Muscleblind-like 1 suppresses breast cancer metastatic colonization and stabilizes metastasis suppressor transcripts
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE76488 | GEO | 2016/10/14
SECONDARY ACCESSION(S): PRJNA307559
REPOSITORIES: GEO
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Project description:Post-transcriptional deregulation is a defining feature of metastatic cancer. While many microRNAs have been implicated as regulators of metastatic progression, less is known about the roles and mechanisms of RNA-binding proteins in this process. We identified muscleblind-like 1 (MBNL1), a gene implicated in myotonic dystrophy, as a robust suppressor of multiorgan breast cancer metastasis. MBNL1 binds the 3' untranslated regions (UTRs) of DBNL (drebrin-like protein) and TACC1 (transforming acidic coiled-coil containing protein 1)-two genes that we implicate as metastasis suppressors. By enhancing the stability of these genes' transcripts, MBNL1 suppresses cell invasiveness. Consistent with these findings, elevated MBNL1 expression in human breast tumors is associated with reduced metastatic relapse likelihood. Our findings delineate a post-transcriptional network that governs breast cancer metastasis through RNA-binding protein-mediated transcript stabilization.
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Project description:Muscleblind-like 1 suppresses breast cancer metastatic colonization and stabilizes metastasis suppressor transcripts
| PRJNA307559 | ENA
Project description:Breast cancer metastasis suppressor 1 (BRMS1) is a predominantly nuclear protein that differentially regulates expression of multiple genes, leading to suppression of metastasis without blocking orthotopic tumor growth in multiple human and murine cancer cells of diverse origins. We hypothesized that miR-146 may be involved in the ability of BRMS1 to supress metastasis because miR-146 expression is altered by BRMS1 and because BRMS1 and miR-146 are both associated with decreased signaling through the nuclear factor-kappaB pathway. BRMS1 significantly up-regulates miR-146a by 6- to 60-fold in metastatic MDA-MB-231 and MDA-MB-435 cells, respectively, and miR-146b by 40-fold in MDA-MB-435 as measured by real-time quantitative reverse transcription-PCR. Transduction of miR-146a or miR-146b into MDA-MB-231 down-regulated expression of epidermal growth factor receptor, inhibited invasion and migration in vitro, and suppressed experimental lung metastasis by 69% and 84%, respectively (mean +/- SE: empty vector = 39 +/- 6, miR-146a = 12 +/- 1, miR-146b = 6 +/- 1). These results further support the recent notion that modulating the levels of miR-146a or miR-146b could have a therapeutic potential to suppress breast cancer metastasis.
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Project description:BackgroundOvarian cancer constitutes one of the most lethal gynecologic malignancies for females. Currently, early detection strategies and therapeutic options for ovarian cancer are far from satisfactory, leading to high diagnosis rates at late stages and disease relapses. New avenues of therapy are needed that target key processes in ovarian cancer progression. While a variety of non-coding RNAs have been proven to regulate ovarian cancer metastatic progression, the functional roles of RNA-binding proteins (RBPs) in this process are less well defined.ResultsIn this study, we identify that the RBP sorbin and SH3 domain containing 2 (SORBS2) is a potent suppressor of ovarian cancer metastatic colonization. Mechanistic studies show that SORBS2 binds the 3' untranslated regions (UTRs) of WFDC1 (WAP four-disulfide core domain 1) and IL-17D (Interleukin-17D), two secreted molecules that are shown to act as metastasis suppressors. Enhanced expression of either WFDC1 or IL-17D potently represses SORBS2 depletion-mediated cancer metastasis promotion. By enhancing the stability of these gene transcripts, SORBS2 suppresses ovarian cancer invasiveness and affects monocyte to myeloid-derived suppressor cell and M2-like macrophage polarization, eliciting a tumor-suppressive immune microenvironment.ConclusionsOur data illustrate a novel post-transcriptional network that links cancer progression and immunomodulation within the tumor microenvironment through SORBS2-mediated transcript stabilization.
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Project description:Metastasis is a multi-step process. Tumor cells occur epithelial-mesenchymal transition (EMT) to start metastasis, then, they need to undergo a reverse progression of EMT, mesenchymal-epithelial transition (MET), to colonize and form macrometastases at distant organs to complete the whole process of metastasis. Although microRNAs (miRNAs) functions in EMT process are well established, their influence on colonization and macrometastases formation remains unclear. Here, we established an EMT model in MCF-10A cells with SNAI1 overexpression, and characterized some EMT-related microRNAs. We identified that miR-182, which was directly suppressed by SNAI1, could enable an epithelial-like state in breast cancer cells in vitro, and enhance colonization and macrometastases in vivo. Subsequent studies showed that miR-182 exerted its function through targeting its suppressor SNAI1. Moreover, higher expression level of miR-182 was detected in metastatic lymph nodes, compared with paired primary tumor tissues. In addition, the expression level of miR-182 was negatively correlated with that of SNAI1 in these clinical specimens. Taking together, our findings describe the role of miR-182 in colonization and macrometastases in breast cancer for the first time, and provide a promise for diagnosis or therapy of breast cancer metastasis.
