Long non-coding RNA TP73-AS1 promotes TFAP2B-mediated proliferation, metastasis and invasion in retinoblastoma via decoying of miRNA-874-3p.
ABSTRACT: Retinoblastoma (RB) is one of the most common ophthalmic tumors, and most of the patients have been identified as advanced at the time of diagnosis, which is directly related to high mortality. Recent studies showed that long noncoding RNA (lncRNA) and miRNAs play key roles in the development?progression?or treatment of cancer, such as RB. However, the role of lncRNA -TP73-AS1 in RB remains unclear. In this study, we performed functional and mechanistic investigation of miRNA-874-3p-TP73-AS1 interaction in RB. The experiments results revealed that miRNA-874-3p had anti-oncogenic functions in RB. Moreover, the bioinformatics analysis shown that TP73-AS1 could bind to miRNA-874-3p. TP73-AS1 was inversely correlated with miRNA-874-3p expression. Furthermore, studies confirmed that TP73-AS1 negatively regulated miRNA-874-3p expression via functioning as a ceRNA. In a word, our results suggest that the TP73-AS1/ miRNA-874-3p / TFAP2B (transcription factor activating enhancer-binding protein 2B) pathway contributes to the progression of RB, which may provide novel insights into the function of lncRNA-driven retinoblastogenesis. Graphical abstract.
Project description:Purpose:Long non-coding RNA P73 antisense RNA 1T (TP73-AS1) is a newly discovered lncRNA involved in the occurrence and development of several cancers. However, its role in lung cancer has not been well investigated yet. Methods:The expressions of TP73-AS1, microRNA-27b-3p (miR-27b-3p) and lysosomal-associated protein transmembrane-4 Beta (LAPTM4B) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The cell proliferation, apoptosis, migration and invasion were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Annexin V-FITC/PI and transwell assays, respectively. Tumor xenografts were applied to explore the role of TP73-AS1 in vivo. The target relationship was predicted by StarBase v.2.0 or TargetScan and confirmed by luciferase reporter assay. Pearson's coefficient assay was applied to assess the expression correlation between two groups. Protein expression levels were detected by Western blot. Results:We found that TP73-AS1 was strikingly up-regulated in lung cancer tissues and cells. TP73-AS1 depletion inhibited the growth and metastasis of lung cancer cells in vitro. Furthermore, TP73-AS1 could act as an endogenous sponge by directly binding miR-27b-3p, and a notable inverse correlation between them was also discovered. Importantly, knockdown of miR-27b-3p could reverse the inhibitory effects of TP73-AS1 depletion on the growth and metastasis of lung cancer cells. Besides, LAPTM4B was directly targeted by miR-27b-3p and could be co-regulated by TP73-AS1 and miR-27b-3p in lung cancer cells. Silencing TP73-AS1 hampered tumor growth by regulating miR-27b-3p/LAPTM4B axis in vivo. Conclusion:TP73-AS1 promoted the progression of lung cancer through regulating miR-27b-3p/LAPTM4B axis and it might be a potential target for diagnosis and treatment of lung cancer.
Project description:Background:Various evidences showed that abnormally expressed long non-coding RNAs (lncRNAs) play important roles in the tumorigenesis and progression of malignancies. However, the exact role and regulatory mechanism of lncRNA TP73-AS1 in the pathogenesis and progression of lung adenocarcinoma remain to be further elucidated. Purpose:The aim of this study was to investigate the functional role and underlying mechanism of lncRNA TP73-AS1 in lung adenocarcinoma progression. Methods:RT-PCR assay was employed to detect TP73-AS1 expression in lung adenocarcinoma tissues and cells. The function of TP73-AS1 in lung adenocarcinoma progression was estimated by MTT assay, EdU assay, flow cytometry, Western blot, wound-healing assay and transwell assay. Results:LncRNA TP73-AS1 expression was significantly increased in lung adenocarcinoma tissues and cell lines. Moreover, functional assays revealed that silencing of lncRNA TP73-AS1 could attenuate cell proliferation, migration, invasion and epithelial-mesenchymal transition of lung adenocarcinoma, while enhanced expression of lncRNA TP73-AS1 led to the opposite results. Additionally, lncRNA TP73-AS1 knockdown could facilitate cell apoptosis and overexpression of lncRNA TP73-AS1 inhibited cell apoptosis. In addition, we further determined that lncRNA TP73-AS1 regulated cell metastasis through inducing the activation of Wnt/?-catenin signaling pathway in lung adenocarcinoma. Conclusion:Our results indicated that lncRNA TP73-AS1 may play an oncogenic role in lung adenocarcinoma progression, which provided a promising therapy strategy for the treatment of lung adenocarcinoma.
