Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (2)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: RIPK1 (cancer-related)
Huang D, Wei Y, Zhu J, Wang FLong non-coding RNA SNHG1 functions as a competitive endogenous RNA to regulate PDCD4 expression by sponging miR-195-5p in hepatocellular carcinoma.
Gene. 2019; 714:143994 [PubMed
] Related Publications
Long non-coding RNA (lncRNA) potentially regulates tumorigenesis. LncRNA small nucleolar RNA host gene 1 (SNHG1) expression remains high in hepatocellular carcinoma cells; however, its biological mechanism in hepatocellular carcinoma remains unknown. In this study, SNHG1 expression in hepatocellular carcinoma cells was detected by qRT-PCR. Proliferative and migratory potentials of hepatocellular carcinoma cells were determined by CCK-8 and Transwell assay, respectively. Then, the nude mice model of xenograft was employed to verify the effect of SNHG1 on tumor formation in vivo. We identified the potential target of SNHG1 through bioinformatics and dual-luciferase reporter gene. Furthermore, Western blot and RIP assay was used for clarifying their interaction and functions in regulating the development of hepatocellular carcinoma. Our results indicated a high expression of SNHG1 in hepatocellular carcinoma cells. Downregulation of SNHG1 inhibited proliferative and migratory potentials of hepatocellular carcinoma cells in vitro and in vivo. Moreover, the expression of programmed cell death 4 (PDCD4) was positively regulated by SNHG1 through competing with miR-195-5p. These results indicated that SNHG1 participated in the development of hepatocellular carcinoma as a ceRNA to competitively bind to miR-195-5p and thus mediate PDCD4 expression.
Zhi H, Lian JLncRNA BDNF-AS suppresses colorectal cancer cell proliferation and migration by epigenetically repressing GSK-3β expression.
Cell Biochem Funct. 2019; 37(5):340-347 [PubMed
] Related Publications
This study was designed to investigate the molecular mechanism and biological roles of long non-coding RNA (lncRNA) brain-derived neurotrophic factor antisense (BDNF-AS) in colorectal cancer (CRC). The quantitative real-time PCR (qRT-PCR) and western blotting were performed to detect the expressions of lncRNA BDNF-AS and glycogen synthase kinase-3β (GSK-3β) in human CRC tissues and cell lines. The cell proliferation, transwell migration, and invasion assays were carried out to evaluate the effect of lncRNA BDNF-AS on the growth of CRC cells. RNA pull-down and RNA immunoprecipitation (RIP) assays were conducted to confirm the interaction between lncRNA BDNF-AS and enhancer of Zeste Homologue 2 (EZH2). Chromatin immunoprecipitation (ChIP) assay was used to verify the enrichment of EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) in the promoter region of GSK-3β in CRC cells. LncRNA BDNF-AS expression was significantly decreased, while GSK-3β was highly expressed in human CRC tissues and cell lines. Moreover, lncRNA BDNF-AS induced inhibition of proliferation, migration, and invasion of CRC cells via inhibiting GSK-3β expression. Mechanistically, BDNF-AS led to GSK-3β promoter silencing in CRC cells through recruitment of EZH2. In conclusion, lncRNA BDNF-AS functioned as an oncogene in CRC and shed new light on lncRNA-directed therapeutics in CRC. SIGNIFICANCE OF THE STUDY: LncRNA BDNF-AS is recently reported to be remarkably downregulated in a variety of tumours and served as a tumour suppressor. However, the functions and underlying mechanism of lncRNA BDNF-AS in CRC pathogenesis have not been reported yet. Our study is the first to demonstrate the effect of lncRNA BDNF-AS in CRC and revealed that lncRNA BDNF-AS expression is negatively correlated with the aggressive biological behaviour of CRC. Further investigation demonstrated that lncRNA BDNF-AS functioned as a tumour suppressor in CRC progression by suppressing GSK-3β expression through binding to EZH2 and H3K27me3 with the GSK-3β promoter, shedding light on the diagnosis and therapy for CRC.
