Long intergenic noncoding RNA 00641 inhibits breast cancer cell proliferation,migration, and invasion by sponging miR-194-5p

Long noncoding RNAs have an essential role in the tumorigenesis of breast cancer (BC). Nonetheless, the consequences of long intergenic noncoding RNA 00641 (LINC00641) in BC remain unidentified. This study shows that LINC00641 expression level was decreased in BC tissues. LINC00641 expression level was negatively related to tumor size, lymph-node metastasis, as well as clinical stage. LINC00641 overexpression inhibited cell proliferation, migration, and invasion but stimulated apoptosis in BC cells. LINC00641 overexpression also remarkably reduced BC growth and metastasis in vivo. LINC00641 acts as a competitive endogenous RNA to sponge miR-194-5p. miR-194-5p level was higher in BC tissues and cells compared with normal-adjacent tissues and normal breast epithelial cell. miR-194-5p expression was negatively correlated with LINC00641 expression in BC tissues. miR-194-5p overexpression reversed the effects of LINC00641 on cell proliferation, cycle, apoptosis, migration, as well as invasion. In conclusion, LINC00641 inhibits BC cell proliferation, migration, as well as invasion by sponging miR-194-5p.     

Circular RNA circDVL1 inhibits clear cell renal cell carcinoma progression through the miR-412-3p/PCDH7 axis

Clear cell renal cell carcinoma (ccRCC) is a primary kidney cancer with high aggressive phenotype and extremely poor prognosis. Accumulating evidence suggests that circular RNAs (circRNAs) play pivotal roles in the occurrence and development of various human cancers. However, the expression, clinical significance and regulatory role of circRNAs in ccRCC remain largely unclear. Here we report that circDVL1 to be reduced in the serums and tissues from ccRCC patients, and to negatively correlate with ccRCC malignant features. Overexpression of circDVL1 inhibits proliferation, induces G1/S arrest, triggers apoptosis, and reduces migration and invasion in different ccRCC cells in vitro. Correspondingly, circDVL1 overexpression suppresses ccRCC tumorigenicity in a mouse xenograft model. Mechanistically, circDVL1 serves as a sponge for oncogenic miR-412-3p, thereby preventing miR-412-3p-mediated repression of its target protocadherin 7 (PCDH7) in ccRCC cells. Collectively, our results demonstrate that circDVL1 exerts tumor-suppressive function during ccRCC progression through circDVL1/miR-412-3p/PCDH7 axis, and suggest that circDVL1 could be a novel diagnostic and prognositc marker and therapeutic target for ccRCC.     

miR-605-5p promotes invasion and proliferation by targeting TNFAIP3 in non–small-cell lung cancer

Lung cancer is an significant cause of death worldwide, and non–small-cell lung cancer (NSCLC) is the most common type of lung cancer. MicroRNAs (miRNAs) have been identified to play key roles in NSCLC development. Recently, it has been reported that miR-605-5p is a cancer-related miRNA in several types of tumors. In this study, we study the role of miR-605-5p in NSCLC cells. We find that miR-605-5p is upregulated in NSCLC cells. Overexpression of miR-605-5p significantly promotes lung cancer invasion and migration in H460 and H1299 cells. Besides this, miR-605-5p also promotes lung cancer cell carcinoma proliferation and metastasis in vivo. However, downregulation of miR-605-5p inhibits cell invasion and migration by inhibiting lung cancer cell carcinoma proliferation and metastasis. In addition, the luciferase report assay identifies 3′-untranslated region tumor necrosis factor α-induced protein 3 (TNFAIP3) as a target of miR-605-5p. Silencing of TNFAIP3 promotes invasion and proliferation in lung cancer. In addition, the knockdown of TNFAIP3 restores the significant decrease in invasion and proliferation in miR-605-5p-inhibitor–transfected lung cancer cells. In conclusion, miR-605-5p promotes invasion and proliferation by targeting TNFAIP3 in NSCLC, and may provide possible biomarkers for NSCLC therapy.     