Project description:Recent studies have shown that long non-coding RNAs (lncRNAs) are involved in a variety of biological processes and diseases in humans, including cancer. Our study serves as the first comprehensive analysis of lncRNA TP73-AS1 in esophageal cancer. We utilized a lncRNA microarray to analyze the expression profile of lncRNAs in esophageal squamous cell carcinoma. Our results show that lncRNA TP73-AS1 and BDH2 levels are generally upregulated in esophageal cancer tissues and are strongly correlated with tumor location or TNM stage in clinical samples. LncRNA TP73-AS1 knockdown inhibited BDH2 expression in EC9706 and KYSE30 cells, whereas BDH2 knockdown repressed esophageal cancer cell proliferation and induced apoptosis via the caspase-3 dependent apoptotic pathway. Overexpression of BDH2 in lncRNA TP73-AS1 knockdown cells partially rescued cell proliferation rates and suppressed apoptosis. In mouse xenografts, tumor size was reduced in lncRNA TP73-ASI siRNA-transfected tumors, suggesting that downregulation of lncRNA TP73-AS1 attenuated EC proliferation in vitro and in vivo. In addition, BDH2 or lncRNA TP73-AS1 knockdown enhanced the chemosensitivity of esophageal cancer cells to 5-FU and cisplatin. Our results suggest that lncRNA TP73-AS1 may be a novel prognostic biomarker that could serve as a potential therapeutic target for the treatment of esophageal cancer.
Project description:Previous studies have revealed that long noncoding RNAs (lncRNAs) function as crucial regulators in various biological processes, including tumorigenesis. Although the expression of lncRNA TP73-antisense RNA1 (AS1) has been identified in hepatocellular carcinoma and glioma, the biological function of TP73-AS1 in gastric cancer (GC) remains unclear. Thus, the present study employed a comprehensive analysis on the function of lncRNA TP73-AS1 in GC. The aim of the present study was to determine the clinical significance and biological function of TP73-AS1 in human GC tissues and cells. Additionally, the expression of TP73-AS1 was increased in GC tissues and cell lines and increased expression level of TP73-AS1 was associated with poor prognosis in patients with GC. Functional assays revealed that silencing of TP73-AS1 may suppress cell proliferation and enhance the chemotherapeutic response of GC cells to cisplatin through targeting the high mobility group 1/receptor for advanced glycation endproducts signaling pathway. Collectively, the results of the present study demonstrated that TP73-AS1 may be a novel lncRNA for the clinical prognosis of GC and a potential therapeutic target for the treatment of GC.
Project description:Evidence has indicated the important roles of long non-coding RNAs (lncRNAs) in the human cancer biology, providing potential targets for cancer intervention. However, the expression profile and function of lncRNA TP73-AS1 in human epithelial ovarian cancer (EOC) remain to be investigated. In the EOC specimens and cell lines, TP73-AS1 was identified to be significantly up-regulated. EOC patients with high TP73-AS1 expression had poor survival rate. The gain and loss of functional assay uncovered that TP73-AS1 promoted the proliferation, invasion and reduced the apoptosis of EOC cells in vitro. And, the knockdown of TP73-AS1 inhibited the tumor growth in vivo. By using chromatin immunoprecipitation and luciferase reporter assay, we identified TP73-AS1 epigenetically repressed p21 via recruiting EZH2. In conclusion, this finding supports that TP73-AS1 promotes the EOC progression via epigenetically repressing p21, serving as a prognosis predictor for EOC patients.
