The Transcribed-Ultra Conserved Regions (T-UCRs) are a class of novel non-coding RNAs that arise from the dark matter of the genome. T-UCRs are highly conserved between mouse, rat, and human genomes, ...which might indicate a definitive role for these elements in health and disease. The growing body of evidence suggests that T-UCRs contribute to oncogenic pathways. Neuroblastoma is a type of childhood cancer that is challenging to treat. The role of non-coding RNAs in the pathogenesis of neuroblastoma, in particular for cancer development, progression, and therapy resistance, has been documented. Exosmic non-coding RNAs are also involved in shaping the biology of the tumor microenvironment in neuroblastoma. In recent years, the involvement of T-UCRs in a wide variety of pathways in neuroblastoma has been discovered. Here, we present an overview of the involvement of T-UCRs in various cellular pathways, such as DNA damage response, proliferation, chemotherapy response,
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)) amplification, gene copy number, and immune response, as well as correlate it to patient survival in neuroblastoma.
Neuroblastoma is a solid tumor (a lump or mass), often found in the small glands on top of the kidneys, and most commonly affects infants and young children. Among neuroblastomas, high-risk ...neuroblastomas are very aggressive and resistant to most kinds of intensive treatment. Immunotherapy, which uses the immune system to fight against cancer, has shown great promise in treating many types of cancer. However, high-risk neuroblastoma is often resistant to this approach as well. Recent studies revealed that small vesicles known as exosomes, which are envelopes, could deliver a cargo of small RNA molecules and provide communication between neuroblastoma cells and the surrounding cells and trigger metastasis and resistance to immunotherapy. In this chapter, we describe the role of exosomes and small RNA molecules in the metastasis and regression of neuroblastoma and the potential therapeutic approaches to combat this menace.
The ARF tumor suppressor protein activates p53 in response to oncogenic stress, whereas ribosomal protein L11 induces p53 following ribosomal stress. Both proteins bind to central, albeit ...non-overlapping, regions of MDM2 and suppress MDM2 activity toward p53. However, it is not known whether the two pathways are functionally connected. Here we show that ARF directly binds to L11 in vitro and in cells, which then forms a complex with MDM2 and p53. L11 collaboratively enhances ARF-induced p53 transcriptional activity and cell cycle arrest. Supporting these results, knocking down L11 reduces ARF-mediated p53 accumulation and alleviates ARF-induced cell cycle arrest. Interestingly, overexpression of ARF increases the levels of ribosome-free L11 and enhances the interaction of L11 with MDM2 and p53. These results demonstrate that ARF activates p53, at least partly by induction of ribosomal stress, which results in L11 suppression of MDM2, and suggest that the ARF-MDM2-p53 and the L11-MDM2-p53 pathways are functionally connected.
ARF and L11 can activate p53 in response to different stress signals.
ARF and L11 physically and functionally interact with each other to activate p53.
ARF crosstalks with L11 in p53 response to stress.
Discovery of a direct link between ARF and L11 in the p53 network.
In the originally published version of this Article, the positions of the final two authors in the author list were inadvertently inverted during the production process. This error has now been ...corrected in both the PDF and HTML versions of the Article.
The oncoprotein c-Myc is essential for cell growth and proliferation while its deregulated overexpression is associated with most human cancers. Thus tightly regulated levels and activity of c-Myc ...are critical for maintaining normal cell homeostasis. c-Myc is down-regulated in response to several types of stress, including UV-induced DNA damage. Yet, mechanism underlying UV-induced c-Myc reduction is not completely understood. Here we report that L11 promotes miR-130a targeting of c-myc mRNA to repress c-Myc expression in response to UV irradiation. miR-130a targets the 3'-untranslated region (UTR) of c-myc mRNA. Overexpression of miR-130a promotes the Ago2 binding to c-myc mRNA, significantly reduces the levels of both c-Myc protein and mRNA and inhibits cell proliferation. UV treatment markedly promotes the binding of L11 to miR-130a, c-myc mRNA as well as Ago2 in cells. Inhibiting miR-130a significantly suppresses UV-mediated c-Myc reduction. We further show that L11 is relocalized from the nucleolus to the cytoplasm where it associates with c-myc mRNA upon UV treatment. Together, these results reveal a novel mechanism underlying c-Myc down-regulation in response to UV-mediated DNA damage, wherein L11 promotes miR-130a-loaded miRISC to target c-myc mRNA.
