package, pyCancerSig, to perform sample profiling by integrating single nucleotide variation (SNV), structural variation (SV) and microsatellite instability (MSI) profiles into a unified profile. It also provides a command to decipher underlying cancer processes, employing an unsupervised learning technique, Non-negative Matrix Factorization, and a command to visualize the results. The package accepts common standard file formats (vcf, bam). The program was evaluated using a cohort of breast- and colorectal cancer from The Cancer Genome Atlas project (TCGA). The result showed that by integrating multiple mutations modes, the tool can correctly identify cases with known clear mutational signatures and can strengthen signatures in cases with unclear signal from an SNV-only profile. The software package is available at https://github.com/jessada/pyCancerSig. Conclusions: pyCancerSig has demonstrated its capability in identifying known and unknown cancer processes, and at the same time, illuminates the association within and between the mutation modes. [ABSTRACT FROM AUTHOR]

A hydrolytically stable mesoporous Gd(III)-MOF {[Gd2(TATAB)2]·6 DMF}n (1) has been successfully prepared by reaction of Gd(NO3)3·6H2O with a flexible ligand 4,4′,4′′-s-triazine-1,3,5-triyltri-p-aminobenzoate (H3TATAB) under solvothermal conditions. Further, the nanostructure 1 could be obtained via an ultrasonic treatment method. Nitrogen adsorption measurements revealed the presence of mesoporosity as well as a moderate high BET surface areas in the activated nanostructure 1 (1a), which was further used in the 5-Fu loading with the uptake capacity of 47 wt%. Meanwhile, the controlled release of 5-Fu in a simulated human body with liquid phosphate-buffered saline solution was realized. In the biological study, the anti-proliferation activity of 5-Fu@1a on A549 human non-small lung cancer (NSCLC) cells after 5-Fu@1a exposure was evaluated by the CCK-8 preformation. The effect of 5-Fu@1a on A549 NSCLC cell migration and invasion ability was detected by transwell assay. The mechanism was revealed by the detection of the NLRP3 inflammasome activation level in A549 through western blot and ELISA assay. For further explore the inhibitory effect of 5-Fu@1a, the anti-tumor ability was evaluated in the in vivo xenograft model. [ABSTRACT FROM AUTHOR]

Genetic and epigenetic changes deregulate RNA and protein expression in cancer cells. In this regard, tumors exhibit an abnormal proteome in comparison to the corresponding normal tissues. Translation control is a crucial step in the regulation of gene expression regulation under normal and pathological conditions that ultimately determines cellular fate. In this context, evidence shows that transfer and ribosomal RNA (tRNA and rRNA) modifications affect the efficacy and fidelity of translation. The number of RNA modifications increases with the complexity of organisms, suggesting an evolutionary diversification of the possibilities for fine-tuning the functions of coding and non-coding RNAs. In this review, we focus on alterations of modifications of transfer and ribosomal RNA that affect translation in human cancer. This variation in the RNA modification status can be the result of altered modifier expression (writers, readers or erasers), but also due to components of the machineries (C/D or H/ACA boxes) or alterations of proteins involved in modifier expression. Broadening our understanding of the mechanisms by which site-specific modifications modulate ribosome activity in the context of tumorigenesis will enable us to enrich our knowledge about how ribosomes can influence cell fate and form the basis of new therapeutic opportunities. [ABSTRACT FROM AUTHOR]

The human DNA damage response (DDR) is a complex signaling network constituting many factors responsible for the preservation of genomic integrity. Human polyomaviruses (HPyVs) are able to harness the DDR machinery during their infectious cycle by expressing an array of tumor (T) antigens. These molecular interactions between human polyomavirus T antigens and the DDR create conditions that promote viral replication at the expense of host genomic stability to cause disease as well as carcinogenesis in the cases of the Merkel cell polyomavirus and BK polyomavirus. This review focuses on the six HPyVs with disease association, emphasizing strain-dependent differences in their selective manipulation of the DDR. Appreciation of the HPyV–DDR interface at a molecular scale is conducive to the development of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