High-throughput sequencing identified circular RNA circUBE2K mediating RhoA associated bladder cancer phenotype via regulation of miR-516b-5p/ARHGAP5 axis

Bladder cancer (BC) is known as a common and lethal urinary malignancy worldwide. Circular RNAs (circRNAs), an emerging non-coding RNA, participate in carcinogenesis process of several cancers including BC. In this study, high-throughput sequencing and RT-qPCR were applied to discover and validate abnormal high expression of circUBE2K in BC tissues. Fluorescence in situ hybridization (FISH) was used to detect hsa_circ_0009154 (circUBE2K) expression and subcellular localization in BC tissues. High circUBE2K predicted unfavorable prognoses in BCs, as well as correlated with clinical features. CCK8, transwell, EdU and wound healing assays demonstrated down-regulating circUBE2K decreased BC cell phenotype as proliferation, invasion, and migration, respectively. Further studies showed that circUBE2K promoted BC progression via sponging miR-516b-5p and enhancing ARHGAP5 expression through regulating RhoA activity. Dual-luciferase reporter, FISH and RNA pulldown assays were employed to verify the relationships among circUBE2K/miR-516b-5p/ARHGAP5/RhoA axis. Down-regulating miR-516b-5p or overexpressing ARHGAP5 restored RhoA activity mediated BC cell properties after silencing circUBE2K. Subcutaneous xenograft and metastasis model identified circUBE2K significantly increased BC cell metastasis and proliferation in-vivo. Taken together, we found that circUBE2K is a tumor-promoting circRNA in BC that functions as a ceRNA to regulate ARHGAP5 expression via sponging miR-516b-5p.Subject terms: Non-coding RNAs, Bladder cancer     

Circular RNA hsa_circ_0110389 promotes gastric cancer progression through upregulating SORT1 via sponging miR-127-5p and miR-136-5p

Increasing studies have found that circular RNAs (circRNAs) are aberrantly expressed and play important roles in the occurrence and development of human cancers. However, the function of circRNAs on environmental carcinogen-induced gastric cancer (GC) progression remains poorly elucidated. In the present study, hsa_circ_0110389 was identified as a novel upregulated circRNA in malignant-transformed GC cells through RNA-seq, and subsequent quantitative real-time PCR verified that hsa_circ_0110389 was significantly increased in GC tissues and cells. High hsa_circ_0110389 expression associates with advanced stages of GC and predicts poor prognosis. Knockdown and overexpression assays demonstrated that hsa_circ_0110389 regulates proliferation, migration, and invasion of GC cells in vitro. In addition, hsa_circ_0110389 was identified to sponge both miR-127-5p and miR-136-5p and SORT1 was validated as a direct target of miR-127-5p and miR-136-5p through multiple mechanism assays; moreover, hsa_circ_0110389 sponged miR-127-5p/miR-136-5p to upregulate SORT1 expression and hsa_circ_0110389 promoted GC progression through the miR-127-5p/miR-136-5p–SORT1 pathway. Finally, hsa_circ_0110389 knockdown suppressed GC growth in vivo. Taken together, our findings firstly identify the role of hsa_circ_0110389 in GC progression, which is through miR-127-5p/miR-136-5p–SORT1 pathway, and our study provides novel insight for the identification of diagnostic/prognostic biomarkers and therapeutic targets for GC.Subject terms: Gastrointestinal cancer, Non-coding RNAs     

miR-342-3p suppresses proliferation,migration and invasion by targeting FOXM1 in human cervical cancer

FOXM1 is a well-established oncogenic factor that has been reported to be involved in multiple biological processes including cell proliferation, growth, angiogenesis, migration and invasion. It can also be regulated by miRNAs. In this study, we reported that FOXM1 is directly targeted by miR-342-3p, which is down-regulated along with its host gene, EVL, in human cervical cancer tissues compared to the adjacent normal tissues. Functional studies suggested that the overexpression of miR-342-3p inhibits cell proliferation, migration and invasion in cervical cell lines. FOXM1 is upregulated and negatively correlates with miR-342-3p in cervical cancer tissues, and the overexpression of FOXM1 rescues the phenotype changes induced by the overexpression of miR-342-3p.     

Circ-PTPDC1 promotes the Progression of Gastric Cancer through Sponging Mir-139-3p by Regulating ELK1 and Functions as a Prognostic Biomarker

Circular RNAs (circRNAs) is a novel class of non-coding RNAs resulting from the non-canonical splicing of linear pre-mRNAs. However, the role of circRNAs in gastric cancer (GC) remains indistinct. This study aims to explore their potential modulation in GC and its prognostic value. We first screen for circRNA expression patterns in GC through GC and adjacent noncancerous tissues by microarray. Based on the bioinformatics analysis of the microarray data, we screened out a novel circRNA, circ-PTPDC1. Then we demonstrated that circ-PTPDC1 was up-regulated in GC cells, tissues, and serum. Its overexpression was positively correlated with age, invasion depth, advanced clinical stages, and worse survival in patients with GC. We further revealed that circ-PTPDC1 promotes the proliferation, migration, and invasion of GC cell lines via sponging miR-139-3p by regulating ELK1. Importantly, we identified that circ-PTPDC1 promotes tumor upgrowth and metabasis in vivo. Additionally, we established its prognostic prediction model based on the follow-up data of the patients. Our study revealed a novel regulatory mechanism and a comprehensive landscape of circ-PTPDC1 in GC, suggesting that circ-PTPDC1 has the potential to be a biomarker for early detection and prognostic prediction of GC.     

