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Pathology, Research and Practice Aug 2023Cancer genes are largely categorized into tumor suppressor gene (TSG) and proto-oncogene, but many have dual activities depending on the cellular context. In the present...
Cancer genes are largely categorized into tumor suppressor gene (TSG) and proto-oncogene, but many have dual activities depending on the cellular context. In the present study, we analyzed DYRK1B, ESRP1, MTSS1, ADAMTS1, and INPP5F genes known to possess the dual activities in sporadic colon cancers (CCs). By the mutation analysis, we identified DYRK1B, ESRP1, MTSS1, ADAMTS1, and INPP5F frameshift mutations in 2, 2, 3, 3, and 1 CCs in instability-high (MSI-H) cases (1.1-3.2% of MSI-H CCs), respectively, but not microsatellite stable (MSS) cases. One CC showed regional heterogeneous mutations (RHM) of ESRP1 mutation. Immunohistochemistry identified protein expression of ESRP1, MTSS1, and ADAMTS1 in the CCs, revealing that approximately 30% of CCs lost the protein expression irrespective of the MSI status. Our study showed that dual TSG and proto-oncogene genes DYRK1B, ESRP1, MTSS1, ADAMTS1, and INPP5F harbored low incidences of inactivating mutations, but that the protein losses were frequent in CCs. Our study suggests a possibility that the dual-function genes could be altered mainly at the expression level, which might contribute to CC pathogenesis.
Topics: Humans; Colorectal Neoplasms; Genes, Tumor Suppressor; Mutation; Frameshift Mutation; Colonic Neoplasms; Microsatellite Instability; Proto-Oncogenes; Microsatellite Repeats; Microfilament Proteins; Neoplasm Proteins
PubMed: 37429176
DOI: 10.1016/j.prp.2023.154659 -
Journal of Cell Science Oct 2020The Ras oncogene is notoriously difficult to target with specific therapeutics. Consequently, there is interest to better understand the Ras signaling pathways to... (Review)
Review
The Ras oncogene is notoriously difficult to target with specific therapeutics. Consequently, there is interest to better understand the Ras signaling pathways to identify potential targetable effectors. Recently, the mechanistic target of rapamycin complex 2 (mTORC2) was identified as an evolutionarily conserved Ras effector. mTORC2 regulates essential cellular processes, including metabolism, survival, growth, proliferation and migration. Moreover, increasing evidence implicate mTORC2 in oncogenesis. Little is known about the regulation of mTORC2 activity, but proposed mechanisms include a role for phosphatidylinositol (3,4,5)-trisphosphate - which is produced by class I phosphatidylinositol 3-kinases (PI3Ks), well-characterized Ras effectors. Therefore, the relationship between Ras, PI3K and mTORC2, in both normal physiology and cancer is unclear; moreover, seemingly conflicting observations have been reported. Here, we review the evidence on potential links between Ras, PI3K and mTORC2. Interestingly, data suggest that Ras and PI3K are both direct regulators of mTORC2 but that they act on distinct pools of mTORC2: Ras activates mTORC2 at the plasma membrane, whereas PI3K activates mTORC2 at intracellular compartments. Consequently, we propose a model to explain how Ras and PI3K can differentially regulate mTORC2, and highlight the diversity in the mechanisms of mTORC2 regulation, which appear to be determined by the stimulus, cell type, and the molecularly and spatially distinct mTORC2 pools.
Topics: Animals; Class I Phosphatidylinositol 3-Kinases; Genes, ras; Humans; Mechanistic Target of Rapamycin Complex 2; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 33033115
DOI: 10.1242/jcs.234930 -
Methods in Molecular Biology (Clifton,... 2020While it has been more than 30 years since its discovery, the ras family of genes has not yet lost its impact on basic and clinical oncology. These genes remain central...
While it has been more than 30 years since its discovery, the ras family of genes has not yet lost its impact on basic and clinical oncology. These genes remain central to the field of molecular oncology as tools for investigating carcinogenesis and oncogenic signaling, as powerful biomarkers for the identification of those who have or are at high risk of developing cancer, and as oncogene targets for the design and development of new chemotherapeutic drugs. Mutational activation of the K-RAS proto-oncogene is an early event in the development and progression of the colorectal, pancreatic, and lung cancers that are the major causes of cancer death in the world. The presence of point mutational "hot spots" at sites necessary for the activation of this proto-oncogene has led to the development of a number of highly sensitive PCR-based methods that are feasible for the early detection of K-RAS oncogene mutations in the clinical setting. In light of these facts, mutation at the K-RAS oncogene has the potential to serve as a useful biomarker in the early diagnosis and risk assessment of cancers with oncogenic ras signaling. This chapter describes a highly sensitive method for detecting mutant K-RAS, enriched PCR, and its application to early detection of alterations in this oncogene in preneoplastic and early neoplastic lesions of the colon and rectum.
Topics: Cell Line, Tumor; Colorectal Neoplasms; DNA; DNA Mutational Analysis; Electrophoresis, Polyacrylamide Gel; Genes, ras; Humans; Point Mutation; Polymerase Chain Reaction; Precancerous Conditions; Proto-Oncogene Mas; Workflow
PubMed: 31989570
DOI: 10.1007/978-1-0716-0223-2_24 -
Rlf-Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer.Cancer Discovery Dec 2021Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel...