NoncoRNA (http://www.ncdtcdb.cn:8080/NoncoRNA/) is a manually curated database of experimentally supported non-coding RNAs (ncRNAs) and drug target associations that aim to potentially provide a high-quality data resource for exploring drug sensitivity/resistance-related ncRNAs in various human cancers. ncRNA are RNA molecular that do not encode proteins, but are involved in gene regulation and cellular functions in variety of human diseases, including neurodegenerative diseases and cancers. Here, we developed NoncoRNA which contained 8233 entries between 5568 ncRNAs and 154 drugs in 134 cancers. Each entry in the NoncoRNA contains detailed information on the ncRNAs, drugs, and cancers, the ncRNA expression pattern and experimental detection techniques, drug response and other targets, literature references, and other information. NoncoRNA offers a user-friendly, open access web interface to easily browse, search, and download data. NoncoRNA also provides a submission page for researchers to submit newly validated ncRNA-drug-cancer associations. NoncoRNA might serve as an immeasurable resource for understanding the roles of ncRNAs in cancer therapy. [ABSTRACT FROM AUTHOR]

Background: While many studies have assessed the predictive value of secreted phosphoprotein (SPP) genes in cancer, the findings have been inconsistent. To resolve these inconsistencies, we systematically analyzed the available data to determine whether SPP1 and SPP2 are prognostic markers in the context of human cancer.Methods: The expression of SPP1 and SPP2 was assessed by Oncomine analysis. The PrognoScan database was used to assess the prognostic value of SPP1 and SPP2, with cBioPortal used to assess copy number variations. The STRING database was used to generate a Protein - Protein Interaction (PPI) network for SPP genes.Results: SPP1 was more likely to be over-expressed in breast, bladder, colorectal, head, neck, liver, lung, and esophageal cancers. SPP2 was expressed at lower levels in colorectal cancer, leukemia, liver cancer and pancreatic cancer. In addition, SPP1 and SPP2 mutations mainly occurred in cutaneous melanoma and endometrial cancer.Conclusions: Our results suggest that SPP1 and SPP2 may be effective therapeutic or diagnostic targets in certain cancers. Further research is required to confirm these results and verify the value of SPP1 and SPP2 as clinical markers of cancer prognosis. [ABSTRACT FROM AUTHOR]

N6-Methyladenosine (m6A), a pervasive posttranscriptional modification which is reversible, has been among hotspot issues in the past several years. The balance of intracellular m6A levels is dynamically maintained by methyltransferase complex and demethylases. Meanwhile, m6A reader proteins specifically recognize modified residues and convey messages so as to set up an efficient and orderly network of m6A regulation. The m6A mark has proved to affect every step of RNA life cycle, from processing in nucleus to translation or degradation in cytoplasm. Subsequently, disorders in m6A methylation are directly related to aberrant RNA metabolism, which results in tumorigenesis and altered drug response. Therefore, uncovering the underlying mechanism of m6A in oncogenic transformation and tumor progression seeks opportunities for novel targets in cancer therapy. In this review, we conclude the extensive impact of m6A on RNA metabolism and highlight its relevance with human cancer, implicating the far-reaching value in clinical application. [ABSTRACT FROM AUTHOR]

Long-stranded non-coding RNAs (lncRNAs) are RNA molecules that are longer than 200 nucleotides and do not code for proteins. They play a significant role in various biological processes, including epigenetics, cell cycle, and cell differentiation. Many studies have shown that the occurrence of human cancer is closely related to the abnormal expression of lncRNA. In recent years, lncRNAs have been a hot topic in cancer research. TRPM2-AS, a novel lncRNA, is aberrantly expressed in many human cancers, and its overexpression is strongly linked to poor clinical outcomes in patients. It has been demonstrated that TRPM2-AS acts as a ceRNA, participates in signaling pathways, and interacts with biological proteins and other molecular mechanisms to regulate gene expression. In addition, it can regulate the proliferation, migration, invasion, apoptosis, and treatment resistance of cancer cells. As a result, TRPM2-AS may be a potential target for cancer treatment and a possible biomarker for cancer prognosis. This review outlined the expression, biological processes, and molecular mechanisms of TRPM2-AS in various malignancies, and discussed potential therapeutic uses. [ABSTRACT FROM AUTHOR]

Abstract Human cancers results in large part from the accumulation of multiple mutations. The progression of premalignant cells is an evolutionary process in which mutations provide the fundamental driving force for genetic diversity. The increased mutation rate in premalignant cells allows selection for increased proliferation and survival and ultimately leads to invasion, metastasis, recurrence, and therapeutic resistance. Therefore, it is important to understand the molecular determinants of the mutational processes. Recent genome-wide sequencing data showed that apolipoprotein B mRNA editing catalytic polypeptide-like 3B (APOBEC3B) is a key molecular driver inducing mutations in multiple human cancers. APOBEC3B, a DNA cytosine deaminase, is overexpressed in a wide spectrum of human cancers. Its overexpression and aberrant activation lead to unexpected clusters of mutations in the majority of cancers. This phenomenon of clustered mutations, termed kataegis (from the Greek word for showers), forms unique mutation signatures. In this review, we will discuss the biological function of APOBEC3B, its tumorigenic role in promoting mutational processes in cancer development and the clinical potential to develop novel therapeutics by targeting APOBEC3B.

