LINC01116 promotes proliferation and migration of endometrial stromal cells by targeting FOXP1 via sponging miR-9-5p in endometriosis

Endometriosis is a common multi-factorial gynaecological disease. Recent studies have revealed that long non-coding RNAs (lncRNAs) are involved in the pathogenesis of endometriosis. In the present study, the expression profiles of lncRNAs in 6 pairs of endometriosis ectopic endometrium (ecEM) and eutopic endometrium (euEM) tissues were analysed by RNA sequencing. From the profiles, LINC01116 was found to be up-regulated in ecEM tissues compared to euEM tissues and was verified by quantitative real-time PCR (qRT-PCR). Then, functional experiments demonstrated that LINC01116 promoted the proliferation and migration of ectopic primary endometrial stromal cells (ESCs), while miR-9-5p exerted the opposite effects. Dual-luciferase reporter assays verified that LINC01116 directly sponged miR-9-5p and relieved the suppression of its target, Forkhead box protein P1 (FOXP1). Rescue experiments further demonstrated that LINC01116 could promote proliferation and migration of ESCs by targeting FOXP1 via sponging miR-9-5p. Overall, our study illuminates that LINC01116 promotes the progression of endometriosis through the miR-9-5p/FOXP1 axis. This finding provides a novel therapeutic target for patients with endometriosis.     

Knockdown of LINC01116 inhibits cell migration and invasion in head and neck squamous cell carcinoma through epithelial-mesenchymal transition pathway

Long noncoding RNAs (lncRNAs) are linked to tumor development and progression. The aim of this study was to determine the prognostic significance and biological role of LINC01116 in head and neck squamous cell carcinoma (HNSCC). We identified 21 aberrantly expressed lncRNAs specific to HNSCC that were common in two microarray datasets. LINC01116 was highly overexpressed in HNSCC tissues and was correlated to shorter overall survival and relapse-free survival duration, as analyzed by the online Gene Expression Profiling Interactive Analysis platform. LINC01116 was also overexpressed in oral squamous cell carcinoma and nasopharyngeal carcinoma tissues, and LINC01116 silencing significantly inhibited the migration and invasion capacities of both cell lines by blocking the epithelial-mesenchymal transition process. In addition, 125 coexpressing genes were identified by circlncRNAnet, and were mainly located on human autosomes and enriched in transforming growth factor-β signaling pathway. These findings indicate that LINC01116 might be a potential therapeutic target for HNSCC.     

Downregulation of LINC00894-002 Contributes to Tamoxifen Resistance by Enhancing the TGF-β Signaling Pathway

Tamoxifen is a widely used personalized medicine for estrogen receptor (ER)-positive breast cancer, but approximately 30% of patients receiving the treatment relapse due to tamoxifen resistance (TamR). Recently, several reports have linked lncRNAs to cancer drug resistance. However, the role of lncRNAs in TamR is unclear. To identify TamR-related lncRNAs, we first used a bioinformatic approach to predict whether they have connection with known TamR-associated genes by starBase v2.0 and divided them into two groups. Group A contains lncRNAs that connect with known TamR genes and group B contains lncRNAs that show no predicted interaction. Among the 12 lncRNAs in group A, 58.3% of them are either up- or downregulated in MCF-7/TamR cells compared to the sensitive cells. In contrast, the expression levels of all group B lncRNAs are not changed in MCF-7/TamR cells. LINC00894-002 exhibits the most sophisticated network pattern and is the most downregulated lncRNA in MCF-7/TamR cells. Moreover, we find that LINC00894-002 is directly upregulated by ERα. Knocking down LINC00894-002 downregulates expression of miR-200a-3p and miR-200b-3p, upregulates the expression of TGF-β2 and ZEB1, and finally contributes to TamR. Herein, we report the first case of an inhibitory lncRNA against TamR through the miR-200-TGF-β2-ZEB1 signaling pathway.     