The mechanism by which HIV and HCV cooperatively accelerate hepatocyte damage is not clearly understood; however, each virus affects the TRAIL: TRAIL-receptor system. We, therefore, questioned ...whether the independent effects of HCV and HIV combine to synergistically result in TRAIL dependent hepatocyte killing. We describe that Huh7 hepatocytes treated with HIV gp120 results in both increase TRAIL-R2 expression and an acquired sensitivity to TRAIL mediated killing. Moreover HCV infection and HCV core expression alone in Huh7 cells upregulates TRAIL. Co-incubation of HIV gp120 primed hepatocytes with HCV core expressing hepatocytes results in the selective death of the HIV gp120 primed hepatocytes that is selectively blocked by TRAIL-R2-Fc fusion protein. Liver biopsies from HIV mono-infected patients have increased TRAIL-R2; biopsies from HCV infected patients have increased TRAIL, while co-infected liver biopsies have increased PARP cleavage within hepatocytes indicating enhanced apoptosis. These findings suggest a pathogenic model to understand why HIV/HCV co-infection accelerates liver injury.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background: Neuroblastoma is the most common extracranial solid malignancy in children. Amplification/stabilization of the MYCN oncogene defines a group of neuroblastoma with a high risk of ...recurrence. Despite current aggressive treatment regimens, the prognosis for high-risk neuroblastoma patients remains poor with survival less than 40%. Most of the affected children ultimately die of the disease, which highlights the urgent need for novel therapeutic approaches. MicroRNAs (miRNAs) are small non-coding RNAs with gene expression regulatory functions whose expression is dysregulated in all types of human cancers, including neuroblastoma. However, the role of miRNAs in the regulation of MYCN and the development of drug resistance is currently unknown.
Hypothesis: We hypothesize that miRNA-15 family act as a tumor suppressor in neuroblastoma.
Methods: Neuroblastoma patient tumors were expanded in vivo. miRNAs were profiled by Nanostring and validated by qRT-PCR using TaqMan assays. miRNAs or their inhibitors were overexpressed by lipid reagent mediated transfection or lentiviral infection. Western blotting and qRT-PCR assays detected MYCN expression. Luciferase reporter and Ago-2 immunoprecipitation assays were performed to test miRNA-15 directly targeting of MYCN through interaction with 3’UTR of MYCN mRNA. Cell proliferation assay was carried out through MTT; cell migration by wound-healing; whereas invasion by examining the ability of cells to pass through a Matrigel-coated membrane matrix in neuroblastoma cells. Tumor growth was measured in neuroblastoma xenografts treated with neuroblastoma cells alone or with miRNA-15. MYCN (mRNA and protein), and miRNA-15 levers were assessed in xenograft tumors. Student’s t-test was used to evaluate the differences between treatment groups. All statistical tests were two-sided.
Results: Based on the MYCN expression, neuroblastoma patient-derived xenografts (PDX) were divided into MYCN higher and lower expression. miRNA-15 family such as miRNA-15a-5p, miRNA-15b-5p, and miRNA-16-5p were downregulated in PDX with higher MYCN expression. By luciferase and Ago-IP assays, we found miRNA-15a-5p, miRNA-15b-5p, and miRNA-16-5p can directly bind with 3’UTR region of the MYCN mRNA. R2 database involving 105 neuroblastoma patients show an inverse correlation between MYCN mRNA and miRNA-15 host gene. The forced expression of the miRNA-15a-5p, miRNA-15b-5p, and miRNA-16-5p in neuroblastoma cells resulted in a significant reduction in the levels of MYCN and suppressed cell proliferation, migration, and invasion. Conversely, the inhibition of miRNA-15 family expression dramatically accelerated MYCN expression. Injection of neuroblastoma cells with miRNAs inhibits the tumor formation in neuroblastoma xenografts.