Abnormal translate regulation is an important phenomenon in cancer initiation and progression. Eukaryotic translation initiation factor 4A1 (eIF4A1) protein is an ATP-dependent Ribonucleic Acid (RNA) helicase, which is essential for translation and has bidirectional RNA unwinders function. In this review, we discuss the levels of expression, regulatory mechanisms and protein functions of eIF4A1 in different human tumors. eIF4A1 is often involved as a target of microRNAs or long non-coding RNAs during the epithelial-mesenchymal transition, associating with the proliferation and metastasis of tumor cells. eIF4A1 protein exhibits the promising biomarker for rapid diagnosis of pre-cancer lesions, histological phenotypes, clinical staging diagnosis and outcome prediction, which provides a novel strategy for precise medical care and target therapy for patients with tumors at the same time, relevant small molecule inhibitors have also been applied in clinical practice, providing reliable theoretical support and clinical basis for the development of this gene target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Zhang, Yang, Yao, Gou, Cao, Pan, Li, Pan and Zhang.)

The name of the family Polyomaviridae, derives from the early observation that cells infected with murine polyomavirus induced multiple (poly) tumors (omas) in immunocompromised mice. Subsequent studies showed that many members of this family exhibit the capacity of mediating cell transformation and tumorigenesis in different experimental models. The transformation process mediated by these viruses is driven by viral pleiotropic regulatory proteins called T (tumor) antigens. Similar to other viral oncoproteins T antigens target cellular regulatory factors to favor cell proliferation, immune evasion and downregulation of apoptosis. The first two human polyomaviruses were isolated over 45 years ago. However, recent advances in the DNA sequencing technologies led to the rapid identification of additional twelve new polyomaviruses in different human samples. Many of these viruses establish chronic infections and have been associated with conditions in immunosuppressed individuals, particularly in organ transplant recipients. This has been associated to viral reactivation due to the immunosuppressant therapy applied to these patients. Four polyomaviruses namely, Merkel cell polyomavirus (MCPyV), Trichodysplasia spinulosa polyomavirus (TSPyV), John Cunningham Polyomavirus (JCPyV) and BK polyomavirus (BKPyV) have been associated with the development of specific malignant tumors. However, present evidence only supports the role of MCPyV as a carcinogen to humans. In the present review we present a summarized discussion on the current knowledge concerning the role of MCPyV, TSPyV, JCPyV and BKPyV in human cancers.

Numerous studies on the nature of neoplastic growth have demonstrated that oncogenic viruses may be one of the factors causing cancer. According to various estimates, 10–20% of all human cancers are caused by viruses. For example, the Epstein–Barr virus (EBV), hepatitis B and C viruses, human papillomavirus (HPV), human T-lymphotropic virus type 1 (HTLV-1), human herpesvirus type 8 (HHV-8), and Merkel cell polyomavirus were implicated in initiating tumors. At the same time, the long period between viral infection and the manifestation of cancer significantly complicates the search for a causal relationship between the presence of a virus in the human organism and the malignant transformation. For this reason, the role of certain viruses in the initiation of neoplastic processes in humans remains an unresolved issue. [ABSTRACT FROM AUTHOR]