LINC01116 modulates EMT process via binding with AGO1 mRNA in oesophageal squamous cell carcinoma

Recent researches have uncovered that long non-coding RNAs (lncRNAs) are closely correlated with the development of different diseases, while biological functions and hidden molecular mechanisms of antisense lncRNAs in oesophageal squamous cell carcinoma (OSCC) remain unclear. Here, we identified upregulation of LINC01116 in RNA sequencing data, online database, and in OSCC and intraepithelial neoplasia (IEN) specimens. Functionally, LINC01116 facilitates OSCC advancement and metastasis in vitro and vivo. Mechanistically, elevated expression of LINC01116 in OSCC cells other than tumor stroma and cytoplasmic enables it to activate AGO1 expression via complementary binding with AGO1 mRNA to facilitate EMT process of OSCC.     

Hypoxia-related LncRNAs signature predicts prognosis and is associated with immune infiltration and progress of head and neck squamous cell carcinoma

BackgroundDisclosing prognostic information is necessary to enable good treatment selection and improve patient outcomes. Previous studies suggest that hypoxia is associated with an adverse prognosis in patients with HNSCC and that long non-coding RNAs (lncRNAs) show functions in hypoxia-associated cancer biology. Nevertheless, the understanding of lncRNAs in hypoxia related HNSCC progression remains confusing.MethodsData were downloaded from TCGA and GEO database. Bioinformatic tools including R packages GEOquery, limma, pheatmap, ggplot2, clusterProfiler, survivalROC and survcomp and LASSO cox analysis were utilized. Si-RNA transfection, CCK8 and real-time quantified PCR were used in functional study.ResultsGEO data (GSE182734) revealed that lncRNA regulation may be important in hypoxia related response of HNSCC cell lines. Further analysis in TCGA data identified 314 HRLs via coexpression analysis between differentially expressed lncRNAs and hypoxia-related mRNAs. 23 HRLs were selected to build the prognosis predicting model using lasso Cox regression analyses. Our model showed excellent performance in predicting survival outcomes among patients with HNSCC in both the training and validation sets. We also found that the risk scores were related to tumor stage and to tumor immune infiltration. Moreover, LINC01116 were selected as a functional study target. The knockdown of LINC01116 significantly inhibited the proliferation of HNSCC cells and effected the hypoxia induced immune and the NF-κB/AKT signaling.ConclusionsData analysis of large cohorts and functional experimental validation in our study suggest that hypoxia related lncRNAs play an important role in the progression of HNSCC, and its expression model can be used for prognostic prediction.     

LINC00461 promotes cell migration and invasion in breast cancer through miR-30a-5p/integrin β3 axis

Mounting evidence has demonstrated that long noncoding RNAs (lncRNAs) are dysregulated and implicated in the occurrence and development of a wide range of human malignancies. LINC00461, a novel cancer-related lncRNA, has been reported to be highly expressed and serve as oncogene in glioma; however, its biological role in breast cancer (BC) remains obscure. This study aimed to explore the role of LINC00461 in BC and elucidate the potential molecular mechanisms involved. In the current study, LINC00461 was found to be significantly upregulated in both BC tissues and cell lines. Besides, we found that high LINC00461 expression was associated with TNM stage and differentiation. Furthermore, functional studies demonstrated that LINC00461 expedited BC cell migration and invasion. Notably, LINC00461 was observed to enhance the expression of vimentin and zinc-finger E-box binding homeobox factor 1, suppress the expression of E-cadherin, and promote the activation of extracellular signal-regulated kinase and AKT signaling pathways. Mechanical investigations revealed that LINC00461 positively modulated integrin β3 (ITGB3) expression as miR-30a-5p sponge in BC cells. Taken together, LINC00461 exerts an oncogenic role in BC through miR-30a-5p/ITGB3 axis. Our data indicate that LINC00461 may be used to be a novel candidate therapeutic target and a valuable diagnostic biomarker for BC.     