Translation and transcription are frequently dysregulated in cancer. These two processes are generally regulated by distinct sets of factors. The CBFB gene, which encodes a transcription factor, has recently emerged as a highly mutated driver in a variety of human cancers including breast cancer. Here we report a noncanonical role of CBFB in translation regulation. RNA immunoprecipitation followed by deep sequencing (RIP-seq) reveals that cytoplasmic CBFB binds to hundreds of transcripts and regulates their translation. CBFB binds to mRNAs via hnRNPK and enhances translation through eIF4B, a general translation initiation factor. Interestingly, the RUNX1 mRNA, which encodes the transcriptional partner of CBFB, is bound and translationally regulated by CBFB. Furthermore, nuclear CBFB/RUNX1 complex transcriptionally represses the oncogenic NOTCH signaling pathway in breast cancer. Thus, our data reveal an unexpected function of CBFB in translation regulation and propose that breast cancer cells evade translation and transcription surveillance simultaneously through downregulating CBFB.
Song W, Gu Y, Lu S, et al.LncRNA TRERNA1 facilitates hepatocellular carcinoma metastasis by dimethylating H3K9 in the CDH1 promoter region via the recruitment of the EHMT2/SNAI1 complex.
Cell Prolif. 2019; 52(4):e12621 [PubMed
] Related Publications
OBJECTIVES: Long non-coding RNAs (LncRNAs) play an important role in hepatocellular carcinoma development, however, as a crucial driver of hepatocellular carcinoma (HCC) metastasis, their functions in tumour metastasis remain largely unknown.
MATERIALS AND METHODS: The lncRNA TRERNA1 expression levels were detected in HCC by quantitative real-time PCR (qPCR). The function of TRERNA1 was examined by wound-healing assays, transwell assays and tail vein injection experiments. The potential regulatory mechanisms of TRERNA1 on its target genes were explored by ChIP, RIP, IP and WB assays.
RESULTS: Elevated TRERNA1 levels promoted HCC cell migration and invasion in vitro and in vivo. TRERNA1 recruited EHMT2 to dimethylate H3K9 in the CDH1 promoter region. Furthermore, EHMT2 bound to SNAI1 to suppress CDH1 expression in HCC cells. After inhibiting TRERNA1, the expression level of CDH1 was restored and was involved in the regulation of the EHMT2/SNAI1 complex. The level of TRERNA1 was positively correlated with tumour metastasis and was negatively correlated with the expression of CDH1 in HCC tissues.
CONCLUSIONS: For the first time, the current study reveals that TRERNA1 promotes cell metastasis and the invasion of HCC via the recruitment of EHMT2 and/or the EHMT2/SNAI1 complex to suppress CDH1. These data identify a novel mechanism that regulates TRERNA1 in metastatic HCC and provides a potential targeted therapy for HCC patients.
BACKGROUND: Acquired drug resistance is a constraining factor in clinical treatment of glioblastoma (GBM). However, the mechanisms of chemoresponsive tumors acquire therapeutic resistance remain poorly understood. Here, we aim to investigate whether temozolomide (TMZ) resistance of chemoresponsive GBM was enhanced by long non-coding RNA SBF2 antisense RNA 1 (lncRNA SBF2-AS1) enriched exosomes.
METHOD: LncSBF2-AS1 level in TMZ-resistance or TMZ-sensitive GBM tissues and cells were analyzed by qRT-PCR and FISH assays. A series of in vitro assay and xenograft tumor models were performed to observe the effect of lncSBF2-AS1 on TMZ-resistance in GBM. CHIP assay were used to investigate the correlation of SBF2-AS1 and transcription factor zinc finger E-box binding homeobox 1 (ZEB1). Dual-luciferase reporter, RNA immunoprecipitation (RIP), immunofluorescence and western blotting were performed to verify the relation between lncSBF2-AS1, miR-151a-3p and XRCC4. Comet assay and immunoblotting were performed to expound the effect of lncSBF2-AS1 on DNA double-stand break (DSB) repair. A series of in vitro assay and intracranial xenografts tumor model were used to determined the function of exosomal lncSBF2-AS1.
