Che-1/miR-590-3p/TAZ axis sustains multiple myeloma disease.
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ABSTRACT:
SUBMITTER: Bruno T
PROVIDER: S-EPMC10997508 | biostudies-literature | 2024 Apr
REPOSITORIES: biostudies-literature
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Che-1/miR-590-3p/TAZ axis sustains multiple myeloma disease.
Bruno Tiziana T Catena Valeria V Corleone Giacomo G Cortile Clelia C Cappelletto Maria Chiara MC Bellei Barbara B De Nicola Francesca F Amadio Bruno B Gumenyuk Svitlana S Marchesi Francesco F Annibali Ombretta O Blandino Giovanni G Fanciulli Maurizio M Di Agostino Silvia S
Leukemia 20240217 4
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Project description:Multiple myeloma (MM) is a blood disease characterized by the malignant accumulation of monoclonal plasma cells in the bone marrow. Among the pathological consequences of the MM, defects in osteogenesis characterized by osteolytic lesions, osteopenia, and pathologic fractures are frequently described. Che-1/AATF (Che-1) is a co-transcriptional factor involved in MM transformation and proliferation. Here, we show that Che-1 expression in MM contributes to maintaining low level of WWTR1 (TAZ), a transcriptional coactivator downstream of the Hippo-signaling pathway. We report that the miR-590-3p, deriving from the mRNA splicing of the EIF4H host gene, can target TAZ, contributing to downregulating its expression in MM. Furthermore, we demonstrate by in vivo and in vitro experiments that Che-1 transcriptionally induces EIF4H gene. We provide data to support that miR-590-3p is secreted by MM cells in vitro and in vivo and that can inhibit TAZ levels and the physiological transcriptional expression of osteogenic-related genes, in mesenchymal stem cells. Our findings unveil an unexplored novel Che-1/miR-590-3p/TAZ axis in MM tumorigenesis by providing a rationale to explore the therapeutic potential of metastatic bone lesions.
2024-04-10 | GSE234642 | GEO
Project description:Che-1/miR-590-3p/TAZ axis sustains multiple myeloma disease
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Project description:Introduction:In East Asia, hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancer types. Long noncoding RNA (lncRNA) prostate androgen-regulated transcript 1 (PART1) was reported to play crucial roles in regulating cancer progression. However, roles and mechanisms of action of PART1 in hepatocellular carcinoma (HCC) still remain unknown. Methods:Quantitative real-time polymerase chain reaction (RT-qPCR) method was used to detect the PART1 expression level in HCC cells. Cell proliferation, colony formation, and transwell invasion assays were performed to investigate the biological roles of PART1 on HCC cell behaviors. Bioinformatic analysis methods were performed to analyze connections of microRNA-590-3p (miR-590-3p) with PART1 or high mobility group box 2 (HMGB2) in HCC. Moreover, expression levels of PART1, miR-590-3p, and HMGB2 in HCC tissues and normal tissues were analyzed at ENCORI. Results:PART1 expression was found to be significantly upregulated in HCC tissues and cells. Functionally, silencing of PART1 significantly suppressed HCC cell proliferation, colony formation and invasion in vitro, while forcing PART1 exerts opposite biological effects. Mechanically, miR-590-3p/HMGB2 axis was downstream target of PART1, and silencing of miR-590-3p or forcing of HMGB2 could rescue the stimulation effects of PART1 overexpression on HCC cell behaviors. Discussion:Our results provided evidence that PART1 serves as oncogenic lncRNA through sponging miR-590-3p to upregulate HMGB2 expression in HCC.
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Project description:BackgroundOxidative stress within the bone marrow niche of multiple myeloma contributes to disease progression and drug resistance. Recent studies have associated the Hippo pathway with miRNA biogenesis and oxidative stress in solid tumors. Oxidative stress and miRNA pathway inter-relates in several cancers. Our group recently showed that TAZ functions as a tumor suppressor in MM. However, the role of TAZ in oxidative stress in MM is unknown.AimsWe sought to examine the role of TAZ in myeloma cells' response to BM oxidative stress. We postulated that TAZ might be associated with an oxidative stress phenotype and distinct miRNA signature in MM.Methods and resultsUsing human myeloma cell lines and clinical samples, we demonstrate that TAZ promotes myeloma cells' sensitivity to oxidative stress and anticancer-induced cytotoxicity by inducing miR-224 to repress the NRF2 antioxidant program in MM. We show that low expression of TAZ protein confers an oxidative stress-resistant phenotype in MM. Furthermore, we provide evidence that overexpression of miR-224 in myeloma cells expressing low amounts of TAZ protein inhibits cell growth and enhances sensitivity to anti-myeloma therapeutics.ConclusionOur findings uncover a potential role for TAZ in oxidative stress response in MM via the miR-224-NRF2 molecular pathway. This provides the scientific ground to explore miR-224 as a potential molecular target to modify TAZ expression and enhance myeloma sensitivity to treatment.