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Project description:BackgroundMetastasis is the predominant cause of mortality in patients with breast cancer. Long noncoding RNAs (lncRNAs) have been shown to drive important phenotypes in tumors, including invasion and metastasis. However, the lncRNAs involved in metastasis and their molecular and cellular mechanisms are still largely unknown.MethodsThe transcriptional and posttranscriptional processing of LINC00478-associated cytoplasmic RNA (LacRNA) was determined by RT-qPCR, semiquantitative PCR and 5'/3' RACE. Paired-guide CRISPR/cas9 and CRISPR/dead-Cas9 systems was used to knock out or activate the expression of LacRNA. Cell migration and invasion assay was performed to confirm the phenotype of LacRNA. Tail vein model and mammary fat pad model were used for in vivo study. The LacRNA-PHB2-cMyc axis were screened and validated by RNA pulldown, mass spectrometry, RNA immunoprecipitation and RNA-seq assays.ResultsHere, we identified a novel cytoplasmic lncRNA, LacRNA (LINC00478-associated cytoplasmic RNA), derived from nucleus-located lncRNA LINC00478. The nascent transcript of LINC00478 full-length (LINC00478_FL) was cleaved and polyadenylated, simultaneously yielding 5' ends stable expressing LacRNA, which is released into the cytoplasm, and long 3' ends of nuclear-retained lncRNA. LINC00478_3'RNA was rapidly degraded. LacRNA significantly inhibited breast cancer invasion and metastasis in vitro and in vivo. Mechanistically, LacRNA physically interacted with the PHB domain of PHB2 through its 61-140-nt region. This specific binding affected the formation of the autophagy degradation complex of PHB2 and LC3, delaying the degradation of the PHB2 protein. Unexpectedly, LacRNA specifically interacted with PHB2, recruited c-Myc and promoted c-Myc ubiquitination and degradation. The negatively regulation of Myc signaling ultimately inhibited breast cancer metastasis. Furthermore, LacRNA and LacRNA-mediated c-Myc signaling downregulation are significantly associated with good clinical outcomes, take advantage of these factors we constructed a prognostic predict model.ConclusionTherefore, our findings propose LacRNA as a potential prognostic biomarker and a new therapeutic strategy.
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Project description:Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene in several solid tumors. The role of BRMS1 in non-small cell lung cancer (NSCLC) is not well established. To assess in vitro and in vivo metastatic behavior H1299 NSCLC cells stably expressing BRMS1 or a vector control were created. BRMS1 expression significantly decreases both migration and invasion of NSCLC cells in vitro. Importantly, in flank xenografts, BRMS1 suppresses the formation of pulmonary and hepatic metastases but does not significantly affect primary tumor growth. To evaluate whether BRMS1 is related to the progression of NSCLC, we examined BRMS1 expression in human NSCLC. Both BRMS1 mRNA and protein levels are diminished in NSCLC compared to adjacent non-cancerous lung. BRMS1 expression is also lower in squamous cell carcinoma compared to adenocarcinoma. Moreover, preservation of tumor BRMS1 expression is associated with improved patient survival. Thus, BRMS1 functions as a metastasis suppressor and may be a prognostic indicator for human NSCLC.
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Project description:The skeleton is the most common metastasis site of breast cancer cells and the molecular underpinning of this process is incompletely understood. The tumor suppressor gene deleted in liver cancer-1 (DLC1) encodes a multi-domain protein including a RhoGTPase activating protein (RhoGAP) domain and has been reported to suppress the lung colonization of breast cancer cells. However, the role of DLC1 in breast cancer bone metastasis and the importance of RhoGAP-dependent and -independent pathways in this process remain unclear. Here, we showed that DLC1 silencing is linked to enhanced bone-tropism of breast cancer cell lines and poor prognosis of clinical samples. In the study presented here, DLC1 was overexpressed in the SCP2 breast cancer cells, and the control SCP2 and overexpression cells were treated with TGFbeta. Microarray profiling of mRNA levels was performed in the control and overexpression cells with or without TGFbeta treatment.
| S-ECPF-GEOD-46214 | biostudies-other
Project description:Metastasis is the main cause of death in cancer patients. TGF-β is pro-metastatic for malignant cancer cells. Here we report a loss-of-function screen in mice with metastasis as readout and identify OTUD1 as a metastasis-repressing factor. OTUD1-silenced cancer cells show mesenchymal and stem-cell-like characteristics. Further investigation reveals that OTUD1 directly deubiquitinates the TGF-β pathway inhibitor SMAD7 and prevents its degradation. Moreover, OTUD1 cleaves Lysine 33-linked poly-ubiquitin chains of SMAD7 Lysine 220, which exposes the SMAD7 PY motif, enabling SMURF2 binding and subsequent TβRI turnover at the cell surface. Importantly, OTUD1 is lost in multiple types of human cancers and loss of OTUD1 increases metastasis in intracardial xenograft and orthotopic transplantation models, and correlates with poor prognosis among breast cancer patients. High levels of OTUD1 inhibit cancer stemness and shut off metastasis. Thus, OTUD1 represses breast cancer metastasis by mitigating TGF-β-induced pro-oncogenic responses via deubiquitination of SMAD7.
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Project description:The skeleton is the most common metastasis site of breast cancer cells and the molecular underpinning of this process is incompletely understood. The tumor suppressor gene deleted in liver cancer-1 (DLC1) encodes a multi-domain protein including a RhoGTPase activating protein (RhoGAP) domain and has been reported to suppress the lung colonization of breast cancer cells. However, the role of DLC1 in breast cancer bone metastasis and the importance of RhoGAP-dependent and -independent pathways in this process remain unclear. Here, we showed that DLC1 silencing is linked to enhanced bone-tropism of breast cancer cell lines and poor prognosis of clinical samples. In the study presented here, DLC1 was overexpressed in the SCP2 breast cancer cells, and the control SCP2 and overexpression cells were treated with TGFbeta. Microarray profiling of mRNA levels was performed in the control and overexpression cells with or without TGFbeta treatment.
2013-12-19 | E-GEOD-46214 | biostudies-arrayexpress