RESULT: It was found that SBF2-AS1 was upregulated in TMZ-resistant GBM cells and tissues, and overexpression of SBF2-AS1 led to the promotion of TMZ resistance, whereas its inhibition sensitized resistant GBM cells to TMZ. Transcription factor ZEB1 was found to directly bind to the SBF2-AS1 promoter region to regulate SBF2-AS1 level and affected TMZ resistance in GBM cells. SBF2-AS1 functions as a ceRNA for miR-151a-3p, leading to the disinhibition of its endogenous target, X-ray repair cross complementing 4 (XRCC4), which enhances DSB repair in GBM cells. Exosomes selected from temozolomide-resistant GBM cells had high levels of SBF2-AS1 and spread TMZ resistance to chemoresponsive GBM cells. Clinically, high levels of lncSBF2-AS1 in serum exosomes were associated with poor response to TMZ treatment in GBM patients.
CONCLUSION: We can conclude that GBM cells remodel the tumor microenvironment to promote tumor chemotherapy-resistance by secreting the oncogenic lncSBF2-AS1-enriched exosomes. Thus, exosomal lncSBF2-AS1 in human serum may serve as a possible diagnostic marker for therapy-refractory GBM.
Li J, He M, Xu W, Huang SLINC01354 interacting with hnRNP-D contributes to the proliferation and metastasis in colorectal cancer through activating Wnt/β-catenin signaling pathway.
J Exp Clin Cancer Res. 2019; 38(1):161 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Long non-coding RNAs (lncRNAs) have been identified to play an important role in the development and progression of various tumors, including colorectal cancer (CRC). However, the regulatory molecular mechanism by lncRNA in CRC initiation and progression has not been fully clarified.
METHODS: TCGA database was used to identify the involvement of LINC01354 in CRC. qRT-PCR and western blot were used to determine RNA and protein expression. The gain- and loss-of-function assays were conducted to explore the function of LINC01354 in the progression of CRC. In order to investigate the LINC01354-mediated mRNA in CRC tumorigenesis, we applied the profiling analysis as well as GO and KEGG analysis. Pulldown and RIP assays were applied to detect the interaction of hnRNP-D with LINC01354 and β-catenin.
RESULTS: The upregulation of LINC01354 in CRC and its prognostic significance were identified by TCGA database and confirmed in CRC tissues. Functionally, forced expression of LINC01354 promoted, while knockdown of LINC01354 inhibited cell proliferation, migration and EMT phenotype formation of CRC cells. A significant enrichment of the Wnt/β-catenin signaling pathway genes under LINC01354 overexpression. In addition, LINC01354 modulated the mRNA stability of β-catenin through interacting with hnRNP-D, thereby activating Wnt/β-catenin signaling pathway.
CONCLUSIONS: Our investigations proposed novel regulatory axis of LINC01354/hnRNP-D/Wnt/β-catenin, which might be in favor of exploring novel therapeutic regimens for the clinical treatment of CRC.
BACKGROUND: Long noncoding RNAs (lncRNAs), defined as the transcripts longer than 200 nt without protein-coding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer. A reciprocal translocation between chromosome 9 and 22 generates the chimeric Bcr-Abl oncogene, which is associated with several hematological malignancies. However, the functional relevance between aberrantly expressed lncRNAs and Bcr-Abl-mediated leukemia remains obscure.
METHODS: LncRNA cDNA microarray was used to identify novel lncRNAs involved in Bcr-Abl-mediated cellular transformation. To study the functional relevance of novel imatinib-upregulated lncRNA (IUR) family in Abl-induced tumorigenesis, Abl-transformed cell survival and xenografted tumor growth in mice was evaluated. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR knockdown (KD) transgenic mice were further conducted to corroborate the role of lncRNA-IUR in Abl-induced tumorigenesis. Transcriptome RNA-seq, Western blot, RNA pull down and RNA Immunoprecipitation (RIP) were employed to determine the mechanisms by which lncRNA-IUR-5 regulates Bcr-Abl-mediated tumorigenesis.
