OIP5-AS1 modulates epigenetic regulator HDAC7 to enhance non-small cell lung cancer metastasis via miR-140-5p.
ABSTRACT: Long non-coding RNAs have been reported to be involved in non-small cell lung cancer (NSCLC) progression. However, whether Opa-interacting protein 5 antisense RNA 1 (OIP5-AS1) serves a role in NSCLC remains unclear. Bioinformatics analysis of The Cancer Genome Atlas datasets showed clinical significance and relevance of OIP5-AS1 in NSCLC. Western blotting and reverse transcription-quantitative PCR revealed protein and RNA expression levels of the genes [including OIP5-AS1, microRNA (miR)-140-5p, histone deacetylase 7 (HDAC7) and vascular endothelial growth factor A (VEGFA)]. Direct associations between the genes (miR-140-5p and OIP5-AS1, or miR-140-5p and HDAC7) were confirmed using a dual-luciferase reporter assay. Lymphatic vessel formation and invasion ability were detected using a lymphatic vessel formation assay and Transwell invasion assay. OIP5-AS1 knockdown attenuated lymphatic vessel length and invasion. The role of OIP5-AS1 was reverted by miR-140-5p. HDAC7 and VEGFA are downstream effectors of miR-140-5p-mediated NSCLC metastasis. OIP5-AS1, miR-140-5p, HDAC7 and VEGFA were all dysregulated in human clinical NSCLC tumor tissues. In conclusion, the present results demonstrated a novel mechanism for OIP5-AS1-induced metastatic phenotypes of NSCLC via the miR-140-5p/HDAC7/VEGFA axis.
Project description:Long noncoding RNAs (lncRNAs) have been reported to play a significant role in the occurrence and progression of tumors. In different tumors, they can either act as an oncogene or tumor suppressor via modulating various target mRNAs. OIP5-AS1 belongs to lncRNA family. It has been reported to be involved in the tumorigenesis of some cancers, such as bladder cancer, gastric cancer, and multiple myeloma. However, the role it plays in hepatocellular carcinoma (HCC) remains unclear. This study aims to explore the inherent mechanism of lncRNA OIP5-AS1 in HCC. In the first place, qRT-PCR found that OIP5-AS1 and VEGFA expressions were significantly increased while miR-3163 was obviously reduced in HCC cells and tissues. Next, a series of functional experiments found that knockdown of OIP5-AS1 suppressed HCC cell proliferation, migration and angiogenesis abilities while promoting cell apoptosis simultaneously. Last but not least, miR-3163 inhibition or VEGFA overexpression can reverse the anti-tumor effect of OIP5-AS1. In summary, OIP5-AS1 affects HCC proliferation, metastasis, and angiogenesis in HCC by regulating VEGFA expression through sponging miR-3163.
Project description:Nasopharyngeal carcinoma (NPC) is often associated with the infection of Epstein-Barr virus in nasopharynx and is mainly happened in South China and Southeast Asia. Recently, noncoding RNAs have been reported to regulate NPC carcinogenesis. LncRNA OIP5-AS1 participates in tumorigenesis and progression; however, the inherent mechanism of OIP5-AS1-mediated progression of NPC is unclear. In the current study, we aimed to explore the role of OIP5-AS1 in NPC progression. We measured the cell viability, apoptosis, migration, and invasion in NPC cells after OIP5-AS1 modulation. Moreover, we determined whether OIP5-AS1 exerts its oncogenic functions <i>via</i> sponging miR-183-5p in NPC. Furthermore, we determined whether glutamate ammonia ligase (GLUL) was a downstream target of miR-183-5p. We found that OIP5-AS1 downregulation inhibited the viability, migration and invasion of NPC <i>via</i> targeting miR-183-5p. We also identified that GLUL might be a potential downstream target of miR-183-5p in NPC cells. Mechanistically, OIP5-AS1 promotes cell motility <i>via</i> regulating miR-183-5p and GLUL in NPC cells. We concluded that OIP5-AS1 performed its biological functions <i>via</i> targeting miR-183-5p and GLUL in NPC cells.
