CXCR7-mediated progression of osteosarcoma in the lungs.
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ABSTRACT:
SUBMITTER: Goguet-Surmenian E
PROVIDER: S-EPMC3776992 | biostudies-other | 2013 Sep
REPOSITORIES: biostudies-other
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Project description:BackgroundIt has been known for decades that circRNAs are deregulated in cancer. Here, we characterized the role and underlying mechanism of circ_0088212 in osteosarcoma.MethodsThe expression levels of circ_0088212, miR-520 h, and APOA1 were determined by RT-qPCR. RNase R digestion was performed to verify the circular structure of circ_0088212. CCK8 and transwell invasion assays were conducted to examine the in vitro malignancy of osteosarcoma. Caspase-3 activity was also measured. An in vivo model of osteosarcoma was constructed to examine the in vivo effect of circ_0088212 on osteosarcoma. Luciferase reporter, RNA RIP, and RNA pull-down assays were performed to verify the interaction between miR-520 h and APOA1 or circ_0088212.ResultsCirc_0088212 and APOA1 were expressed at low levels in osteosarcoma tissues and cells, while miR-520 h was highly expressed. Overexpression of circ_0088212 was found to inhibit the in vitro and in vivo growth of osteosarcoma. Mechanistically, miR-520 h was the target of circ_0088212 and APOA1 was the target of miR-520 h. Circ_0088212 downregulated miR-520 h expression, while miR-520 h overexpression abolished the inhibitory effect of circ_0088212 on osteosarcoma cell proliferation and migration. Furthermore, miR-520 h overexpression led to reduced APOA1 expression, while APOA1 overexpression counteracted the oncogenic effect of miR-520 h in osteosarcoma cells.ConclusionOur findings demonstrated that circ_0088212 might exert a tumor-suppressive activity in osteosarcoma by sponging and sequestering miR-520 h away from APOA1. This suggests that the circ_0088212/miR-520 h/APOA1 axis may be a promising therapeutic target for osteosarcoma intervention.
| S-EPMC8461379 | biostudies-literature
Project description:Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents and children. The pathogenesis of this disease is complex and the mechanisms involved have not been fully elucidated. Thioredoxin-interacting protein (TXNIP), as a member of the α-rhodopsin inhibitory protein family, can combine with thioredoxin to inhibit its antioxidant function. This process inhibits glucose absorption and metabolic rearrangement necessary for the regulation of cellular growth. In recent years, TXNIP has emerged as a new candidate target for tumors. However, the biological function and role of TXNIP in OS remains unclear. This study confirmed the low expression of TXNIP in OS tissues and cells, which was significantly related to the poor survival rate and clinical characteristics of patients with OS. Various cell phenotype experiments have shown that TXNIP inhibits the proliferation, migration, and invasion of OS cells, and promotes their apoptosis. Further studies found that the tumor suppressor effect of TXNIP was mediated by upregulating DNA damage-inducible transcript 4 (DDIT4) and inhibiting the phosphorylation of mechanistic target of rapamycin complex 1 (mTORC1) downstream substrate S6. Based on the above, our study explored the key role of TXNIP/DDIT4/mTORC1 suppression as a regulatory axis in the progression of OS, and laid the foundation for precise targeted therapy for OS.
| S-EPMC9442022 | biostudies-literature
Project description:The CXCL12/CXCR4 axis has been posited widely to have significant roles in many primary tumors and metastases. It is known that CXCR7 can also be engaged by CXCL12, but the exact function of CXCR7 is controversial. This prompted us to investigate the expression, specific function and signal transduction of CXCR7 in hepatocellular carcinoma (HCC). In this study, CXCR7 and CXCR4 were differentially expressed in nine cell lines of HCC, and that elevated expression of both CXCR7 and CXCL4 were correlated with highly metastatic ability of HCC cells. Moreover, CXCR7 expression was significantly upregulated in metastatic HCC samples compared with the non-metastatic ones by staining of high-density tissue microarrays constructed from a cohort of 48 human HCC specimens. CXCR7 overexpression enhanced cell growth and invasiveness in vitro, and tumorigenicity and lung metastasis in vivo. By contrast, CXCR7 stable knockdown markedly reduced these malignant behaviors. In addition, it was observed that alterations in CXCR7 expression were positively correlated with the phosphorylation levels of mitogen-activated protein kinase (MAPK) pathway proteins. Targeting extracellular regulated kinase pathway by using U0126 inhibitor or using CCX771, a selective CXCR7 antagonist, drastically reduced CXCR7-mediated cell proliferation. Importantly, by using human biotin-based antibody arrays, several differentially expressed proteins were identified in CXCR7-overexpression and depletion groups. Comparative analysis indicated that upstream regulators including TP53 and IL-6 were involved in CXCR7 signal transduction. CXCR7 expression was further proved to regulate expression of vascular endothelial growth factor A and galectin-3, which may contribute to tumor angiogenesis and invasiveness. Consequently, elevated expression of CXCR7 contributes to HCC growth and invasiveness via activation of MAPK and angiogenesis signaling pathways. Targeting CXCR7 may prevent metastasis and provide a potential therapeutic strategy for HCC.
