Induction of DISE by tumor suppressive microRNAs
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ABSTRACT:
PROVIDER: PRJNA436738 | ENA |
REPOSITORIES: ENA
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Project description:Many siRNAs and shRNAs induce a form of cell death in all cancer cells by silencing a set of critical survival genes in a process called death induced by survival gene elimination (DISE). Mechanistically, a 6mer seed sequence (position 2-7 of the guide strand) is sufficient to confer DISE-inducing activity. We have now performed a strand-specific screen testing the toxicity of all 4096 possible 6mer seed sequences in a neutral double-stranded siRNA backbone. We found an asymmetric preference for guanine in positions 1-3 and a G content of >80% of the 6mer seed in the most toxic siRNAs, which target survival genes that are GC rich in their 3'UTR. During over 800 million years of evolution, miRNAs have evolved to avoid guanine in their seed sequences. However, two tumor suppressive miRNAs were found to be killing cancer cells through DISE using G rich toxic 6mer seeds in cells exposed to genotoxic stress: 1) the p53 inducible miR-34 family; and 2) miR-320a, a noncanonical miRNA that is still expressed in cancer cells when miRNA processing genes are mutated. Our data suggest that most miRNAs have evolved to avoid induction of DISE but certain tumor suppressive miRNAs utilize this mechanism to kill cancer cells.
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Project description:6mer seed toxicity in tumour suppressive microRNAs
2018-09-11 | GSE111379 | GEO
Project description:6mer seed toxicity in tumour suppressive microRNAs
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Project description:UTX condensation underlies its tumor suppressive activity
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Project description:To identify target genes of tumor suppressive microRNAs in human cancer, several cell lines (bladder cancer, prostate cancer, renal cell carcinoma, and head and neck squamous cell carcinoma) were subjected to Agilent whole genome microarrays. miR-517a, miR-218, miR-145, miR-1 and miR-874 function as tumor suppressors.
2012-02-09 | GSE24782 | GEO
Project description:To identify target genes of tumor suppressive microRNAs in human cancer, several cell lines (bladder cancer, prostate cancer, renal cell carcinoma, and head and neck squamous cell carcinoma) were subjected to Agilent whole genome microarrays. miR-517a, miR-218, miR-145, miR-1 and miR-874 function as tumor suppressors. Human cancer cell lines (BOY, T24, A498, PC3, DU145, FaDu, SAS, HSC3, IMC3) were transfected with miRNAs (miR-517a, miR-218, miR-145, miR-1, miR-874). The miRNA-transfected human cancer cell lines were compared to control cell lines.
2012-02-09 | E-GEOD-24782 | biostudies-arrayexpress
Project description:microRNA dysregulation is a common feature of cancer cells, but the complex roles of microRNAs in cancer are not fully elucidated. Here we used functional genomics to identify oncogenic microRNAs in non-small cell lung cancer and to evaluate their impact on response to EGFR targeting therapy. Our data demonstrate that microRNAs with an AAGUGC-motif in their seed-sequence increase both cancer cell proliferation and sensitivity to EGFR inhibitors. Global transcriptomics, proteomics and target prediction resulted in the identification of several tumor suppressors involved in the G1/S transition as targets of AAGUGC-microRNAs. The clinical implications of our findings were evaluated by analysis of public domain data supporting the link between this microRNA seed-family, their tumor suppressor targets and cancer cell proliferation. In conclusion we propose that AAGUGC-microRNAs are an integral part of an oncogenic signaling network, and that these findings have potential therapeutic implications, especially in selecting patients for EGFR-targeting therapy.
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Project description:The tumor microenvironment in brain metastases is characterized by high myeloid cell content with immune-suppressive and cancer-permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T cell-directed therapies fail to elicit effective anti-tumor immune responses. Here we seek to evaluate the applicability of radio-immunotherapy to modulate tumor immunity and overcome inhibitory effects that diminish anti-cancer activity. Radiotherapy-induced immune modulation resulted in an increase in cytotoxic T cell numbers and prevented the induction of lymphocyte-mediated immune suppression. Radio-immunotherapy led to significantly improved tumor control with prolonged median survival in experimental breast-to-brain metastases. However, long-term efficacy was not observed. Recurrent brain metastases showed accumulation of blood-borne PD-L1+ myeloid cells after radio-immunotherapy indicating the establishment of an immune-suppressive environment to counteract re-activated T cell responses. This finding was further supported by transcriptional analyses indicating a crucial role for monocyte-derived macrophages in mediating immune-suppression and regulating T cell function. Therefore, selective targeting of immune suppressive functions of myeloid cells is expected to be critical for improved therapeutic efficacy of radio-immunotherapy in brain metastases.
2021-02-12 | GSE164049 | GEO
Project description:To identify tumor suppressive microRNAs repressed by DNA hypermethylation in gastric cancer (GC), we analyzed methylome and miRNome of EpCAM+/CD44+ GC cells. Among a set of microRNAs hypermethylated and downregulated in GC, mir-1271 was uncovered as a microRNA repressed by DNA hypermethylation in GC. Forced expression of mir-1271 significantly suppressed growth, migration, and invasion of GC cells both in vitro and in vivo. To identify target genes and cancer signaling pathways regulated by mir-1271, we examined differentially-expressed genes responsive to mir-1271 by performing RNA-sequencing.
2018-06-12 | GSE87785 | GEO
Project description:Dicer is a key endoribonuclease of the microRNA biogenetic machinery. Downregulation of Dicer has been associated with aberrant expression of microRNAs and the promotion of tumorigenesis. Calcitriol, the hormonal form of vitamin D3, increases microRNA expression in tumor cells, but the mechanism is not yet understood. Given the essential role of Dicer in microRNAs biogenesis, the purpose of this study was to evaluate whether this gene is a target for calcitriol and to explore the effects of this hormone on microRNA expression. Our findings demonstrate that calcitriol increased Dicer mRNA and protein in SiHa and HeLa cervical cancer cells, which expressed the vitamin D receptor. The inductive effect of calcitriol on Dicer mRNA was not observed in C33-A cells lacking this nuclear receptor. To explore the potential effect of Dicer upregulation by calcitriol on microRNA processing, we performed a microRNA profiling study in SiHa cells treated with calcitriol. The analysis of microRNA expression revealed that this hormone promotes the maturation of a subset of microRNAs with potential regulatory function in cancer pathways. Among these, miR-22 and miR-296-3p have already been associated with tumor-supressive effects. Our results suggest that Dicer upregulation by calcitriol could be associated, at least in part, with an increase in the maturation of a subset of tumor-suppressor microRNAs in cervical cancer cells.
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