Project description:BACKGROUND:TP73 antisense RNA 1 (TP73-AS1) is a long noncoding RNA which has been shown to be involved in the progression of multiple malignant tumors. Previous studies have demonstrated the oncogenic role of TP73-AS1 in breast cancer. However, its molecular mechanism remains largely unknown in breast tumorigenesis. METHODS:Expression of TP63-AS1, miRNA-125a-3p (miR-125a) and metadherin (MTDH) was detected by real-time quantitative PCR and western blotting. The malignancy was evaluated by cell counting kit 8 (CCK-8), transwell assays, flow cytometry and western blotting. The target binding was confirmed by dual luciferase reporter assay. Xenograft tumor model was performed to detect tumor growth in vivo. RESULTS:Expression of TP73-AS1 was higher in breast cancer tissues and cell lines. Biologically, its knockdown could promote cell apoptosis rate, and inhibit proliferative capacity, migration and invasion ability in HCC-70 and MB231 cells, accompanied with higher cleaved caspase 3 level and lower Ki67, N-cadherin and Vimentin level. Moreover, TP73-AS1 downregulation restrained the tumor growth of HCC-70 cells in vivo. Mechanically, TP73-AS1 functioned as a molecular "sponge" for miR-125a to modulate MTDH, a downstream target of miR-125a. Intriguingly, both miR-125a overexpression and MTDH silencing exerted a tumor-suppressive effect in the malignant progression of HCC-70 and MB231 cells, which was counteracted by TP73-AS1 upregulation and miR-125a downregulation, respectively. CONCLUSION:Knockdown of TP73-AS1 inhibited cell proliferation, migration and invasion, but facilitated apoptosis in breast cancer cells in vitro through targeting miR-125a and upregulating MTDH, suggesting a novel TP73-AS1/miR-125a/MTDH pathway in the malignant progression of breast cancer.
Project description:Long non-coding RNAs (lncRNAs) function as tumor suppressors or oncogenes in tumor development and progression. The purpose of the present study was to investigate the clinical significance and functional role of lncRNA TP73-AS1 in gastric cancer (GC). Reverse transcription-quantitative polymerase chain reaction analysis demonstrated that TP73-AS1 was significantly upregulated in GC tissues compared with adjacent normal tissues. The higher expression of TP73-AS1 was closely associated with lymph node metastasis and tumor-node-metastasis stage in patients with GC. Those patients with GC showing a higher expression of TP73-AS1 were predicted to have shorter disease-free survival and overall survival rates. The knockdown of TP73-AS1 was shown to markedly inhibit cell proliferation, cell colony formation and cell invasion. In addition, the downregulation of TP73-AS1 suppressed the expression of transcription factor 4 and ?-catenin, which suggested that a decrease in TP73-AS1 suppressed the WNT/?-catenin signaling pathway in GC. Therefore, these results indicated that TP73-AS1 may be a target for GC treatment.
Project description:MicroRNA (miRNA) sponges are vital components of posttranscriptional gene regulation. Yet, only a limited number of miRNA sponges have been identified. Here, we show that the recently evolved noncoding tumor suppressor transcript, antisense RNA to TP73 gene (TP73-AS1), functions as a natural sponge of human-specific miRNA miR-941. We find unusually nine high-affinity miR-941 binding sites clustering within 1?kb region on TP73-AS1, which forms miR-941 sponge region. This sponge region displays increased sequence constraint only in humans, and its formation can be traced to the tandem expansion of a 71-nt-long sequence containing a single miR-941 binding site in old world monkeys. We further confirm TP73-AS1 functions as an efficient miR-941 sponge based on massive transcriptome data analyses, wound-healing assay, and Argonaute protein immunoprecipitation experiments conducted in cell lines. The expression of miR-941 and its sponge correlate inversely across multiple healthy and cancerous tissues, with miR-941 being highly expressed in tumors and preferentially repressing tumor suppressors. Thus, the TP73-AS1 and miR-941 duo represents an unusual case of the extremely rapid evolution of noncoding regulators controlling cell migration, proliferation, and tumorigenesis.