Long non‐coding RNA LINC00673 silencing inhibits proliferation and drug resistance of prostate cancer cells via decreasing KLF4 promoter methylation

Prostate cancer is one of the major causes of cancer‐related mortality in men across the world. Recently, long non‐coding RNAs (lncRNAs) and Kruppel‐like factor 4 (KLF4) have been reported to participate in the biology of multiple cancers including prostate cancer. Here, this study aimed to explore the possible role of LINC00673 in prostate cancer via KLF4 gene promoter methylation. Microarray‐based gene expression profiling of prostate cancer was employed to identify differentially expressed lncRNAs and genes, after which the expression of LINC00673 and KLF4 in prostate cancer tissues was determined using RT‐qPCR. Next, the relationship between LINC00673 and KLF4 was evaluated using in silico analysis. Further, the effect of LINC00673 and KLF4 on cell proliferation and drug resistance of transfected cells was examined with gain‐ and loss‐of‐function experimentation. It was found that LINC00673 was highly expressed, while KLF4 was poorly expressed in prostate cancer tissues. Additionally, LINC00673 could bind to KLF4 gene promoter region and recruit methyltransferase to the KLF4 gene promoter region. Moreover, LINC00673 silencing was demonstrated to reduce methylation of the KLF4 gene promoter to elevate the expression of KLF4, thus suppressing the proliferation and drug resistance of prostate cancer cells. In summary, LINC00673 silencing could drive demethylation of the KLF4 gene promoter and thus inhibit the proliferation and drug resistance of prostate cancer cells, suggesting that silencing of LINC00673 and elevation of KLF4 could serve as tumour suppressors in prostate cancer.     

LINC00261 suppresses human colon cancer progression via sponging miR-324-3p and inactivating the Wnt/β-catenin pathway

Growing evidence indicates long noncoding RNAs (lncRNAs) are significant regulators in the progression of various malignant tumors including colon cancer. Dysregulation of lncRNA LINC00261 has been identified in many cancers. Investigations on LINC00261 function have revealed that LINC00261 could act as a crucial tumor suppressor in various cancers. But, the biological involvement of LINC00261 in colon cancer is still barely known. Here, we found LINC00261 was reduced in colon cancer cells. Meanwhile, overexpressed LINC00261 repressed colon cancer cell viability and proliferation capacity. In addition, colony cancer cell colony formation was inhibited and apoptosis was enhanced by upregulation of LINC00261. Also, colon cancer cell migration and invasion both were restrained by LINC00261. miR-324-3p can exert important functions in several carcinomas, but its role in colon cancer is uninvestigated. In the current study, miR-324-3p was examined and miR-324-3p was greatly increased in colon cancer cells. Moreover, the association between miR-324-3p and LINC00261 was confirmed via performing RNA immunoprecipitation and RNA-pull-down experiments. In cancer biology, aberrant modulation of the Wnt signaling pathway remains a prevalent theme. Overexpression of LINC00261 obviously impaired colon cancer progression via inactivating the Wnt pathway. Furthermore, in the xenograft model assay, an increase of LINC00261 could suppress colon tumor growth via sponging miR-324-3p and inactivating the Wnt pathway. Overall, our results showed that LINC00261 repressed colon cancer progression via regulating miR-324-3p and the Wnt pathway. LINC00261 could be established as a novel therapeutic target for colon cancer.     

LINC01451 drives epithelial-mesenchymal transition and progression in bladder cancer cells via LIN28/TGF-β/Smad pathway