LncRNA BLACAT1 regulates VASP expression via binding to miR-605-3p and promotes giloma development

Glioma, an aggressive tumor in brain, presents a very poor prognosis. Emerging evidence has demonstrated that dysfunction of long noncoding RNAs (lncRNAs) is closely related to giloma development. However, the roles of lncRNA BLACAT1 in glioma are not unknown. In this study, we utilized in vitro and in vivo experiments to explore the effects of BLACAT1 on glioma cells. BLACAT1 levels were increased in glioma tissues. Upregulation of BLACAT1 showed poor prognosis. Silencing of BLACAT1 markedly repressed glioma proliferation, migration, and invasion, and suppressed glioma growth in vivo. We also illustrated that BLACAT1 worked as the sponge for miR-605-3p and promoted VASP expression. miR-605-3p was downregulated in glioma and repressed glioma proliferation, migration, and invasion. And VASP is upregulated and contributed to glioma progression. Summarily, this study highlights the important roles of BLACAT1/miR-605-3p/VASP axis in glioma progression.     

Decrease of circARID1A retards glioblastoma invasion by modulating miR-370-3p/ TGFBR2 pathway

Increasing evidence suggests that circular RNAs (circRNAs) are involved in regulating tumor biological activity. Glioblastoma (GBM) is one of the most lethal diseases characterized by highly aggressive proliferative and invasive behaviors. We aimed to explore how circRNAs influenced GBM biological activity. By circRNA array analysis we found that circARID1A was significantly up-regulated in GBM. Next, we found that circARID1A was up-regulated in GBM tissues and cell lines. Interfering with circARID1A inhibited the migration and invasion of a human GBM cell line U87. By performing dual-luciferase reporter assays, RNA pull-down and fluorescent in situ hybridization (FISH), we determined that circARID1A directly bound to miR-370-3p. Moreover, we confirmed that transforming growth factor beta receptor 2 (TGFBR2) was the target gene of miR-370-3p by performing RNA pull-down, dual-luciferase reporter assays and western blotting. Further experiments verified that circARID1A promoted GBM cell migration and invasion by modulating miR-370-3p/ TGFBR2 pathway. In addition, we demonstrated that silencing circARID1A restrain the growth of GBM in vivo. Finally, we showed that circARID1A was abundant in GBM cell derived exosomes. In conclusion, circARID1A participated in regulating migration and invasion of GBM via modulation of miR-370-3p/ TGFBR2 and thus may be a potential serum biomarker of GBM.     

miR-338-3p suppresses neuroblastoma proliferation,invasion and migration through targeting PREX2a

MicroRNAs (miRNA) can regulate cancer cell proliferation and metastasis. Here, we show that miR-338-3p is down-regulated in metastatic tumor tissues compared to primary tumors, and that that miR-338-3p can inhibit cell proliferation by inducing cell cycle arrest, as well as restrain cell migration and invasion. PREX2a is confirmed as a direct target of miR-338-3p. Knockdown of PREX2a inhibits cell proliferation, migration and invasion through the PTEN/Akt pathway. miR-338-3p-dependent inhibition of proliferation and invasion can be rescued by PREXa. Overall, this study demonstrates that miR-338-3p affects the PTEN/Akt pathway by down-regulating PREX2a. This newly identified function of miR-338-3p provides novel insights into neuroblastoma and may foster therapeutic applications.     

Circular RNA ubiquitin-associated protein 2 enhances autophagy and promotes colorectal cancer progression and metastasis via miR-582-5p/FOXO1 signaling

Numerous circular RNAs (circRNAs) have been identified as vital regulators in various cancers. The newly reported circular RNA ubiquitin-associated protein 2 (circUBAP2) is a critical player in cell growth and metastasis in various types of cancers, although its role in colorectal cancer (CRC) has yet to be fully elucidated. We find that circUBAP2 is upregulated in CRC tissues and cell lines to induce autophagy both in vitro and in vivo. The effects of circUBAP2 on migration, invasion, and proliferation may be partially related to autophagy. Mechanistically, we uncover that circUBAP2 can directly interact with miR-582-5p and subsequently act as a microRNA sponge to regulate the expression of the miR-582-5p target gene forkhead box protein O1 (FOXO1) and downstream signaling molecules, which collectively advance the progression and metastasis of CRC. These results suggest that circUBAP2 acts as an oncogene via a novel circUBAP2/miR-582-5p/FOXO1 axis, providing a potential biomarker and therapeutic target for CRC management.     