RESULTS: We identified a conserved lncRNA-IUR family as a key negative regulator of Bcr-Abl-induced tumorigenesis. Increased expression of lncRNA-IUR was detected in both human and mouse Abl-transformed cells upon imatinib treatment. In contrast, reduced expression of lncRNA-IUR was observed in the peripheral blood lymphocytes derived from Bcr-Abl-positive acute lymphoblastic leukemia (ALL) patients compared to normal subjects. Knockdown of lncRNA-IUR remarkably promoted Abl-transformed leukemic cell survival and xenografted tumor growth in mice, whereas overexpression of lncRNA-IUR had opposite effects. Also, silencing murine lncRNA-IUR promoted Bcr-Abl-mediated primary bone marrow transformation and Abl-transformed leukemia cell survival in vivo. Besides, knockdown of murine lncRNA-IUR in transgenic mice provided a favorable microenvironment for development of Abl-mediated leukemia. Finally, we demonstrated that lncRNA-IUR-5 suppressed Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71.
CONCLUSIONS: The results suggest that lncRNA-IUR may act as a critical tumor suppressor in Bcr-Abl-mediated tumorigenesis by suppressing the STAT5-CD71 pathway. This study provides new insights into functional involvement of lncRNAs in leukemogenesis.
BACKGROUND: Accumulating evidence shows that, the dysregulation of circular RNAs (circRNAs) is associated with the progression of multiple malignancies. But, the underlying mechanisms by which has_circ_0032627 (circDLST) contributed to gastric cancer (GC) remain undocumented.
METHODS: The expression and cellular localization of circDLST and its association with clinicopathological characteristics and prognosis in patients with GC was analysed by using fluorescence in situ hybridization. Gain- and loss-of-function experiments as well as a subcutaneous xenograft tumor model and a liver metastasis model from orthotopic implantation of GC tissues were conducted to assess the role of circDLST in GC cells. CircDLST specific binding with miR-502-5p was confirmed by dual luciferase gene report, RNA immunoprecipitation (RIP) assays and RIP-miRNA expression profiling. qRT-PCR and Western blot analysis was used to detect the effects of circDLST on miR-502-5p-mediated NRAS/MEK1/ERK1/2 signaling in GC cells.
RESULTS: The expression levels of circDLST were dramatically elevated in GC tissues as compared with the adjacent normal tissues, and acted as an independent prognostic factor of poor survival in patients with GC. Knockdown of circDLST inhibited the cell viability, colony formation, DNA synthesis, cell invasion and liver metastasis in vitro and in vivo, whereas overexpression of circDLST had the opposite effects. Furthermore, circDLST was co-localized with miR-502-5p in the cytoplasm of GC cells, and acted as a sponge of miR-502-3p in GC cells, which abrogated the tumor promoting effects of circDLST by inactivating the NRAS/MEK1/ERK1/2 signaling in GC cells.
CONCLUSION: CircDLST promotes the tumorigenesis and metastasis of GC cells by sponging miR-502-5p to activate the NRAS/MEK1/ERK1/2 signaling.
Miao L, Liu HY, Zhou C, He XLINC00612 enhances the proliferation and invasion ability of bladder cancer cells as ceRNA by sponging miR-590 to elevate expression of PHF14.
J Exp Clin Cancer Res. 2019; 38(1):143 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Bladder cancer (BC) is a common type of cancer that involves tumors of the urinary system and poses a serious threat to human health. Long noncoding RNAs (lncRNAs) have emerged as crucial biomarkers and regulators in many cancers. Novel lncRNA biomarkers in BC urgently need to be investigated in regard to its function and regulatory mechanisms.
METHODS: Identification of differentially expressed lncRNAs in BC tissue was performed via microarray analysis. To investigate the biological functions of LINC00612, loss-of-function and gain-of-function experiments were performed in vitro and in vivo. Bioinformatics analysis, dual-luciferase reporter assays, AGO2-RIP assays, RNA pull-down assays, real-time quantitative PCR (RT-qPCR) arrays, fluorescence in situ hybridization assays, and western blot assays were conducted to explore the underlying mechanisms of competitive endogenous RNAs (ceRNAs).
