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Bioengineered Mar 2022Optic atrophy 3 (OPA3) is an integral protein of the mitochondrial outer membrane. The current study explored the expression of in hepatocellular carcinoma (HCC), its...
Optic atrophy 3 (OPA3) is an integral protein of the mitochondrial outer membrane. The current study explored the expression of in hepatocellular carcinoma (HCC), its association with the prognosis and its involvement in HCC cell proliferation and aerobic glycolysis. In addition, the transcription factors that activate its expression were screened and validated. Gene expression data in normal liver and liver cancer were acquired from the Genotype-Tissue Expression Project (GTEx) and The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma (TCGA-LIHC). Chromatin immunoprecipitation-seq data (GSM1010876) in Cistrome Data Browser was used for searching transcriptional factors binding to the promoter. HCC cell lines HLF and JHH2 were used for and studies. Results showed that is significantly upregulated in HCC and associated with unfavorable prognosis. knockdown impaired HCC cell growth and . Besides, it decreased glucose uptake, lactate production, intracellular ATP levels, and extracellular acidification rate (ECAR) of HLF and JHH2 cells. MYB Proto-Oncogene Like 2 (MYBL2) can bind to the promoter of and enhance its transcription. knockdown decreased aerobic glycolysis in HCC cells. overexpression reversed these alterations. In conclusion, this study revealed a novel MYBL2-OPA3 axis that enhances HCC cell proliferation and aerobic glycolysis.
Topics: Carcinoma, Hepatocellular; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; Liver Neoplasms; Optic Atrophy; Proto-Oncogenes; Trans-Activators; Transcription Factors
PubMed: 35176941
DOI: 10.1080/21655979.2021.2017630 -
Biomolecules Sep 2022Despite a global decrease in colorectal cancer (CRC) incidence, the prevalence of early-onset colorectal cancer (EOCRC), or those occurring in individuals before the age...
Despite a global decrease in colorectal cancer (CRC) incidence, the prevalence of early-onset colorectal cancer (EOCRC), or those occurring in individuals before the age of 50, has steadily increased over the past several decades. When compared to later onset colorectal cancer (LOCRC) in individuals over 50, our understanding of the genetic and molecular underpinnings of EOCRCs is limited. Here, we conducted transcriptomic analyses of patient-matched normal colonic segments and tumors to identify gene expression programs involved in carcinogenesis. Amongst differentially expressed genes, we found increased expression of the proto-oncogene () and its downstream targets in tumor samples. We identified tumors with high and low differential expression and found patients with high- tumors were older and overweight or obese. We also detected elevated expression of the long-non-coding RNA (lncRNA) in most tumors and found gains in copy number for both and gene loci in 35% of tumors evaluated. Our transcriptome analyses indicate that EOCRC can be sub-classified into groups based on differential expression and suggest that deregulated contributes to CRCs that develop in younger patients.
Topics: Carcinogenesis; Colorectal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, myc; Humans; RNA, Long Noncoding
PubMed: 36139061
DOI: 10.3390/biom12091223 -
Cell Death and Differentiation Jan 2018In 1984, we investigated the t(14;18) chromosomal translocations that frequently occur in patients with follicular lymphoma. We first identified a locus on chromosome 18... (Review)
Review
In 1984, we investigated the t(14;18) chromosomal translocations that frequently occur in patients with follicular lymphoma. We first identified a locus on chromosome 18 involved in these translocations with the chromosome 14 containing the immunoglobulin heavy chain locus. Within this region on chromosome 18, we then discovered a gene that we called BCL2, which was activated by the translocations. Since that time, many studies determined that BCL2 is one of the most important oncogenes involved in cancer by inhibiting apoptosis. In 2002, we studied 13q deletions in chronic lymphocytic leukemia (CLL) and found that the microRNA cluster miR-15a/miR-16-1 (miR-15/16) is deleted by 13q deletions. In 2005, we discovered that miR-15/16 function as tumor suppressors by directly targeting BCL2. Thus the loss of two negative regulators of BCL2 expression results in overexpression of BCL2. Very recently, a specific BCL2 inhibitor ABT-199 (Venetoclax) was developed and approved by FDA for CLL treatment. Thus it took 32 years from fundamental discovery of a critical oncogene to the development of a drug capable to cure CLL. In this review, we discuss the discovery, functions and clinical relevance of miR-15/16 and BCL2.
Topics: Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 13; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; MicroRNAs; Proto-Oncogene Proteins c-bcl-2; Sulfonamides
PubMed: 28984869
DOI: 10.1038/cdd.2017.159 -
Modern Pathology : An Official Journal... Jan 2018With the advent of next-generation sequencing technologies and large whole-exome and genome studies in prostate and other cancers, our understanding of the landscape of... (Review)
Review
With the advent of next-generation sequencing technologies and large whole-exome and genome studies in prostate and other cancers, our understanding of the landscape of genomic alterations has dramatically been refined. In additional to well-known alterations in genomic regions involving 8p, 8q, 10q23, common ETS translocations and androgen receptor amplifications, newer technology have uncovered recurrent mutations in SPOP, FOXA1, MED12, IDH and complex large scale genomic alterations (eg, chromoplexy). This review surveys the enhanced landscape of genomic alterations in clinically localized and advanced prostate cancer.
