NUMB suppression by miR-9-5P enhances CD44+ prostate cancer stem cell growth and metastasis.
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ABSTRACT:
SUBMITTER: Wang X
PROVIDER: S-EPMC8160147 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenesis. CSCs in many tumors--including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary--have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic capacities are enriched in the CD44(+) cell population, but whether miRNAs regulate CD44(+) prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target, was underexpressed in CD44(+) prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44(+) prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44(-) prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44(+) prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.
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Project description:As part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Li et al., 2015), that described how we intended to replicate selected experiments from the paper 'The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44' (Liu et al., 2011). Here we report the results. We found the microRNA, miR-34a, was expressed at twice the level in CD44+ prostate cancer cells purified from xenograft tumors (LAPC4 cells) compared to CD44- LAPC4 cells, whereas the original study reported miR-34a was underexpressed in CD44+ LAPC4 cells (Figure 1B; Liu et al., 2011). When LAPC4 cells engineered to express miR-34a were injected into mice, we did not observe changes in tumor growth or CD44 expression; however, unexpectedly miR-34a expression was lost in vivo. In the original study, LAPC4 cells expressing miR-34a had a statistically significant reduction in tumor regeneration and reduced CD44 expression compared to control (Figure 4A and Supplemental Figures 4A,B and 5C; Liu et al., 2011). Furthermore, when we tested if miR-34a regulated CD44 through binding sites in the 3'UTR we did not find a statistically significant difference, whereas the original study reported miR-34a decreased CD44 expression that was partially abrogated by mutation of the binding sites in the CD44 3'UTR (Figure 4D; Liu et al., 2011). Finally, where possible, we report meta-analyses for each result.
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Project description:BackgroundThe long non-coding RNA (lncRNA), MALAT1, plays a key role in the development of different cancers, and its expression is associated with worse prognosis in patients. However, its mechanism of action and its regulation are not well known in prostate cancer (PCa). A general mechanism of action of lncRNAs is their interaction with other epigenetic regulators including microRNAs (miRNAs).MethodsUsing lentiviral stable miRNA transfection together with cell biology functional assays and gene expression/target analysis, we investigated the interaction between MALAT1 and miR-423-5p, defined as a target with in silico prediction analysis, in PCa.ResultsThrough bioinformatic analysis of data available from TCGA, we have found that MALAT1 expression correlates with high Gleason grade, metastasis occurrence, and reduced survival in PCa patients. These findings were validated on a TMA of PCa showing a significant correlation between MALAT1 expression with both stage and grading. We report that, in PCa cells, MALAT1 expression and activity is regulated by miR-423-5p that binds MALAT1, downregulates its expression and inhibits its activity in promoting proliferation, migration, and invasion. Using NanoString analysis, we unraveled downstream cell pathways that were affected by miR-423-5p expression and MALAT1 downregulation and identified several alterations in genes that are involved in metastatic response and angiogenic pathways. In addition, we showed that the overexpression of miR-423-5p increases survival and decreases metastases formation in a xenograft mouse model.ConclusionsWe provide evidence on the role of MALAT1 in PCa tumorigenesis and progression. Also, we identify a direct interaction between miR-423-5p and MALAT1, which results in the suppression of MALAT1 action in PCa.
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Project description:Prostate cancer (PCa) has become the most frequently occurring cancer among western men according to the latest report, and patients' prognosis is often poor in the event of tumor progression, therefore, many researches are devoted to exploring the molecular mechanism of PCa metastasis. MicroRNAs (miRNA) have proved to play an important role in this process. In present study, by combining clinical samples with public databases, we found that miR-629-5p increased to varying degrees in primary localized PCa tissues and metastatic PCa tissues compared with adjacent normal tissues, and bioinformatics analysis suggested that high level of miR-629-5p was related to poor prognosis. Functionally, miR-629-5p drove PCa cell proliferation, migration and invasion in vitro, and promoted growth of PCa cells in vivo. Moreover, A-kinase Anchor Protein 13 (AKAP13) was screened as a direct target of miR-629-5p, that expression was negatively correlated with the malignant phenotype of tumor cells. In the end, through verification in clinical specimens, we found that AKAP13 could be independently used as a clinical prognostic indicator. Overall, the present study indicates that miR-629-5p plays an oncogenic role in PCa by targeting AKAP13, which provides a new idea for clinical diagnosis and treatment of complex refractory PCa.
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Project description:PurposeDistal metastases are a major cause of poor prognosis in colorectal cancer patients. Approximately 95% of metastatic colorectal cancers are defined as DNA mismatch repair proficient (pMMR). Our previous study found that miR-6511b-5p was downregulated in pMMR colorectal cancer. However, the mechanism of miR-6511b-5p in pMMR colorectal cancer metastases remain unclear.MethodsWe first used quantitative real-time PCR to evaluate the role of miR-6511b-5p in colorectal cancer. Second, we conducted invasion assays and wound healing assays to investigate the role of miR-6511b-5p and CD44 in colorectal cancer cells metastases. Third, luciferase reporter assay, in situ hybridization (ISH), and immunohistochemistry assays were performed to study the relationship between miR-6511b-5p and BRG1. Finally, real-time quantitative PCR, immunohistochemistry, and chromatin immunoprecipitation (ChIP) assays were performed to analyze the relationship between BRG1 and CD44 in colorectal cancer.ResultsWe found that lower expression of miR-6511b-5p appeared more often in pMMR colorectal cancer patients compared with dMMR (mismatch repair deficient) cases, and was positively correlated with metastases. In vitro, overexpression of miR-6511b-5p inhibited metastasis by decreasing CD44 expression via directly targeting BRG1 in colorectal cancer. Furthermore, BRG1 knockdown decreased the expression of CD44 by promoting CD44 methylation in colorectal cancer cells.ConclusionOur data suggest that miR-6511b-5p may act as a promising biomarker and treatment target for pMMR colorectal cancer, particularly in metastatic patients. Mechanistically, miR-6511b-5p suppresses invasion and migration of colorectal cancer cells through methylation of CD44 via directly targeting BRG1.