RESULTS: LINC00612 was upregulated in BC tissues and cell lines. Functionally, downregulation of LINC00612 inhibited cell proliferation and invasion in vitro and in vivo, whereas overexpression of LINC00612 resulted in the opposite effects. Bioinformatics analysis and luciferase assays revealed that miR-590 was a direct target of LINC0061, which was validated by dual-luciferase reporter assays, AGO2-RIP assays, RNA pull-down assays, RT-qPCR arrays, and rescue experiments. Additionally, miR-590 was shown to directly target the PHD finger protein 14 (PHF14) gene. LNIC00612 modulated the expression of E-cadherin and vimentin by competitively sponging miR-590 to elevate the expression of PHF14, thus affecting BC cellular epithelial-mesenchymal transition (EMT).
CONCLUSIONS: Our results indicate that LINC00612 enhances the proliferation and invasion ability of BC cells by sponging miR-590 to upregulate PHF14 expression and promote BC cellular EMT, suggesting that LINC00612 may act as a potential biomarker and therapeutic target for BC.
BACKGROUND: As a subclass of noncoding RNAs, circular RNAs (circRNAs) have been demonstrated to play a critical role in regulating gene expression in eukaryotes. Recent studies have revealed the pivotal functions of circRNAs in cancer progression. However, little is known about the role of circTADA2A, also named hsa_circ_0043278, in osteosarcoma (OS).
METHODS: CircTADA2A was selected from a previously reported circRNA microarray comparing OS cell lines and normal bone cells. QRT-PCR was used to detect the expression of circTADA2A in OS tissue and cell lines. Luciferase reporter, RNA immunoprecipitation (RIP), RNA pull-down and fluorescence in situ hybridization (FISH) assays were performed to confirm the binding of circTADA2A with miR-203a-3p. OS cells were stably transfected with lentiviruses, and Transwell migration, Matrigel invasion, colony formation, proliferation, apoptosis, Western blotting, and in vivo tumorigenesis and metastasis assays were employed to evaluate the roles of circTADA2A, miR-203a-3p and CREB3.
RESULTS: Our findings demonstrated that circTADA2A was highly expressed in both OS tissue and cell lines, and circTADA2A inhibition attenuated the migration, invasion and proliferation of OS cells in vitro as well as tumorigenesis and metastasis in vivo. A mechanistic study revealed that circTADA2A could readily sponge miR-203a-3p to upregulate the expression of CREB3, which was identified as a driver gene in OS. Furthermore, miR-203a-3p inhibition or CREB3 overexpression could reverse the circTADA2A silencing-induced impairment of malignant tumor behavior.
CONCLUSIONS: CircTADA2A functions as a tumor promoter in OS to increase malignant tumor behavior through the miR-203a-3p/CREB3 axis, which could be a novel target for OS therapy.
BACKGROUND: Circular RNAs (circRNAs) are a novel type of noncoding RNAs and play important roles in tumorigenesis, including gastric cancer (GC). However, the functions of most circRNAs remain poorly understood. In our study, we aimed to investigate the functions of a new circRNA circ-DONSON in GC progression.
METHODS: The expression of circ-DONSON in gastric cancer tissues and adjacent normal tissues was analyzed by bioinformatics method, qRT-PCR, Northern blotting and in situ hybridization (ISH). The effects of circ-DONSON on GC cell proliferation, apoptosis, migration and invasion were measured by using CCK8, colony formation, EdU, immunofluorescence (IF), FACS and Transwell assays. qRT-PCR and Western blotting were utilized to validate how circ-DONSON regulates SOX4 expression. ChIP, DNA fluorescence in situ hybridization (DNA-FISH) and DNA accessibility assays were used to investigate how circ-DONSON regulates SOX4 transcription. The interaction between circ-DONSON and NURF complex was evaluated by mass spectrum, RNA immunoprecipitation (RIP), pulldown and EMSA assays. Xenograft mouse model was used to analyze the effect of circ-DONSON on GC growth in vivo.
RESULTS: Elevated expression of circ-DONSON was observed in GC tissues and positively associated with advanced TNM stage and unfavorable prognosis. Silencing of circ-DONSON significantly suppressed the proliferation, migration and invasion of GC cells while promoting apoptosis. circ-DONSON was localized in the nucleus, recruited the NURF complex to SOX4 promoter and initiated its transcription. Silencing of the NURF complex subunit SNF2L, BPTF or RBBP4 similarly attenuated GC cell growth and increased apoptosis. circ-DONSON knockdown inhibited GC growth in vivo.