The circular RNA circBCL2L1 regulates innate immune responses via microRNA-mediated downregulation of TRAF6 in teleost fish

Growing numbers of studies have shown that circular RNAs (circRNAs) can function as regulatory factors to regulate the innate immune response, cell proliferation, cell migration, and other important processes in mammals. However, the function and regulatory mechanism of circRNAs in lower vertebrates are still unclear. Here, we discovered a novel circRNA derived from the gene encoding Bcl-2-like protein 1 (BCL2L1) gene, named circBCL2L1, which was related to the innate immune responses in teleost fish. Results indicated that circBCL2L1 played essential roles in host antiviral immunity and antibacterial immunity. Our study also identified a microRNA, miR-30c-3-3p, which could inhibit the innate immune response by targeting inflammatory mediator TRAF6. And TRAF6 is a key signal transduction factor in innate immune response mediated by TLRs. Moreover, we also found that the antiviral and antibacterial effects inhibited by miR-30c-3-3p could be reversed with the expression of circBCL2L1. Our data revealed that circBCL2L1 functioned as a competing endogenous RNA (ceRNA) of TRAF6 by competing for binding with miR-30c-3-3p, leading to activation of the NF-κB/IRF3 inflammatory pathway and then enhancing the innate immune responses. Our results suggest that circRNAs can play an important role in the innate immune response of teleost fish.     

Up-regulated circBACH2 contributes to cell proliferation,invasion, and migration of triple-negative breast cancer

An increasing amount of evidence has proven the vital role of circular RNAs (circRNAs) in cancer progression. However, there remains a dearth of knowledge on the function of circRNAs in triple-negative breast cancer (TNBC). Utilizing a circRNA microarray dataset, four circRNAs were identified to be abnormally expressed in TNBC. Among them, circBACH2 was most significantly elevated in TNBC cancerous tissues and its high expression was positively correlated to the malignant progression of TNBC patients. In normal human mammary gland cell line, the overexpression of circBACH2 facilitated epithelial to mesenchymal transition and cell proliferation. In TNBC cell lines, circBACH2 knockdown suppressed the malignant progression of TNBC cells. Mechanistically, circBACH2 sponged miR-186-5p and miR-548c-3p, thus releasing the C-X-C chemokine receptor type 4 (CXCR4) expression. The interference of miR-186-5p/miR-548c-3p efficiently promoted the cell proliferation, migration, and invasion suppressed by circBACH2 knockdown in the TNBC cell lines. Finally, circBACH2 knockdown repressed the growth and lung metastasis of TNBC xenografts in nude mice. In summary, circBACH2 functions as an oncogenic circRNA in TNBC through a novel miR-186-5p/miR-548c-3p/CXCR4 axis.Subject terms: Cancer, Cell biology     

Circular RNA hsa_circ_0004015 regulates the proliferation,invasion, and TKI drug resistance of non-small cell lung cancer by miR-1183/PDPK1 signaling pathway

Circular RNAs (circRNAs) were recently reported to be involved in the pathogenesis of Non-small cell lung cancer (NSCLC), however, the molecular mechanisms of circRNAs in cell proliferation, invasion and TKI drug resistance remain largely undetermined. Here, we identified hsa_circ_0004015 was upregulated in NSCLC tissues, and was associated with the poor overall survival rate of NSCLC patients. Knockdown of hsa_circ_0004015 significantly decreased cell viability, proliferation, and invasion, whereas overexpression exhibited opposed effects in vivo and in vitro. Furthermore, hsa_circ_0004015 could enhance the resistance of HCC827 to gefitinib. In mechanism, hsa_circ_0004015 acted as a sponge for miR-1183, and PDPK1 was revealed to be target gene of miR-1183. Subsequently, functional assays illustrated that the oncogenic effects of hsa_circ_0004015 was attributed to the regulation of miR-1183/PDPK1 axis. In conclusion, circ_0016760/miR-1183/PDPK1 signaling pathway might play vital roles in the tumorigenesis of NSCLC.     