Project description:Glioblastoma multiform (GBM) is the most common brain tumor characterized by a dismal prognosis. GBM cancer stem cells (gCSC) or tumor-initiating cells are the cell population within the tumor-driving therapy resistance and recurrence. While temozolomide (TMZ), an alkylating agent, constitutes the first-line chemotherapeutic significantly improving survival in GBM patients, resistance against this compound commonly leads to GBM recurrence and treatment failure. Although the roles of protein-coding transcripts, proteins and microRNA in gCSC, and therapy resistance have been comprehensively investigated, very little is known about the role of long noncoding RNAs (lncRNAs) in this context. Using nonoverlapping, independent RNA sequencing and gene expression profiling datasets, we reveal that TP73-AS1 constitutes a clinically relevant lncRNA in GBM. Specifically, we demonstrate significant overexpression of TP73-AS1 in primary GBM samples, which is particularly increased in the gCSC. More importantly, we demonstrate that TP73-AS1 comprises a prognostic biomarker in glioma and in GBM with high expression identifying patients with particularly poor prognosis. Using CRISPRi to downregulate our candidate lncRNA in gCSC, we demonstrate that TP73-AS1 promotes TMZ resistance in gCSC and is linked to regulation of the expression of metabolism- related genes and ALDH1A1, a protein known to be expressed in cancer stem cell markers and protects gCSC from TMZ treatment. Taken together, our results reveal that high TP73-AS1 predicts poor prognosis in primary GBM cohorts and that this lncRNA promotes tumor aggressiveness and TMZ resistance in gCSC.
Project description:Studies published in recent years have demonstrated that abnormal long noncoding RNA (lncRNA) antisense RNA to TP73 gene (TP73-AS1) expression is markedly associated with tumorigenesis, cancer progression and the prognosis of cancer patients. We aimed to explore the prognostic value of TP73-AS1 in multiple cancers. We comprehensively searched PubMed, Embase, Web of Science and the Cochrane Library (up to February 21, 2019). Hazard ratios (HRs), odds ratios (ORs) and the corresponding 95% confidence intervals (95% CIs) were calculated to estimate the association of TP73-AS1 with survival and clinicopathological features. The potential targets and pathways of TP73-AS1 in multiple cancers were summarized. Nineteen studies that involved thirteen types of cancers and 1329 cancer patients were identified as eligible for this meta-analysis. The results showed that high TP73-AS1 expression was significantly correlated with shorter overall survival (OS) (HR?=?1.962, 95% CI 1.630-2.362) and disease-free survival (DFS) (HR?=?2.050, 95% CI 1.293-3.249). The summary HRs of OS were 2.101 (95% CI 1.516-2.911) for gastric cancer (GC) and 1.920 (95% CI 1.253-2.942) for osteosarcoma. Subgroup analysis of OS demonstrated that the differential expression of TP73-AS1 in cancer tissues was a potential source of heterogeneity. Furthermore, increased TP73-AS1 expression was markedly associated with larger tumor size (OR?=?2.759, 95% CI 1.759-4.330), advanced histological grade (OR?=?2.394, 95% CI 1.231-4.656), lymph node metastasis (OR?=?2.687, 95% CI 1.211-5.962), distant metastasis (OR?=?4.145, 95% CI 2.252-7.629) and advanced TNM stage (OR?=?2.633, 95% CI 1.507-4.601). The results of Egger's test and sensitivity analysis verified the robustness of the original results. High TP73-AS1 expression can predict poor survival and poor clinicopathological features in cancer patients and TP73-AS1 might be a potential biomarker and therapeutic target.