UNLABELLED
Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel therapeutic targets. Recurrent genomic rearrangements have been identified in SCLC, most notably an in-frame gene fusion between RLF and MYCL found in up to 7% of the predominant ASCL1-expressing subtype. To explore the role of this fusion in oncogenesis and tumor progression, we used CRISPR/Cas9 somatic editing to generate a Rlf-Mycl-driven mouse model of SCLC. RLF-MYCL fusion accelerated transformation and proliferation of murine SCLC and increased metastatic dissemination and the diversity of metastatic sites. Tumors from the RLF-MYCL genetically engineered mouse model displayed gene expression similarities with human RLF-MYCL SCLC. Together, our studies support RLF-MYCL as the first demonstrated fusion oncogenic driver in SCLC and provide a new preclinical mouse model for the study of this subtype of SCLC.
SIGNIFICANCE
The biological and therapeutic implications of gene fusions in SCLC, an aggressive metastatic lung cancer, are unknown. Our study investigates the functional significance of the in-frame RLF-MYCL gene fusion by developing a Rlf-Mycl-driven genetically engineered mouse model and defining the impact on tumor growth and metastasis. This article is highlighted in the In This Issue feature, p. 2945.
Topics: Animals; Carcinogenesis; Cell Line, Tumor; Gene Fusion; Genes, myc; Lung Neoplasms; Mice; Proto-Oncogene Proteins c-myc; Small Cell Lung Carcinoma; Telomere-Binding Proteins
PubMed: 34344693
DOI: 10.1158/2159-8290.CD-21-0441 -
Clinical and Translational Medicine Aug 2022
Topics: Ferroptosis; Genes, myc; Humans; N-Myc Proto-Oncogene Protein; Neuroblastoma
PubMed: 35908258
DOI: 10.1002/ctm2.963 -
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 -
Clinical & Translational Oncology :... Sep 2021Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy that overlaps with myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) and tends to... (Review)
Review
Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy that overlaps with myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) and tends to transform into acute myeloid leukemia (AML). Among cases of CMML, > 90% have gene mutations, primarily involving TET2 (~ 60%), ASXL1 (~ 40%), SRSF2 (~ 50%), and the RAS pathways (~ 30%). These gene mutations are associated with both the clinical phenotypes and the prognosis of CMML, special CMML variants and pre-phases of CMML. Cytogenetic abnormalities and the size of genome are also associated with prognosis. Meanwhile, cases with ASXL1, DNMT3A, NRAS, SETBP1, CBL and RUNX1 mutations may have inferior prognoses, but only ASXL1 mutations were confirmed to be independent predictors of the patient outcome and were included in three prognostic models. Novel treatment targets related to the various gene mutations are emerging. Therefore, this review provides new insights to explore the correlations among gene mutations, clinical phenotypes, prognosis, and novel drugs in CMML.
Topics: Antineoplastic Agents; Carrier Proteins; Chromosome Aberrations; Core Binding Factor Alpha 2 Subunit; DNA Methylation; DNA Methyltransferase 3A; DNA-Binding Proteins; Dioxygenases; Epigenesis, Genetic; Epigenetic Repression; GTP Phosphohydrolases; Genes, ras; Genome Size; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Membrane Proteins; Mutation; Myelodysplastic Syndromes; Nuclear Proteins; Phenotype; Prognosis; Proto-Oncogene Proteins c-cbl; Repressor Proteins; Serine-Arginine Splicing Factors; Signal Transduction
PubMed: 33861431
DOI: 10.1007/s12094-021-02585-x -
Nature Communications Jan 2024Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic...
Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, the role of wild-type KRAS in tumorigenesis and therapeutic response remains elusive. We report an in vivo murine model of colorectal cancer featuring deletion of wild-type Kras in the context of oncogenic Kras. Deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while incidentally inducing sensitivity to inhibition of MEK1/2. Importantly, loss of the wild-type allele in aggressive models of KRASG12D-driven CRC significantly alters tumour progression, and suppresses metastasis through modulation of the immune microenvironment. This study highlights the critical role for wild-type Kras upon tumour initiation, progression and therapeutic response in Kras mutant CRC.
Topics: Humans; Mice; Animals; Proto-Oncogene Proteins p21(ras); Allelic Imbalance; Genes, ras; Cell Transformation, Neoplastic; Colorectal Neoplasms; Mutation; Tumor Microenvironment
PubMed: 38168062
DOI: 10.1038/s41467-023-44342-4 -
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 -
Journal of Medicinal Chemistry Jun 2023WDR5 is a critical chromatin cofactor of MYC. WDR5 interacts with MYC through the WBM pocket and is hypothesized to anchor MYC to chromatin through its WIN site....
WDR5 is a critical chromatin cofactor of MYC. WDR5 interacts with MYC through the WBM pocket and is hypothesized to anchor MYC to chromatin through its WIN site. Blocking the interaction of WDR5 and MYC impairs the recruitment of MYC to its target genes and disrupts the oncogenic function of MYC in cancer development, thus providing a promising strategy for the treatment of MYC-dysregulated cancers. Here, we describe the discovery of novel WDR5 WBM pocket antagonists containing a 1-phenyl dihydropyridazinone 3-carboxamide core that was identified from high-throughput screening and subsequent structure-based design. The leading compounds showed sub-micromolar inhibition in the biochemical assay. Among them, compound can disrupt WDR5-MYC interaction in cells and reduce MYC target gene expression. Our work provides useful probes to study WDR5-MYC interaction and its function in cancers, which can also be used as the starting point for further optimization toward drug-like small molecules.
Topics: Humans; WD40 Repeats; Genes, myc; Chromatin; Neoplasms; High-Throughput Screening Assays; Intracellular Signaling Peptides and Proteins
PubMed: 37307526
DOI: 10.1021/acs.jmedchem.3c00787