BackgroundThe pathogenesis of bladder cancer (BLCa) is still unclear. Long non-coding RNAs (lncRNAs) participate in diverse biological processes across every branch of life, especially in cancer. Dysregulated lncRNAs in BLCa and their biological significance require further investigations.MethodsHerein, a differential expression profile of lncRNAs in BLCa was conducted by microarray data. The expression level of lncRNA LINC01451 in 70 pairs of BLCa tissue samples and different BLCa cell lines were analyzed via real-time quantitative PCR. The CRISPR-CAS9 technique was employed to establish the LINC01451 stably transfected cell lines. Loss-of-function, as well as gain-of-function assays were carried out to evaluate the effects of LINC01451 on cell proliferation, migration, and invasion. Patient-derived xenograft (PDX) mouse models were adopted in the in vivo experiments. Western blot, biotinylated RNA probe pull-down assay, fluorescence in situ hybridization, and immunohistochemistry were utilized to assess the underlying molecular mechanisms of LINC01451 in BLCa.ResultsLINC01451 was identified a novel functional lncRNA, whose expression level in BLCa tissues was significantly higher compared with the normal tissues. Furthermore, it was found that LINC01451 directly docked LIN28A and LIN28B, and promoted the proliferation, invasion, and metastasis of BLCa. Mechanistically, LINC0145 was shown to depend on LIN28A and LIN28B, facilitated epithelial-mesenchymal transition (EMT) through activating the TGF-β/Smad signaling pathway, which subsequently aggravated BLCa progression.ConclusionsWe demonstrates that LINC01451 drives EMT-induced BLCa progression by activating the LIN28/TGF-β/Smad signaling pathway. Promisingly, LINC01451 acts as a prognostic biomarker and a novel therapeutic target for BLCa.     

Long noncoding RNA LINC00629 restrains the progression of gastric cancer by upregulating AQP4 through competitively binding to miR-196b-5p

Gastric cancer continues to be a common cancer in the world with high incidence and mortality. Accumulating evidence has implicated long noncoding RNAs (lncRNAs) in gastric cancer progression. Here, this study identified the potential role of a novel lncRNA, LINC00629 in gastric cancer and to elucidate the underlying mechanism. Initially, microarray-based gene expression profiling of gastric cancer was employed to identify differentially expressed genes. Next, the expression of LINC00629, microRNA-196b-5p (miR-196b-5p) and aquaporin 4 (AQP4) in clinical gastric cancer tissues was determined and the cell line presenting with the lowest LINC00629 expression was selected. The interaction among LINC00629, miR-196b-5p, and AQP4 was identified. Expression of LINC00629, miR-196b-5p, and AQP4 in gastric cancer cells were altered and then biological behaviors of gastric cancer cells were assessed by 5-ethynyl-2′-deoxyuridine and Transwell assays. Tumor formation in vivo was evaluated in nude mice. In gastric cancer, expression of LINC00629 and AQP4 was downregulated, and expression of miR-196b-5p was upregulated. Proliferation, invasion, and migration of gastric cancer cells were reduced after overexpression of LINC00629. LINC00629 competitively bound to miR-196b-5p, while AQP4 was a target of miR-196b-5p. Either downregulating miR-196b-5p or upregulating AQP4 could restrain the development of gastric cancer in vitro. LINC00629 overexpression repressed the growth of transplanted tumors in vivo. Taken together, LINC00629 competitively bound to miR-196b-5p to upregulate AQP4 expression, thereby inhibiting gastric cancer progression. Therefore, understanding of this mechanism may help to improve gastric cancer treatment.     

Long noncoding RNA LINC01234 promoted cell proliferation and invasion via miR-1284/TRAF6 axis in colorectal cancer

Colorectal cancer is one of the most common and leading malignancies globally. Long noncoding RNAs (lncRNAs) function as potentially critical regulator in colorectal cancer. LINC01234, a novel lncRNA in tumor biology, regulates the progression of various tumors. However, the tumorigenic mechanism of LINC01234 in colorectal cancer is still unclear. This study was performed with the aim to prospectively investigate clinical significance, effect, and mechanism of lncRNA LINC01234 in colorectal cancer. First, we found that LINC01234, localized in the cytoplasm, was increased in both colorectal cancer cell lines and tissues. Subsequent functional assays suggested LINC01234 knockdown suppressed cell proliferation, migration, and invasion of colorectal cancer cells, while blocked cell cycle and induced cell apoptosis. Moreover, we identified that miR-1284 was target of LINC01234, we further demonstrated a negative correlation with LINC01234 in colorectal cancer tissues and cells. Furthermore, miR-1284 targeted and suppressed tumor necrosis factor receptor–associated factor 6 (TRAF6). Loss-of-function assay revealed that LINC01234 silencing suppressed colorectal cancer progression through inhibition of miR-1284. In vivo subcutaneous xenotransplanted tumor model indicated LINC01234 knockdown inhibited in vivo tumorigenic ability of colorectal cancer via downregulation of TRAF6. Collectively, this study clarified the biological significance of LINC01234/miR-1284/TRAF6 axis in colorectal cancer progression, providing insights into LINC01234 as novel potential therapeutic target for colorectal cancer therapeutic from bench to clinic.     