It is known that noncoding RNAs (ncRNAs) cover ∼98% of the transcriptome, but do not encode proteins. Among ncRNAs, long noncoding RNAs (lncRNAs) are a large and diverse class of RNA molecules, and are thought to be a gold mine of potential oncogenes, anti-oncogenes and new biomarkers. Although only a minority of lncRNAs is functionally characterized, it is clear that they are important regulators to modulate gene expression and involve in many biological functions. To reveal the functions and regulatory mechanisms of lncRNAs, it is vital to understand how lncRNAs regulate their target genes for implementing specific biological functions. In this article, we review the computational methods for inferring lncRNA–mRNA interactions and the third-party databases of storing lncRNA–mRNA regulatory relationships. We have found that the existing methods are based on statistical correlations between the gene expression levels of lncRNAs and mRNAs, and may not reveal gene regulatory relationships which are causal relationships. Moreover, these methods do not consider the modularity of lncRNA–mRNA regulatory networks, and thus, the networks identified are not module-specific. To address the above two issues, we propose a novel method, MSLCRN, to infer and analyze m odule- s pecific l ncRNA–mRNA c ausal r egulatory n etworks. We have applied it into glioblastoma multiforme, lung squamous cell carcinoma, ovarian cancer and prostate cancer, respectively. The experimental results show that MSLCRN, as an expression-based method, could be a useful complementary method to study lncRNA regulations. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 therapy are now FDA-approved treatment options for different cancer types. However, the therapeutic efficacy of ICIs varies substantially among cancer types and patients, and only a limited proportion of cancer patients benefit clinically from ICIs. To improve the therapeutic efficacy of cancer treatments involving ICI, the mechanisms of response to ICIs and the heterogeneous pattern of immune checkpoint receptor expression need to be better understood. Here, we review recent studies on ICIs in human cancer, providing the necessary basis for the rational design of immunotherapy and for appropriate patient selection. [ABSTRACT FROM AUTHOR]

Alcohol intake increases the risk of cancer development. Approximately 3.6% human cancers worldwide derive from chronic alcohol drinking, including oral, liver, breast and other organs. Our studies in vivo and in vitro have demonstrated that diluted ethanol increase RNA Pol III gene transcription and promotes cell proliferation and transformation, as well as tumor formation. However, it is unclear about the effect of red wines on the human cancer cells. In present study, we investigated the roles of red wine in human cancer cell growth, colony formation and RNA Pol III gene transcription. Low concentration (12.5 mM to 25 mM) of ethanol enhances cell proliferation of breast and esophageal cancer lines, whereas its higher concentration (100 mM to 200 mM) slightly decreases the rates. In contrast, red wines significantly repress cell proliferation of different human cancer lines from low dose to high dose. The results reveal that the red wine also inhibits colony formation of human breast cancer and esophageal carcinoma cells. The effects of repression on different human cancer lines are in a dose-dependent manner. Further analysis indicates that ethanol increases RNA Pol III gene transcription, whereas the red wines significantly reduce transcription of the genes. Interestingly, the effects of mature wine (brick red) on cancer cell phenotypes are much stronger than young wine (intense violet). Together, these new findings suggest that red wines may contain some bioactive components, which are able to inhibit human cancer cell growth and colony formation. • Red wines repressed proliferation and colony formation of different human cancer cells; • Red wines inhibit RNA Pol III gene transcription, while ethanol increases their activity; • Diluted ethanol enhances these cellular phenotypic changes in human breast cancer and esophageal carcinoma lines; • Repressing cell growth, colony formation and Pol III genes by mature wines are much stronger than ones by young wine; [ABSTRACT FROM AUTHOR]

Background: The selection of reference genes is essential for quantifying gene expression. Theoretically they should be expressed stably and not regulated by experimental or pathological conditions. However, identification and validation of reference genes for human cancer research are still being regarded as a critical point, because cancerous tissues often represent genetic instability and heterogeneity. Recent pan-cancer studies have demonstrated the importance of the appropriate selection of reference genes for use as internal controls for the normalization of gene expression; however, no stably expressed, consensus reference genes valid for a range of different human cancers have yet been identified. Results: In the present study, we used large-scale cancer gene expression datasets from The Cancer Genome Atlas (TCGA) database, which contains 10,028 (9,364 cancerous and 664 normal) samples from 32 different cancer types, to confirm that the expression of the most commonly used reference genes is not consistent across a range of cancer types. Furthermore, we identified 38 novel candidate reference genes for the normalization of gene expression, independent of cancer type. These genes were found to be highly expressed and highly connected to relevant gene networks, and to be enriched in transcription-translation regulation processes. The expression stability of the newly identified reference genes across 29 cancerous and matched normal tissues were validated via quantitative reverse transcription PCR (RT-qPCR). Conclusions: We reveal that most commonly used reference genes in current cancer studies cannot be appropriate to serve as representative control genes for quantifying cancer-related gene expression levels, and propose in this study three potential reference genes (HNRNPL, PCBP1, and RER1) to be the most stably expressed across various cancerous and normal human tissues. [ABSTRACT FROM AUTHOR]