Project description:<b>Background:</b> Long non-coding RNAs (lncRNAs) have been implicated in the pathogenesis of atherosclerosis. LncRNA OIP5 antisense RNA 1 (OIP5-AS1) has been found to be associated with the development of atherosclerosis. In this study, we further investigated the molecular basis of OIP5-AS1 in atherosclerosis pathogenesis. <b>Methods:</b> Oxidative low-density lipoprotein (ox-LDL) was used to treat human umbilical vein endothelial cells (HUVECs). The levels of OIP5-AS1, miR-135a-5p, and Krüppel-like factor 5 (KLF5) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Cell viability, migration, and apoptosis were evaluated using the Cell Counting Kit-8 (CCK-8), Transwell, and flow cytometry, respectively. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and malondialdehyde (MDA) were determined with enzyme-linked immunosorbent assay (ELISA). Targeted interactions among OIP5-AS1, miR-135a-5p, and KLF5 were confirmed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Animal studies were performed to assess the role of OIP5-AS1 in atherosclerosis progression <i>in vivo</i>. <b>Results:</b> Our data showed the significant upregulation of OIP5-AS1 in atherosclerosis serum and ox-LDL-stimulated HUVECs. The silencing of OIP5-AS1 protected against ox-LDL-triggered cytotoxicity in HUVECs and diminished lipids secretion in ApoE<sup>-/-</sup> mice. Moreover, OIP5-AS1 functioned as a molecular sponge of miR-135a-5p, and miR-135a-5p was a functional mediator of OIP5-AS1 in regulating ox-LDL-induced HUVEC injury. KLF5 was a direct target of miR-135a-5p, and the increased expression of miR-135a-5p alleviated ox-LDL-induced cytotoxicity by downregulating KLF5. Furthermore, OIP5-AS1 influenced KLF5 expression through sponging miR-135a-5p. <b>Conclusion:</b> The current work identified that the silencing of OIP5-AS1 protected against ox-LDL-triggered cytotoxicity in HUVECs at least in part by influencing KLF5 expression via acting as a miR-135a-5p sponge.
Project description:Several studies have shown an important role for long non-coding RNA (lncRNA) in breast cancer progression. The present study investigated the role of lncRNA Opa interacting protein 5-antisense RNA 1 (OIP5-AS1) in the progression of breast cancer. OIP5-AS1 was significantly upregulated in breast cancer tissues and in breast cancer cell lines, and OIP5-AS1 downregulation inhibited the malignant behavior of breast cancer in vitro and in vivo. For in-depth exploration of the mechanism of OIP5-AS1 in breast cancer, we found that expression of microRNA-129-5p(miR-129-5p), which was found to bind sites in the sequence of OIP5-AS1, in breast cancer tissues was negatively correlated with OIP5-AS1. Also, luciferase assays indicated that OIP5-AS1 acted as a miR-129-5p sponge, resulting in upregulated expression of the sex-determining region Y-box 2 (SOX2) transcription factor. Our study showed that OIP5-AS1 plays a critical role in promoting breast cancer progression and that OIP5-AS1 downregulation targets SOX2 by miR-129-5p upregulation.
Project description:Lung cancer is the most common type of cancer worldwide, the most prevalent form of which is non?small cell lung cancer (NSCLC). MicroRNAs (miRs) are involved in the progression of NSCLC; however, the specific function of miR?140?5p in NSCLC remains unclear. The present study demonstrated that miR?140?5p was downregulated in the tumor tissues of patients with NSCLC, and it was associated with a poor prognosis. Furthermore, miR?140?5p significantly suppressed cell migration and invasion of the NSCLC cell line A549. In addition, the direct regulatory effect of miR?140?5p on vascular endothelial growth factor?A (VEGFA) was predicted by TargetScan and verified using a luciferase reporter gene assay. The present study also hypothesized that miR?140?5p may inhibit the expression of phosphorylated?protein kinase B by targeting VEGFA. In conclusion, miR?140?5p may be a potential target for the development of anti?neoplastic therapies in lung cancer.