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Project description:BackgroundThere is considerable evidence that microRNAs (miRNAs) regulate several key tumor-associated genes/pathways and may themselves have a dual regulatory function either as tumor suppressors or oncogenic miRNA, depending on the tumor type. MicroRNA-590-3p (miR-590-3p) is a small non-coding RNA involved in the initiation and progression of numerous tumors. However, its expression pattern and biological role in hepatocellular carcinoma (HCC) are controversial.ResultsIn the current work, computational and RT-qPCR analysis revealed that HCC tissues and cell lines exhibited miR-590-3p downregulation. Forced expression of miR-590-3p attenuated HepG2 cells proliferation, migration, and repressed EMT-related gene expression. Bioinformatic, RT-qPCR, and luciferase assays revealed that MDM2 is a direct functional target of miR-590-3p. Moreover, the knockdown of MDM2 mimicked the inhibitory effect of miR-590-3p in HepG2 cells.ConclusionWe have identified not only novel targets for miR-590-3p in HCC, but also novel target genes for miR590-3p/MDM2 pathway in HCC like SNAIL, SLUG, ZEB1, ZEB2, and N-cadherin. Furthermore, these findings demonstrate a crucial role for MDM2 in the regulatory mechanism of EMT in HCC.
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Project description:Colorectal cancer (CRC) is a prevalent malignancy worldwide. The development of genome sequencing technology has allowed the discovery that epigenetic regulation might play a critical role in CRC tumorigenesis. In the present study, we found that the long noncoding RNA (lncRNA) SNHG4 was dramatically increased in CRC tissue samples and cell lines based on both publicly available and experimental data. SNHG4 knockdown suppressed the viability and colony formation capacity of CRC cells. The expression of CDK1 was considerably increased in CRC tissue samples and cells and had a positive correlation with the expression of SNHG4 in CRC. SNHG4 silencing not only caused S phase cell cycle arrest but also significantly downregulated the CDK1, cyclin B1, and cyclin A2 protein levels in CRC cells. miR-590-3p simultaneously bound to SNHG4 and CDK1. miR-590-3p functioned to inhibit CDK1 expression. miR-590-3p overexpression exerted the same effects on the CRC cell phenotype as SNHG4 knockdown. The effects of si-SNHG4 on CRC cells were significantly reversed by anti-miR-590-3p, indicating that SNHG4 relieved the miR-590-3p-induced inhibition of CDK1 by acting as a competing endogenous RNA (ceRNA). In vivo, SNHG4 silencing inhibited subcutaneously transplanted tumor growth and decreased cell cycle marker levels, whereas miR-590-3p inhibition exerted the opposite effects. The in vivo effects of SNHG4 silencing were also reversed by miR-590-3p inhibition. The SNHG4/miR-590-3p/CDK1 axis influences the cell cycle to modulate CRC cell proliferation and subcutaneously transplanted tumor growth. Further application of this axis still requires analysis using more animal models and clinical investigations.
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Project description:Multiple myeloma (MM) is a hematopoietic malignancy characterized by heterogeneity, which corresponds to alternative splicing (AS) profiles and disadjust gene expression. Bioinformatics analysis of AS factors possibly related to MM progression identified the polypyrimidine tract binding protein (PTBP1) as candidate. The purpose of this study was to confirm the incidence and prognostic value of PTBP1 in MM patients. Several cohorts of 2971 patients presenting newly diagnosed and relapsed MM were enrolled. Correlations between PTBP1 expression and clinicopathological characteristics, proliferative activity, and response to therapy of myeloma cells were analyzed. Moreover, the effect of PTBP1 on the AS pattern of specific aerobic glycolysis-related genes was explored in MM patients. Clinically, PTBP1 expression was present at all stages; it increased with disease progression and poor prognosis, which was even stronger elevated in patients with high tumor burden and drug resistance. Mechanistically, PTBP1 modulated AS of PKM2 and aerobic glycolysis-related genes in MM patients, which play synergistic or additive effects in clinical outcome. PTBP1 may be a novel marker for prognostic prediction and a promising therapeutic target for the development of anti-MM treatments.
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Project description:Multiple myeloma (MM) is a hematologic malignancy that results from uncontrolled plasma cell proliferation. Circular RNAs are versatile regulators that influence cancer aggression. The pathogenic mechanism of circXPO1 in MM is still unknown. In this study, the expression of circXPO1, miR-495-3p, and DNA damage-induced transcription 4 (DDIT4) was detected. Knockdown and overexpression assays were used to evaluate the effect of circXPO1 on MM. Specifically, 5-ethynyl-2'-deoxyuridine and cell counting kit-8 assay were used to investigate cell proliferation. Meanwhile, flow cytometry was adopted to detect cell apoptosis and cell cycle. Apoptosis-associated and cell cycle-related proteins were detected by Western blot. Mechanistically, biotin RNA pull-down assay and dual-luciferase assay were implemented to verify the combination among miR495-3p and circXPO1 or DDIT4. The function of circXPO1 in vivo was explored in xenograft experiments. The results showed that circXPO1 was up-regulated in both MM samples and MM cell lines and miR-495-3p was down-regulated in MM patients. Silencing circXPO1 inhibited cell proliferation, increased apoptosis rates, and caused the G1 phase arrest. Overexpression of circXPO1 yielded opposite results. In addition, RNA pull-down experiment demonstrated the interaction between circXPO1 and miR-495-3p. Silencing miR-495-3p rescued the inhibitory function caused by the knockdown of circXPO1. DDIT4 was the target of miR-495-3p. Finally, silencing circXPO1 inhibited the growth of subcutaneous tumors in vivo. In conclusion, our findings showed that circXPO1 could promote MM progression via the miR-495-3p/DDIT4 axis.
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