Conclusion: These data suggest that miRNA-15 family may function as a tumor suppressor by targeting MYCN in neuroblastoma.
Citation Format: Kishore B. Challagundla, Patrick Reynolds, Santhi Gorantla, Larisa Poluektova, Don Coulter, Surinder K. Batra, Srinivas Chava. The tumor suppressive microRNA-15 family targets MYCN in neuroblastoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 781.
Abstract
Neuroblastoma is the most devastating extracranial solid malignancy in children. Despite an intense treatment regimen, the prognosis for high-risk neuroblastoma patients remains poor, with ...less than 40% survival. So far, MYCN status/amplification is considered the most prognostic factor but corresponds to only 25% of neuroblastoma patients. Therefore, it is essential to identify a better prognosis and prediction marker of therapy response in neuroblastoma patients. The identification of master regulators with good prognostic and drug response abilities are not successful due to the complexity and lack of data-driven bioinformatic workflows. We applied robust bioinformatic data mining tools such as Weighted Gene Co-expression Network Analysis, cisTarget, and Single-Cell rEgulatory Network Inference and Clustering on three neuroblastoma patient datasets (n=1252). We found Sin3A Associated Protein 30 (Sap30), a driver transcription factor positively associated with high-risk, progression, stage 4, and poor survival in high-risk neuroblastoma patient cohorts. Tumors of high-risk neuroblastoma patients and relapse-specific patient-derived xenografts showed higher Sap30 levels. The Genomics of Drug Sensitivity in Cancer, The Cancer Cell Line Encyclopedia, and CRISPR-Cas9 screens indicated that Sap30 essentiality is associated with Cisplatin resistance and further showed higher levels in Cisplatin resistant patient-derived xenograft tumor cell lines. The silencing of Sap30 in cells reduced cell growth, induced cell death, mitochondrial membrane potential loss in vitro, and reduced tumorigenicity in vivo. Altogether, these results indicate that Sap30 is a novel prognostic and Cisplatin resistant marker and thus a potential drug target in high-risk neuroblastoma patients.
Citation Format: Philip Prathipati, Anup S. Pathania, Nagendra K. Chaturvedi, Subash C. Gupta, Siddappa N. Byrareddy, Don W. Coulter, Kishore B. Challagundla. SAP30, a novel drug response specific transcription factor in high-risk neuroblastoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2349.
The cell cycle comprises sequential events during which a cell duplicates its genome and divides it into two daughter cells. This process is tightly regulated to ensure that the daughter cell ...receives identical copied chromosomal DNA and that any errors in the DNA during replication are correctly repaired. Cyclins and their enzyme partners, cyclin-dependent kinases (CDKs), are critical regulators of G- to M-phase transitions during the cell cycle. Mitogenic signals induce the formation of the cyclin/CDK complexes, resulting in phosphorylation and activation of the CDKs. Once activated, cyclin/CDK complexes phosphorylate specific substrates that drive the cell cycle forward. The sequential activation and inactivation of cyclin-CDK complexes are tightly controlled by activating and inactivating phosphorylation events induced by cell-cycle proteins. The non-coding RNAs (ncRNAs), which do not code for proteins, regulate cell-cycle proteins at the transcriptional and translational levels, thereby controlling their expression at different cell-cycle phases. Deregulation of ncRNAs can cause abnormal expression patterns of cell-cycle-regulating proteins, resulting in abnormalities in cell-cycle regulation and cancer development. This review explores how ncRNA dysregulation can disrupt cell division balance and discusses potential therapeutic approaches targeting these ncRNAs to control cell-cycle events in cancer treatment.
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Non-coding RNAs (ncRNAs) modulate cell-cycle gene expression, and their dysregulation can lead to disrupted cell-cycle control, contributing to cancer development. This review examines how ncRNA abnormalities affect cell division and discusses potential therapeutic strategies for cancer treatment by targeting these ncRNAs.
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