Topics: Animals; Carcinogenesis; Chromosome Deletion; Chromosomes, Human, Pair 10; Genes, myc; Genomics; Humans; Male; Mice; Models, Animal; Nuclear Proteins; Prostatic Neoplasms; Proto-Oncogene Proteins c-ets; Repressor Proteins; Transcriptional Regulator ERG
PubMed: 29297493
DOI: 10.1038/modpathol.2017.166 -
Cell Death and Differentiation Jun 2023Many lymphoid malignancies arise from deregulated c-MYC expression in cooperation with additional genetic lesions. While many of these cooperative genetic lesions have...
Many lymphoid malignancies arise from deregulated c-MYC expression in cooperation with additional genetic lesions. While many of these cooperative genetic lesions have been discovered and their functions characterised, DNA sequence data of primary patient samples suggest that many more do exist. However, the nature of their contributions to c-MYC driven lymphomagenesis have not yet been investigated. We identified TFAP4 as a potent suppressor of c-MYC driven lymphoma development in a previous genome-wide CRISPR knockout screen in primary cells in vivo [1]. CRISPR deletion of TFAP4 in Eµ-MYC transgenic haematopoietic stem and progenitor cells (HSPCs) and transplantation of these manipulated HSPCs into lethally irradiated animals significantly accelerated c-MYC-driven lymphoma development. Interestingly, TFAP4 deficient Eµ-MYC lymphomas all arose at the pre-B cell stage of B cell development. This observation prompted us to characterise the transcriptional profile of pre-B cells from pre-leukaemic mice transplanted with Eµ-MYC/Cas9 HSPCs that had been transduced with sgRNAs targeting TFAP4. This analysis revealed that TFAP4 deletion reduced expression of several master regulators of B cell differentiation, such as Spi1, SpiB and Pax5, which are direct target genes of both TFAP4 and MYC. We therefore conclude that loss of TFAP4 leads to a block in differentiation during early B cell development, thereby accelerating c-MYC-driven lymphoma development.
Topics: Mice; Animals; Proto-Oncogene Proteins c-myc; Genes, myc; Lymphoma; Precursor Cells, B-Lymphoid; Mice, Transgenic
PubMed: 36894688
DOI: 10.1038/s41418-023-01145-w -
Journal of Molecular Cell Biology Jul 2019The TP53 gene is well known to be the most frequently mutated gene in human cancer. In addition to mutations, there are > 20 different coding region single-nucleotide... (Review)
Review
The TP53 gene is well known to be the most frequently mutated gene in human cancer. In addition to mutations, there are > 20 different coding region single-nucleotide polymorphisms (SNPs) in the TP53 gene, as well as SNPs in MDM2, the negative regulator of p53. Several of these SNPs are known to alter p53 pathway function. This makes p53 rather unique among cancer-critical genes, e.g. the coding regions of other cancer-critical genes like Ha-Ras, RB, and PI3KCA do not have non-synonymous coding region SNPs that alter their function in cancer. The next frontier in p53 biology will consist of probing which of these coding region SNPs are moderately or strongly pathogenic and whether they influence cancer risk and the efficacy of cancer therapy. The challenge after that will consist of determining whether we can tailor chemotherapy to correct the defects for each of these variants. Here we review the SNPs in TP53 and MDM2 that show the most significant impact on cancer and other diseases. We also propose avenues for how this information can be used to better inform personalized medicine approaches to cancer and other diseases.
Topics: Animals; Genes, ras; Humans; Neoplasms; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-mdm2; Retinoblastoma Protein; Signal Transduction; Transcription Factors; Tumor Suppressor Protein p53
PubMed: 31152665
DOI: 10.1093/jmcb/mjz052 -
Philosophical Transactions of the Royal... Jul 2015The frequency of cancer is postulated to be proportional to the number of cells an animal possesses, as each cell is similarly exposed to mutagens with every cell... (Review)
Review
The frequency of cancer is postulated to be proportional to the number of cells an animal possesses, as each cell is similarly exposed to mutagens with every cell division. Larger animals result from more cell divisions with more mutagenic exposure, and hence are expected to have higher frequencies of cancer. Yet, as stipulated by Peto's paradox, larger animals do not have the higher rates of cancers seen in smaller animals despite the significant differences in cell numbers and a longer lifetime that would expose larger animals to more mutagens. The rates of cancer appear to be inversely proportional to animal body size, which scales inversely with specific metabolic rates of mammals. Studies over the past 20 years have linked oncogenes and tumour suppressors to alterations in cancer metabolism, and conversely, mutations in metabolic genes have been documented to trigger tumorigenesis. The by-products and intermediates of metabolism, such as reactive oxygen species, oxoglutarate, citrate and acetate, all have the potential to mutate and alter the genome or epigenome. On the basis of these general observations, it is proposed that metabolic rates correlate with mutagenic rates, which are higher in small animals and give the mechanistic basis for Peto's paradox. The observations discussed in this overview collectively indicate that specific metabolic rate varies inversely with body size, which seems to support the hypothesis that metabolism drives tumorigenesis and accounts for Peto's paradox.