Project description:Kaposi's sarcoma (KS), a highly disseminated tumor of hyperproliferative spindle endothelial cells, is the most common AIDS-associated malignancy caused by infection of Kaposi's sarcoma-associated herpesvirus (KSHV). KSHV-encoded viral interferon regulatory factor 1 (vIRF1) is a viral oncogene but its role in KSHV-induced tumor invasiveness and motility remains unknown. Here, we report that vIRF1 promotes endothelial cell migration, invasion and proliferation by down-regulating miR-218-5p to relieve its suppression of downstream targets high mobility group box 2 (HMGB2) and cytidine/uridine monophosphate kinase 1 (CMPK1). Mechanistically, vIRF1 inhibits p53 function to increase the expression of DNA methyltransferase 1 (DNMT1) and DNA methylation of the promoter of pre-miR-218-1, a precursor of miR-218-5p, and increases the expression of a long non-coding RNA OIP5 antisense RNA 1 (lnc-OIP5-AS1), which acts as a competing endogenous RNA (ceRNA) of miR-218-5p to inhibit its function and reduce its stability. Moreover, lnc-OIP5-AS1 increases DNA methylation of the pre-miR-218-1 promoter. Finally, deletion of vIRF1 from the KSHV genome reduces the level of lnc-OIP5-AS1, increases the level of miR-218-5p, and inhibits KSHV-induced invasion. Together, these results define a novel complex lnc-OIP5-AS1/miR-218-5p network hijacked by vIRF1 to promote invasiveness and motility of KSHV-induced tumors.
Project description:Breast cancer is the most common invasive cancer in women with the highest number of related deaths which is caused by distal metastasis. Recently, integrated analysis of gene expression profile suggested widespread gene dysregulation in various types of cancer. Research in the past decade has focused on long non?coding RNAs (lncRNAs), particularly in cell proliferation, tumor progression and metastasis. OPA?interacting protein 5 antisense transcript 1 (OIP5?AS1) is an evolutionarily conserved long non?coding RNA that has been linked to oncogenesis in multiple cancers. In breast cancer, dysregulation of OIP5?AS1 was reported but the precise role in cancer development and progression remains unclear. In the present study, using small interfering RNA (siRNA) targeting OIP5?AS1, it was shown that knockdown of OIP5?AS1 was associated with alteration of EMT markers and suppressed migration and invasion of breast cancer cells. Among the EMT?related transcription factors, ZEB1 and ZEB2 were significantly downregulated with OIP5?AS1 knockdown. Computational analysis and a dual?luciferase reporter system identified miR?340?5p was the target gene for OIP5?AS1. Further experiments verified the function of OIP5?AS1 in cell invasion was dependent on miR?340a?5p through regulating target gene ZEB2. In vivo study demonstrated that overexpressing OIP5?AS1 in breast cancer cells promoted lung metastasis in nude mice. The findings of the present study revealed the mechanism of OIP5?AS1 in breast cancer metastasis. Overall, our study may provide a potential therapeutic target for breast cancer metastasis.
