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Project description:Key role of dysregulated SF3A3 translation in MYC-induced breast tumorigenesis
| PRJNA615004 | ENA
Project description:As a transcription factor and proto-oncogene, MYC is known to be deregulated in a variety of tumors, including breast cancer. However, no consistent conclusion on the role and mechanism of MYC deregulation during breast cancer carcinogenesis has been formed. Here, we used the UALCAN, bc-GenExMiner, TCGA, cBioportal, STRING and Kaplan-Meier Plotter databases to explore the mRNA expression, prognosis, transcriptional profile changes, signal pathway rewiring and interaction with the cancer stem cells of MYC in breast cancer. We found that the expression of MYC varies in different subtypes of breast cancer, with relatively high frequency in TNBC. As a transcription factor, MYC not only participates in the rewiring of cancer signaling pathways, such as estrogen, WNT, NOTCH and other pathways, but also interacts with cancer stem cells. MYC is significantly positively correlated with breast cancer stem cell markers such as CD44, CD24, and ALDH1. Collectively, our results highlight that MYC plays an important regulatory role in the occurrence of breast cancer, and its amplification can be used as a predictor of diagnosis and prognosis. The interaction between MYC and cancer stem cells may play a crucial role in regulating the initiation and metastasis of breast cancer.
| S-EPMC7757029 | biostudies-literature
Project description:One of the enigmas in tumor biology is that different types of cancers are prevalent in different age groups. One possible explanation is that the ability of a specific oncogene to cause tumorigenesis in a particular cell type depends on epigenetic parameters such as the developmental context. To address this hypothesis, we have used the tetracycline regulatory system to generate transgenic mice in which the expression of a c-MYC human transgene can be conditionally regulated in murine hepatocytes. MYC's ability to induce tumorigenesis was dependent upon developmental context. In embryonic and neonatal mice, MYC overexpression in the liver induced marked cell proliferation and immediate onset of neoplasia. In contrast, in adult mice MYC overexpression induced cell growth and DNA replication without mitotic cell division, and mice succumbed to neoplasia only after a prolonged latency. In adult hepatocytes, MYC activation failed to induce cell division, which was at least in part mediated through the activation of p53. Surprisingly, apoptosis is not a barrier to MYC inducing tumorigenesis. The ability of oncogenes to induce tumorigenesis may be generally restrained by developmentally specific mechanisms. Adult somatic cells have evolved mechanisms to prevent individual oncogenes from initiating cellular growth, DNA replication, and mitotic cellular division alone, thereby preventing any single genetic event from inducing tumorigenesis.
| S-EPMC519000 | biostudies-literature
Project description:We apply desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to provide an in situ lipidomic profile of genetically modified tissues from a conditional transgenic mouse model of MYC-induced hepatocellular carcinoma (HCC). This unique, label-free approach of combining DESI-MSI with the ability to turn specific genes on and off has led to the discovery of highly specific lipid molecules associated with MYC-induced tumor onset. We are able to distinguish normal from MYC-induced malignant cells. Our approach provides a strategy to define a precise molecular picture at a resolution of about 200 μm that may be useful in identifying lipid molecules that define how the MYC oncogene initiates and maintains tumorigenesis.
| S-EPMC3773496 | biostudies-literature
Project description:The c-myc oncogene plays a key role in cellular growth control, and translation initiation factors are among the transcriptional targets of Myc. Here, we describe a defect in translation initiation control in myc-null cells due to alterations in the mammalian target of rapamycin (mTOR) pathway. Myc loss increased sensitivity to dominant inhibition of eukaryotic translation initiation factor 4E function. Polysomal profiles of myc(-/-) cells revealed decreased translation initiation rates, which were accompanied by decreased 40S/60S ribosomal subunit ratios. Because the 40S small ribosomal subunit contains the key regulatory ribosomal protein S6 (rpS6), we considered that myc loss might affect expression of components of the mTOR signaling pathway that regulate rpS6 function. Among mTOR signaling components, Myc directly affected transcription of tuberous sclerosis 2 (TSC2), as shown by quantitative mRNA analysis and by Myc binding to its promoter in chromatin immunoprecipitation assays. Importantly, Myc acted as a strong and direct repressor for TSC2 expression because its loss increased TSC2 mRNA in myc-null and in HL60 shRNA experiments, activation of a mycER construct in myc(-/-) cells suppressed TSC2 induction in a myc box II-dependent manner, and mycER activation recruited Myc to the TSC2 promoter. The biological significance of the effect of Myc on TSC2 expression was shown by markedly reduced TSC2 mRNA levels in myc-transformed cells, stimulation of S6 kinase activity in myc-null cells by TSC2 siRNA, and decreased Myc-induced soft agar colony formation following retroviral transduction of TSC2. Together, these findings show that regulation of TSC2 can contribute to the effects of Myc on cell proliferation and neoplastic growth.
| S-EPMC3022657 | biostudies-literature
Project description:Understanding molecular mechanisms involved in melanoma resistance to drugs is a big challenge. Experimental evidences suggested a correlation between mutational status in B-RAF and melanoma cell susceptibility to drugs, such as paclitaxel, doxorubicin and temozolomide, which generate an accumulation of hydrogen peroxide (H2O2) in the cells. We investigated the survival phenotype and the protein level of c-myc, a B-RAF target molecule, in melanoma cells, carrying a different mutational status in B-RAF, upon paclitaxel, doxorubicin and H2O2 treatment. For the first time, we reported c-myc modulation is critical for melanoma drug response. It appeared drug-specific and post-transcriptionally driven through PP2A; in correlation, cell pre-treatment with okadaic acid (OA), a specific PP2A inhibitor, as well as PP2A silencing of melanoma cells, was able to increase melanoma cell drug-sensitivity and c-myc protein level. This is relevant for designing efficacious therapeutic strategies in melanoma.