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Project description:Osteosarcoma (OS) is the most common primary malignant neoplasm of the bone. Recent studies have indicated that the inhibitory effects of microRNA (miR)-324-3p could affect the development of numerous cancers. However, its biological roles and underlying mechanisms in OS progression remain unexplored. In this study, miR-324-3p expression was markedly reduced in OS cell lines and tissues. Functionally, miR-324-3p overexpression suppressed OS progression and was involved in the Warburg effect. Mechanistically, miR-324-3p negatively regulated phosphoglycerate mutase 1 (PGAM1) expression by targeting its 3'-UTR. Moreover, high expression of PGAM1 promoted OS progression and aerobic glycolysis, which were associated with inferior overall survival in patients with OS. Notably, the tumor suppressor functions of miR-324-3p were partially recovered by PGAM1 overexpression. In summary, the miR-324-3p/PGAM1 axis plays an important role in regulating OS progression by controlling the Warburg effect. Our results provide mechanistic insights into the function of miR-324-3p in glucose metabolism and subsequently on the progression of OS. Targeting the miR-324-3p/PGAM1 axis could be a promising molecular strategy for the treatment of OS.
| S-EPMC10236611 | biostudies-literature
Project description:Osteosarcoma (OS), the most common primary malignancy of the bone, has a poor prognosis due to its high mortality rate and high potential for metastasis. Thus, it is urgently necessary to explore functional molecular targets of therapeutic strategies for osteosarcoma. Here, we reported that TIPE1 expression was decreased in osteosarcoma tissues compared to normal and adjacent nontumor tissues, and its expression was negatively related to tumor stage and tumor size. Functional assays showed that TIPE1 inhibited osteosarcoma carcinogenesis and metastatic potential both in vivo and in vitro. Furthermore, we investigated that the STAT3 signaling pathway was significantly downregulated after TIPE1 overexpression. Mechanistically, TIPE1 bind to the catalytic domain of PRMT1, which deposits an asymmetric dimethylarginine (ADMA) mark on histone/non-histone proteins, and thus inhibited PRMT1 mediated STAT3 methylation at arginine (R) residue 688. This abolished modification decreased STAT3 transactivation and expression, by which subsequently suppressed osteosarcoma malignancy. Taken together, these data showed that TIPE1 inhibits the malignant transformation of osteosarcoma through PRMT1-mediated STAT3 arginine methylation and ultimately decreases the development and metastasis of osteosarcoma. TIPE1 might be a potential molecular therapeutic target and an early biomarker for osteosarcoma diagnosis.
| S-EPMC9508122 | biostudies-literature
Project description:UNLABELLED:The atypical 7-transmembrane chemokine receptor, CXCR7, transactivates the EGFR leading to increased tumor growth in several tumor types. However, the molecular mechanism of CXCR7 ligand-independent EGFR transactivation is unknown. We used cDNA knock-in, RNAi and analysis of mitogenic signaling components in both normal prostate epithelial cells and prostate cancer cells to decipher the proliferation-inducing mechanism of the CXCR7-EGFR interaction. The data demonstrate that CXCR7-induced EGFR transactivation is independent of both the release of cryptic EGFR ligands (e.g., AREG/amphiregulin) and G-protein-coupled receptor signaling. An alternate signaling mechanism involving ?-arrestin-2 (ARRB2/?-AR2) was examined by manipulating the levels of ?-AR2 and analyzing changes in LNCaP cell growth and phosphorylation of EGFR, ERK1/2, Src, and Akt. Depletion of ?-AR2 in LNCaP cells increased proliferation/colony formation and significantly increased activation of Src, phosphorylation of EGFR at Tyr-1110, and phosphorylation/activation of ERK1/2 compared with that with control shRNA. Moreover, ?-AR2 depletion downregulated the proliferation suppressor p21. Stimulation of ?-AR2-expressing cells with EGF resulted in rapid nuclear translocation of phosphorylated/activated EGFR. Downregulation of ?-AR2 enhanced this nuclear translocation. These results demonstrate that ?-AR2 is a negative regulator of CXCR7/Src/EGFR-mediated mitogenic signaling. IMPLICATIONS:This study reveals that ?-AR2 functions as a tumor suppressor, underscoring its clinical importance in regulating CXCR7/EGFR-mediated tumor cell proliferation. Mol Cancer Res; 14(5); 493-503. ©2016 AACR.