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Project description:In cancer cells, microRNAs (miRNAs) are often aberrantly expressed resulting in impaired mRNA translation. In this study we show that miR-193b and miR-30c-1* inhibit, whereas miR-576-5p accelerates invasion of various human melanoma cell lines. Using Boyden chamber invasion assays the effect of selected miRNAs on the invasive capacity of various human melanoma cell lines was analyzed. Upon gene expression profiling performed on transfected A375 cells, CTGF, THBS1, STMN1, BCL9, RAC1 and MCL1 were identified as potential targets. For target validation, qPCR, Western blot analyses or luciferase reporter assays were applied. This study reveals opposed effects of miR-193b / miR-30c-1* and miR-576-5p, respectively, on melanoma cell invasion and on expression of BCL9 and MCL1, possibly accounting for the contrasting invasive phenotypes observed in A375 cells transfected with these miRNAs. The miRNAs studied and their targets identified fit well into a model proposed by us explaining the regulation of invasion associated genes and the observed opposed phenotypes as a result of networked direct and indirect miRNA / target interactions. The results of this study suggest miR-193b and miR-30c-1* as tumor-suppressive miRNAs, whereas miR-576-5p appears as potential tumor-promoting oncomiR. Thus, miR-193b and miR-30c-1* mimics as well as antagomiRs directed against miR-576-5p might become useful tools in future therapy approaches against advanced melanoma.
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Project description:RhoGDI2 specifically suppresses bladder cancer metastasis but not primary tumor growth, which involves tumor-associated macrophages. We report that macrophage-secreted osteopontin binds to CD44s on the tumor cells and promotes invasion and clonal growth. These effects are RhoGDI2-sensitive and require CD44s binding to the Rac GEF TIAM1. Osteopontin expression correlates with tumor aggressiveness and poor clinical outcome in patients. Inhibiting this pathway potently blocked lung and lymph node metastasis; however, primary tumors and established metastasis were less sensitive. Osteopontin-CD44s-TIAM1 promotes clonal growth in vitro but not at high cell density. These data identify osteopontin-CD44-TIAM1-Rac1 axis as a RhoGDI2-sensitive pathway and potential therapeutic target in bladder cancer metastasis. They also elucidate the mechanism behind RhoGDI2 specificity for metastasis over established tumors.
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Project description:Whether serine protease inhibitor Kazal type 1 (SPINK1) being associated with enzalutamide (Enz) resistance and metastasis of castration-resistant prostate cancer (CRPC) has not been clear. SPINK1 promoted Enz resistance by upregulating Androgen receptor splicing variant 7 (ARv7), and enhanced the invasion/migration of Enz-resistant cells via ERK/p38/ MMP9 signaling. Furthermore, miR-5089-5p suppressed SPINK1 mRNA through direct binding to its 3'UTR, and reversed its pro-proliferative and pro-metastatic effects. Mice bearing SPINK1-knockdown Enz-resistant PCa tumors showed significantly longer survival compared with those bearing wild-type tumors, while treatment with miR-5089-5p inhibitor abrogated the protective effects of SPINK1 knockdown. Taken together, SPINK1 can be used as a biomarker of resistance to Enz, and the miR-5089-5p/SPINK1/MAPK/MMP9 axis is a suitable therapeutic target against Enz-resistant and metastatic CRPC.Methods: The expression of SPINK1 in Enz-resistant prostate cancer (PCa) cell lines was detected through next-generation sequencing data and metastatic PCa patients. In vivo and in vitro experiments were performed to investigate the role of SPINK1 in Enz-resistance and metastasis.
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Project description:The prime issue derived from prostate cancer (PCa) is its high prevalence to metastasize to bone. MicroRNA-204-5p (miR-204-5p) has been reported to be involved in the development and metastasis in a variety of cancers. However, the clinical significance and biological functions of miR-204-5p in bone metastasis of PCa are still not reported yet. In this study, we find that miR-204-5p expression is reduced in PCa tissues and serum sample with bone metastasis compared with that in PCa tissues and serum sample without bone metastasis, which is associated with advanced clinicopathological characteristics and poor bone metastasis-free survival in PCa patients. Moreover, upregulation of miR-204-5p inhibits the migration and invasion of PCa cells in vitro, and importantly, upregulating miR-204-5p represses bone metastasis of PCa cells in vivo. Our results further demonstrated that miR-204-5p suppresses invasion, migration, and bone metastasis of PCa cells via inactivating nuclear factor ?B (NF-?B) signaling by simultaneously targeting TRAF1, TAB3, and MAP3K3. In clinical PCa samples, miR-204-5p expression negatively correlates with TRAF1, TAB3, and MAP3K3 expression and NF-?B signaling activity. Therefore, our findings reveal a new mechanism underpinning the bone metastasis of PCa, as well as provide evidence that miR-204-5p might serve as a novel serum biomarker in bone metastasis of PCa. This study identifies a novel functional role of miR-204-5p in bone metastasis of prostate cancer and supports the potential clinical value of miR-204-5p as a serum biomarker in bone metastasis of PCa.
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