| S-EPMC4622542 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-08-12 | E-GEOD-59874 | biostudies-arrayexpress
Project description:Splicing is a central RNA-based process commonly altered in human cancers; however, how the splicing machinery is co-opted during tumorigenesis remains largely unresolved. Here we identify the splice factor SF3A3 at the nexus of an oncogenic translation program that rewires splicing to promote tumorigenesis. Our results suggest that key spliceosomal networks centered on the essential core U2-associated factor, SF3A3, are exquisitely controlled at the translation level during oncogenic stress. Upon oncogene activation, SF3A3 translation is rapidly enabled via a conserved internal stem-loop structure embedded in the transcript 5’ untranslated region (UTR). Uncoupled SF3A3 translation leads to alternative splicing of several mRNAs involved in mitochondrial dynamics, and induces a metabolic switch that fuels cancer initiation properties in MYC-driven breast tumorigenesis in vivo. Finally, we compelling show that SF3A3 is post-transcriptionally altered and predicts for poor prognosis in aggressive triple negative breast cancers. Together, these findings unveil a highly dynamic regulatory network that interfaces mRNA splicing and translation to orchestrate cancer gene expression networks.
2021-03-25 | GSE147505 | GEO
Project description:BackgroundThe functions of long noncoding RNAs (lncRNAs) have been identified in several cancers, but the roles of lncRNAs in colorectal cancer (CRC) are less well understood. The transcription factor MYC is known to regulate lncRNAs and has been implicated in cancer cell proliferation and tumorigenesis.MethodsCRC cells and tissues were profiled to identify lncRNAs differentially expressed in CRC, from which we further selected MYC-regulated lncRNAs. We used luciferase promoter assay, ChIP, RNA pull-down assay, deletion mapping assay, LC-MS/MS and RNA immunoprecipitation to determine the mechanisms of MYC regulation of lncRNAs. Moreover, soft agar assay and in vivo xenograft experiments (four athymic nude mice per group) provided evidence of MYC-regulated lncRNAs in cancer cell transformation and tumorigenesis. The Kaplan-Meier method was used for survival analyses. All statistical tests were two-sided.ResultsWe identified lncRNAs differentially expressed in CRC (P < .05, greater than two-fold) and verified four lncRNAs upregulated and two downregulated in CRC cells and tissues. We further identified MYC-regulated lncRNAs, named MYCLos. The MYC-regulated MYCLos may function in cell proliferation and cell cycle by regulating MYC target genes such as CDKN1A (p21) and CDKN2B (p15), suggesting new regulatory mechanisms of MYC-repressed target genes through lncRNAs. RNA binding proteins including HuR and hnRNPK are involved in the function of MYCLos by interacting with MYCLo-1 and MYCLo-2, respectively. Knockdown experiments also showed that MYCLo-2, differentially expressed not only in CRC but also in prostate cancer, has a role in cancer transformation and tumorigenesis.ConclusionsOur results provide novel regulatory mechanisms in MYC function through lncRNAs and new potential lncRNA targets of CRC.
| S-EPMC4402359 | biostudies-literature
Project description:IntroductionRetinoic acid signaling plays key roles in embryonic development and in maintaining the differentiated status of adult tissues. Recently, the nuclear retinoic acid receptor (RAR) isotypes α, β and γ were found to play specific functions in the expansion and differentiation of the stem compartments of various tissues. For instance, RARγ appears to be involved in stem cell compartment expansion, while RARα and RARβ are implicated in the subsequent cell differentiation. We found that over-expressing c-Myc in normal mouse mammary epithelium and in a c-Myc-driven transgenic model of mammary cancer, disrupts the balance between RARγ and RARα/β in favor of RARγ.MethodsThe effects of c-Myc on RAR isotype expression were evaluated in normal mouse mammary epithelium, mammary tumor cells obtained from the MMTV-Myc transgenic mouse model as well as human normal immortalized breast epithelial and breast cancer cell lines. The in vivo effect of the RARα-selective agonist 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carboxamido]benzoic acid (Am580) was examined in the MMTV-Myc mouse model of mammary tumorigenesis.ResultsModulation of the RARα/β to RARγ expression in mammary glands of normal mice, oncomice, and human mammary cell lines through the alteration of RAR-target gene expression affected cell proliferation, survival and tumor growth. Treatment of MMTV-Myc mice with the RARα-selective agonist Am580 led to significant inhibition of mammary tumor growth (~90%, P<0.001), lung metastasis (P<0.01) and extended tumor latency in 63% of mice. Immunocytochemical analysis showed that in these mice, RARα responsive genes such as Cyp26A1, E-cadherin, cellular retinol-binding protein 1 (CRBP1) and p27, were up-regulated. In contrast, the mammary gland tumors of mice that responded poorly to Am580 treatment (37%) expressed significantly higher levels of RARγ. In vitro experiments indicated that the rise in RARγ was functionally linked to promotion of tumor growth and inhibition of differentiation. Thus, activation of the RARα pathway is linked to tumor growth inhibition, differentiation and cell death.ConclusionsThe functional consequence of the interplay between c-Myc oncogene expression and the RARγ to RARα/β balance suggests that prevalence of RARγ over-RARα/β expression levels in breast cancer accompanied by c-Myc amplification or over-expression in breast cancer should be predictive of response to treatment with RARα-isotype-specific agonists and warrant monitoring during clinical trials.
| S-EPMC3680916 | biostudies-literature