| S-EPMC4867265 | biostudies-literature
Project description:Long noncoding RNAs (lncRNAs) have been certified as important regulators in tumorigenesis. LncRNA GAS6-AS2 (GAS6-AS2) was a newly identified tumor-related lncRNA, and its dysregulation and oncogenic effects in melanoma and bladder cancer had been reported in previous studies. However, the expression pattern and potential function of GAS6-AS2 in osteosarcoma (OS) have not been investigated. In this study, we identified a novel OS-related lncRNA GAS6-AS2. We found that GAS6-AS2 was distinctly upregulated in both OS specimens and cell lines. Distinct up-regulation of GAS6-AS2 in OS was correlated with advanced clinical stages and shorter survivals. In addition, USF1 could directly bind to the GAS6-AS2 promoter and contribute to its overexpression. Furthermore, GAS6-AS2 knockdown caused tumor suppressive effects via reducing cellular proliferation, migration and invasion, and promoting OS cell apoptosis. Besides, GAS6-AS2 directly bound to miR-934 and downregulated its expression. Mechanistically, GAS6-AS2 positively regulated the expression of BCAT1 through sponging miR-934. Taken together, our data illustrated how GAS6-AS2 played an oncogenic role in OS and might offer a potential therapeutic target for treating OS.
| S-EPMC7185141 | biostudies-literature
Project description:Osteosarcoma is a bone tumor frequently diagnosed in children and young adults. Despite advances in chemotherapy and surgical resection, tumors metastasize in 30% of osteosarcoma patients. In addition, side effects caused by chemotherapeutic drugs, as well as the development of chemoresistance, highlight the need to identify the molecular mechanisms involved in the pathogenesis of osteosarcoma. We compared 65 osteosarcoma samples to their adjacent normal tissues, as well as commercially obtained osteosarcoma cell lines with normal osteoblast cell lines, and identified a role for the microRNA (miR)-140/ubiquitin-specific protease 22 (USP22)/lysine-specific demethylase 1 (LSD1)/p21 axis in the development of osteosarcoma. Osteosarcoma tissues and cells exhibited poor miR-140 and p21 expression, whereas the expression of USP22 and LSD1 was increased. Overexpression of miR-140 inhibited cell proliferation, migration, and invasion and promoted cell apoptosis by directly targeting USP22, resulting in its decreased expression. Overexpression of USP22 reversed the effects of miR-140 overexpression in osteosarcoma cells. Overexpression of miR-140 or USP22 knockdown led to the ubiquitination and degradation of LSD1. miR-140 overexpression also suppressed tumorigenesis in vivo. This study revealed a role for miR-140 in the restriction of osteosarcoma development and identified miR-140 as a potential target for therapeutic intervention.
| S-EPMC8040122 | biostudies-literature
Project description:BackgroundOsteosarcoma (OS) is a highly malignant primary bone tumor. Family of homology 60A (FAM60A) reportedly contributes to the malignant growth of some tumors.MethodsHerein we investigated the mRNA expression level of FAM60A by combining OS and non-cancer samples from public databases. Immunohistochemistry was performed to determine protein expression levels of FAM60A in patients with OS. Further, RT-qPCR and western blotting were conducted to evaluate FAM60A expression in various OS cell lines. CCK-8 assay, colony formation assay, and flow cytometry were applied to determine the function of FAM60A. Finally, functional enrichment analysis was performed based on FAM60A co-expressed genes.ResultsFAM60A mRNA expression level was found to be significantly upregulated (standardized mean difference = 1.27, 95% CI [0.67-1.88]). Survival analyses suggested that higher expression of FAM60A was indicative of poor prognoses. Similarly, FAM60A protein expression level was also observed to be upregulated. Knocking down FAM60A expression inhibited OS cell proliferation, increased apoptosis, and blocked cells from entering the S phase. Besides, cell cycle was the most prominently enriched pathway, and BUB1, DTL, and EXO1 were identified as hub genes.ConclusionsFAM60A expression was found to be markedly upregulated in OS; furthermore, FAM60A was observed to promote OS cell proliferation, inhibit apoptosis, and participate in cell cycle regulation. Besides, FAM60A may interact with hub genes to participate in the progress of OS.
| S-EPMC10501228 | biostudies-literature
Project description:BackgroundLiver and lung metastases are the predominant cause of colorectal cancer (CRC)-related mortality. Chemokine-receptor pairs have a critical role in determining the metastatic progression of tumours. Our hypothesis was that disruption of CXCR7/CXCR7 ligands axis could lead to a decrease in CRC metastases.MethodsPrimary tumours and metastatic tissues from patients with CRC were tested for the expression of CXCR7 and its ligands. Relevance of CXCR7/CXCR7 ligands for CRC metastasis was then investigated in mice using small pharmacological CXCR7 antagonists and CRC cell lines of human and murine origins, which - injected into mice - enable the development of lung and liver metastases.ResultsFollowing injection of CRC cells, mice treated daily with CXCR7 antagonists exhibited a significant reduction in lung metastases. However, CXCR7 antagonists failed to reduce the extent of liver metastasis. Moreover, there were subtle differences in the expression of CXCR7 and its ligands between lung and liver metastases.ConclusionOur study suggests that the activation of CXCR7 on tumour blood vessels by its ligands may facilitate the progression of CRC within lung but not within liver. Moreover, we provide evidence that targeting the CXCR7 axis may be beneficial to limit metastasis from colon cancer within the lungs.
| S-EPMC3516689 | biostudies-literature