Oncogenic miRNA-182-5p Targets Smad4 and RECK in Human Bladder Cancer

Onco-miR-182-5p has been reported to be over-expressed in bladder cancer (BC) tissues however a detailed functional analysis of miR-182-5p has not been carried out in BC. Therefore the purpose of this study was to: 1. conduct a functional analysis of miR-182-5p in bladder cancer, 2. assess its usefulness as a tumor marker, 3. identify miR-182-5p target genes in BC. Initially we found that miR-182-5p expression was significantly higher in bladder cancer compared to normal tissues and high miR-182-5p expression was associated with shorter overall survival in BC patients. To study the functional significance of miR-182-5p, we over-expressed miR-182-5p with miR-182-5p precursor and observed that cell proliferation, migration and invasion abilities were increased in BC cells. However cell apoptosis was inhibited by miR-182-5p. We also identified Smad4 and RECK as potential target genes of miR-182-5p using several algorithms. 3′UTR luciferase activity of these target genes was significantly decreased and protein expression of these target genes was significantly up-regulated in miR-182-5p inhibitor transfected bladder cancer cells. MiR-182-5p also increased nuclear beta-catenin expression and while Smad4 repressed nuclear beta-catenin expression. In conclusion, our data suggests that miR-182-5p plays an important role as an oncogene by knocking down RECK and Smad4, resulting in activation of the Wnt-beta-catenin signaling pathway in bladder cancer.     

Long noncoding RNA lnc-ABCA12-3 promotes cell migration,invasion, and proliferation by regulating fibronectin 1 in esophageal squamous cell carcinoma

Long noncoding RNAs (lncRNAs) have been shown to play important roles in human cancers, including esophageal squamous cell carcinoma (ESCC). We previously demonstrated that a novel lncRNA, lnc-ABCA12-3, was overexpressed in ESCC tissues. However, the exact function of lnc-ABCA12-3 is unknown. In the current study, we aimed to evaluate the expression of lnc-ABCA12-3 in ESCC and to explore the potential mechanism of lnc-ABCA12-3 in cell migration, invasion, and proliferation. We showed that lnc-ABCA12-3 was upregulated in ESCC tumor tissues and cell lines. The increased expression of lnc-ABCA12-3 was positively associated with advanced tumor-node-metastasis stages and poor prognosis. The knockdown of lnc-ABCA12-3 inhibited the cell migration, invasion, and proliferation abilities of KYSE-510 and Eca-109 cells. We also found that fibronectin 1 (FN1) was upregulated in ESCC tumor tissues. The expression of FN1 messenger RNA was positively correlated with the expression of lnc-ABCA12-3 in ESCC tumor tissues. After lnc-ABCA12-3 knockdown, the expression of FN1 was downregulated. In addition, the overexpression of FN1 restored the abilities of cell migration, invasion and proliferation in Eca-109 cells. Further studies indicated that lnc-ABCA12-3 acted as a competing endogenous RNA for miR-200b-3p to regulate FN1 expression. In conclusion, these results suggest that lnc-ABCA12-3 is a novel oncogene in tumorigenesis and that its high expression is related to a poor prognosis for patients with ESCC. lnc-ABCA12-3 promotes cell migration, invasion, and proliferation via the regulation of FN1 in ESCC. Our data suggest that lnc-ABCA12-3 might serve as a potential prognostic biomarker and therapeutic target for ESCC.     

Circular RNA TUBA1C accelerates the progression of non-small-cell lung cancer by sponging miR-143-3p

Non-small-cell lung cancer (NSCLC) is one of the most common solid tumors and the leading cause of lung cancer-related fatality. Growing evidence has indicated that circular RNAs (circRNAs) play important roles in the progression of multiple human cancers. As a novel circRNA, very little research has focused on the function of circRNA TUBA1C (circTUBA1C) in cancer development, including NSCLC. In the present study, we found that the expression of circTUBA1C was significantly upregulated in NSCLC tissues. The loss-of function assays suggested that circTUBA1C deficiency notably hampered cell proliferation as well as accelerated cell apoptosis in NSCLC. In mechanism, we discovered that circTUBA1C could act as a sponge for miR-143-3p and then negatively regulate miR-143-3p. Moreover, rescue assays demonstrated that knockdown of miR-143-3p could reverse circTUBA1C silence-mediated effects on cell proliferation and apoptosis. Besides, we established a xenografted tumor model to investigate the function of circTUBA1C in vivo. The result illustrated that the decline of tumor growth resulted from circTUBA1C deficiency could be recovered by miR-143-3p knockdown. Taken together, these findings indicated the important role of circTUBA1C/miR-143-3p axis in NSCLC, which may provide a potential target for NSCLC therapy.