Identification of pathological grade and prognosis-associated lncRNA for ovarian cancer

Ovarian carcinoma (OC) is one of the most common malignant tumors in female genitals. In recent years, the therapeutic effect of OC has been significantly improved through the application of effective chemotherapy regimen. However, the 5-year survival rate is also lower than 30% due to high rate of relapse. So, it is needed to screen reliable predictive and prognostic markers of OC. Ovarian cancer gene expression data and corresponding clinical data used were downloaded from Gene Expression Omnibus database. Weighted gene expression network analysis (WGCNA) and Cox proportional hazards regression (PHR) were used to screen Pathological Grade and Prognosis-associated long noncoding RNA (lncRNA). Kaplan-Meier analysis and receiver operating characteristic curves analysis were performed to evaluate the predictive ability of the selected lncRNA. Gene Ontology (GO) enrichment and Gene Set Enrichment Analysis (GSEA) enrichment analysis methods were used to explore the possible mechanisms of the selected lncRNA affecting the development of OC. Five reliably lncRNAs (LINC00664, LINC00667, LINC01139, LINC01419, and LOC286437) was identified through a series of bioinformatics methods. In testing cohorts, we found that the five lncRNAs in predicting the risk of OC recurrence is robustness, and multivariate Cox PHR analysis indicate that the five lncRNAs is an independent risk factor for OC recurrence. Moreover, GO and GSEA enrichment analysis showed that the five lncRNAs are involved in multiple ovarian cancer occurrence mechanism. In summary, all these findings indicated that the five lncRNAs can effectively predict the risk of recurrence of ovarian cancer.     

Long non-coding RNA LINC00488 facilitates thyroid cancer cell progression through miR-376a-3p/PON2

Objective: Long non-coding RNAs (lncRNAs) recently have been identified as influential indicators in a variety of malignancies. The aim of the present study was to identify a functional lncRNA LINC00488 and its effects on thyroid cancer in the view of cell proliferation and apoptosis.Methods: In order to evaluate the effects of LINC00488 on the cellular process of thyroid cancer, we performed a series of in vitro experiments, including cell counting kit-8 (CCK-8) assay, EdU (5-ethynyl-2′-deoxyuridine) assay, flow cytometry, transwell chamber assay, Western blot and RT-qPCR. The target gene of LINC00488 was then identified by bioinformatics analysis (DIANA and TargetScan). Finally, a series of rescue experiments was conducted to validate the effect of LINC00488 and its target genes on proliferation, migration, invasion and apoptosis of thyroid cancer.Results: Our findings revealed that LINC00488 was highly expressed in thyroid cancer cell lines (BCPAP, BHP5-16, TPC-1 and CGTH-W3) and promoted the proliferation, migration and invasion, while inhibited the apoptosis of thyroid cancer cells (BCPAP and TPC-1). The results of bioinformatics analysis and dual luciferase reporter gene assay showed that LINC00488 could directly bind to miR-376a-3p and down-regulated the expression level of miR-376a-3p. In addition, Paraoxonase-2 (PON2) was a target gene of miR-376a-3p and negatively regulated by miR-376a-3p. Rescue experiment indicated that LINC00488 might enhance PON2 expression by sponging miR-376a-3p in thyroid cancer.Conclusion: Taken together, our study revealed that lncRNA LINC00488 acted as an oncogenic gene in the progression of thyroid cancer via regulating miR-376a-3p/PON2 axis, which indicated that LINC00488-miR-376a-3p-PON2 axis could serve as novel biomarkers or potential targets for the treatment of thyroid cancer.