Project description:Background: Resistance to tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML) remains a problem in clinical treatment, and the mechanism has not been fully clarified. Autophagy can protect cancer cells under chemotherapeutic stimulation. Long noncoding RNAs (lncRNAs) are critical in drug resistance of CML. The role of lncRNAs in autophagy and drug resistance of CML needs to be further explored. Methods: Western blot and immunofluorescence were used to evaluate the autophagy activity in the drug-resistant CML cell line K562/G01 and its parental cell line K562. Then the sensitivity of K562/G01 cells to the first generation TKI imatinib (IM) after autophagy inhibition was determined by CCK-8 assays. The lncRNA OIP5-AS1 related to the drug resistance of CML cells was determined by Gene Expression Omnibus database analysis. Western blot and drug-sensitivity assays were used to detect changes in autophagy and sensitivity to the IM in resistant CML cells after OIP5-AS1 knockdown. The interactions of OIP5-AS1, miR-30e-5p, and ATG12 were explored by RNA immunoprecipitation and dual-luciferase reporter assays. Results: In this study, we found that autophagy was associated with drug resistance in CML cells. Moreover, the upregulation of OIP5-AS1 in K562/G01 cells was related to the enhancement of autophagy. Knockdown of OIP5-AS1 suppressed autophagy and enhanced the sensitivity of K562/G01 cells to IM. Furthermore, OIP5-AS1 regulated ATG12 by competitively binding miR-30e-5p, thereby affecting autophagy-related drug resistance. Conclusion: Our study reveals that OIP5-AS1 promotes the autophagy-related IM resistance in CML cells by regulating miR-30e-5p/ATG12 axis, providing new insights into the drug resistance mechanism of CML.
Project description:<h4>Background</h4>Acute lung injury (ALI) is a pulmonary disorder that leads to acute respiration failure and thereby results in a high mortality worldwide. Increasing studies have indicated that toll-like receptor 4 (TLR4) is a promoter in ALI, and we aimed to explore the underlying upstream mechanism of TLR4 in ALI.<h4>Methods</h4>We used lipopolysaccharide (LPS) to induce an acute inflammatory response in vitro model and a murine mouse model. A wide range of experiments including reverse transcription quantitative polymerase chain reaction, western blot, enzyme linked immunosorbent assay, flow cytometry, hematoxylin-eosin staining, RNA immunoprecipitation, luciferase activity and caspase-3 activity detection assays were conducted to figure out the expression status, specific role and potential upstream mechanism of TLR4 in ALI.<h4>Result</h4>TLR4 expression was upregulated in ALI mice and LPS-treated primary bronchial/tracheal epithelial cells. Moreover, miR-26a-5p was confirmed to target TLR4 according to results of luciferase reporter assay. In addition, miR-26a-5p overexpression decreased the contents of proinflammatory factors and inhibited cell apoptosis, while upregulation of TLR4 reversed these effects of miR-26a-5p mimics, implying that miR-26a-5p alleviated ALI by regulating TLR4. Afterwards, OPA interacting protein 5 antisense RNA 1 (OIP5-AS1) was identified to bind with miR-26a-5p. Functionally, OIP5-AS1 upregulation promoted the inflammation and miR-26a-5p overexpression counteracted the influence of OIP5-AS1 upregulation on cell inflammatory response and apoptosis.<h4>Conclusion</h4>OIP5-AS1 promotes ALI by regulating the miR-26a-5p/TLR4 axis in ALI mice and LPS-treated cells, which indicates a promising insight into diagnostics and therapeutics in ALI.
Project description:Hypoxia reprogrammed glucose metabolism affects the Warburg effect of tumor cells, but the mechanism is still unclear. Long-chain non-coding RNA (lncRNA) has been found by many studies to be involved in the Warburg effect of tumor cells under hypoxic condition. Herein, we find that lncRNA OIP5-AS1 is up-regulated in cervical cancer tissues and predicts poor 5-years overall survival in cervical cancer patients, and it promotes cell proliferation of cervical cancer cells <i>in vitro</i> and <i>in vivo</i>. Moreover, OIP5-AS1 is a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis which is IDH2 or hypoxia inducible factor-1α (HIF-1α) dependent. In cervical cancer cells, OIP5-AS1 promotes IDH2 expression by inhibiting miR-124-5p, and IDH2 promotes the Warburg effect of cervical under hypoxic condition through regulating HIF-1α expression. In conclusion, hypoxia induced OIP5-AS1 promotes the Warburg effect through miR-124-5p/IDH2/HIF-1α pathway in cervical cancer.