Topics: Aging; Animals; Body Size; Cell Division; Genes, Tumor Suppressor; Humans; Models, Biological; Mutation; Neoplasms; Proto-Oncogenes
PubMed: 26056367
DOI: 10.1098/rstb.2014.0223 -
Oncology Reports Jun 2022DEK is known to be a potential proto‑oncogene and is highly expressed in gastric cancer (GC); thus, DEK is considered to contribute to the malignant progression of GC....
DEK is known to be a potential proto‑oncogene and is highly expressed in gastric cancer (GC); thus, DEK is considered to contribute to the malignant progression of GC. DEK is an RNA‑binding protein involved in transcription, DNA repair, and selection of splicing sites during mRNA processing; however, its precise function remains elusive due to the lack of clarification of the overall profiles of gene transcription and post‑transcriptional splicing that are regulated by DEK. We performed our original whole‑genomic RNA‑Seq data to analyze the global transcription and alternative splicing profiles in a human GC cell line by comparing DEK siRNA‑treated and control conditions, dissecting both differential gene expression and potential alternative splicing events regulated by DEK. The siRNA‑mediated knockdown of DEK in a GC cell line led to significant changes in gene expression of multiple cancer‑related genes including both oncogenes and tumor suppressors. Moreover, it was revealed that DEK regulated a number of alternative splicing in genes which were significantly enriched in various cancer‑related pathways including apoptosis and cell cycle processes. This study clarified for the first time that DEK has a regulatory effect on the alternative splicing, as well as on the expression, of numerous cancer‑related genes, which is consistent with the role of DEK as a possible oncogene. Our results further expand the importance and feasibility of DEK as a clinical therapeutic target for human malignancies including GC.
Topics: Alternative Splicing; Chromosomal Proteins, Non-Histone; Humans; Oncogene Proteins; Poly-ADP-Ribose Binding Proteins; Proto-Oncogenes; RNA, Small Interfering; Stomach Neoplasms
PubMed: 35475534
DOI: 10.3892/or.2022.8322 -
Frontiers in Immunology 2023Neuroblastoma (NB) is a common extracranial tumor in children and is highly heterogeneous. The factors influencing the prognosis of NB are not simple.
INTRODUCTION
Neuroblastoma (NB) is a common extracranial tumor in children and is highly heterogeneous. The factors influencing the prognosis of NB are not simple.
METHODS
To investigate the effect of cell senescence on the prognosis of NB and tumor immune microenvironment, 498 samples of NB patients and 307 cellular senescence-related genes were used to construct a prediction signature.
RESULTS
A signature based on six optimal candidate genes (TP53, IL-7, PDGFRA, S100B, DLL3, and TP63) was successfully constructed and proved to have good prognostic ability. Through verification, the signature had more advantages than the gene expression level alone in evaluating prognosis was found. Further T cell phenotype analysis displayed that exhausted phenotype PD-1 and senescence-related phenotype CD244 were highly expressed in CD8+ T cell in MYCN-amplified group with higher risk-score.
CONCLUSION
A signature constructed the six MYCN-amplified differential genes and aging-related genes can be used to predict the prognosis of NB better than using each high-risk gene individually and to evaluate immunosuppressed and aging tumor microenvironment.
Topics: Child; Humans; N-Myc Proto-Oncogene Protein; Gene Amplification; Genes, myc; Cellular Senescence; Neuroblastoma; Tumor Microenvironment; Membrane Proteins; Intracellular Signaling Peptides and Proteins
PubMed: 38035110
DOI: 10.3389/fimmu.2023.1309138 -
International Journal of Molecular... Apr 2022The () is proto-oncogene that is classified as a member of the transcription factor family, which has been found to be consistently overexpressed in about half of the... (Review)
Review
The () is proto-oncogene that is classified as a member of the transcription factor family, which has been found to be consistently overexpressed in about half of the patients with clinically significant prostate cancer (PCa). The overexpression of can mostly be attributed to the fusion of the and () genes, and this fusion is estimated to represent about 85% of all gene fusions observed in prostate cancer. Clinically, individuals with gene fusion are mostly documented to have advanced tumor stages, increased mortality, and higher rates of metastasis in non-surgical cohorts. In the current review, we elucidate ERG's molecular interaction with downstream genes and the pathways associated with PCa. Studies have documented that plays a central role in PCa progression due to its ability to enhance tumor growth by promoting inflammatory and angiogenic responses. has also been implicated in the epithelial-mesenchymal transition (EMT) in PCa cells, which increases the ability of cancer cells to metastasize. In vivo, research has demonstrated that higher levels of ERG expression are involved with nuclear pleomorphism that prompts hyperplasia and the loss of cell polarity.
Topics: Carcinogenesis; Gene Expression Regulation, Neoplastic; Humans; Male; Oncogene Proteins, Fusion; Prostatic Neoplasms; Proto-Oncogene Proteins c-ets; Proto-Oncogenes; Transcriptional Regulator ERG
PubMed: 35563163
DOI: 10.3390/ijms23094772