CONCLUSION: circ-DONSON promotes GC progression through recruiting the NURF complex to initiate SOX4 expression.
Wu J, Tang Q, Ren X, et al.Reciprocal interaction of HOTAIR and SP1 together enhance the ability of Xiaoji decoction and gefitinib to inhibit EP4 expression.
J Ethnopharmacol. 2019; 237:128-140 [PubMed
] Related Publications
ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal prescription Xiaoji decoction (XJD) has long been used for cancer treatment. However, the molecular mechanisms underlying the effects of this medicine, particularly to enhance the efficiency of EGFR-TKI in the treatment of lung cancer have not been well elucidated.
MATERIALS AND METHODS: Cell viability and cell cycle distribution were detected by MTT assay and flow cytometry, respectively. The phosphorylation of ERK1/2 and protein levels of SP1 and EP4 were determined by Western blot. The expression of the HOX transcript antisense RNA (HOTAIR) was measured by qRT-PCR. Transient transfection experiments were used to overexpress the HOTAIR, SP1 and EP4 genes. The interaction between HOTAIR and SP1 were further examined via RNA immunoprecipitation (RIP) assay. A tumor xenograft model was used to confirm the in vitro findings.
RESULTS: We showed that XJD inhibited growth and induced cell arrest of human non-small cell lung cancer (NSCLC) cells. We also found that XJD increased the phosphorylation of ERK1/2 and inhibited levels of HOTAIR and SP1, EP4 proteins, which were blocked by inhibitor of MEK/ERK. There was reciprocal interaction between HOTAIR and SP1. Silencing of HOTAIR reduced EP4 protein levels and repressed the growth of NSCLC cells, while overexpression of HOTAIR and SP1 overcame XJD-reduced EP4 protein expression. Additionally, excessive expressed EP4 reversed the effect of XJD on cell growth. Importantly, there was synergy of XJD with another cancer treatment drug, EGFR-TKI gefitinib, in this process. We also found that XJD inhibited tumor growth in a xenograft nude mice model.
CONCLUSIONS: Our results show that XJD inhibits NSCLC cell growth via ERK1/2-mediated reciprocal repression of HOTAIR and SP1 protein expression, followed by reduced EP4 gene expression. XJD and gefitinib exhibit synergy in this process. The in vitro and in vivo study provides a novel mechanism by which XJD enhances the growth inhibitory effect of gefitinib in gefitinib-resistant NSCLC cells.
Zhang L, Chen Y, Li C, et al.RNA binding protein PUM2 promotes the stemness of breast cancer cells via competitively binding to neuropilin-1 (NRP-1) mRNA with miR-376a.
Biomed Pharmacother. 2019; 114:108772 [PubMed
] Related Publications
Others and ours studies have established the promoting roles of NRP-1 (neuropilin-1) in breast cancer, however, the underlying mechanisms by which NRP-1 is regulated are still confused. Here, bioinformatics analysis indicated that RNA binding protein PUM2 could bind to NRP-1 mRNA. Clinical samples showed that PUM2 expression was significantly increased in breast cancer tissues, negatively correlated with the overall survival and relapse-free survival of breast cancer patients, and positively correlated with NRP-1 expression. Meanwhile, PUM2 expression was remarkably increased in non-adherent spheroids. in vitro experiments demonstrated that PUM2 knockdown attenuated the stemness of breast cancer cells, evident by the decrease of spheroid formation capacity, ALDH1 activity and stemness marker expression. Mechanistically, RNA immunoprecipitation (RIP) and luciferase reporter analysis indicated that PUM2 competitively bound to NRP 3'UTR with miR-376a, which had been previously confirmed by us to suppress the stemness of breast cancer cells, and increased NRP-1 mRNA stability and expression. Furthermore, ectopic expression of NRP-1 or miR-376a knockdown rescued the inhibitory effects of NRP-1 knockdown on the stemness of breast cancer cells. Thus, our results suggest that PUM2 could facilitate the stemness of breast cancer cells by competitively binding to NRP-1 3'UTR with miR-376a.
Dong D, Mu Z, Wei N, et al.Long non-coding RNA ZFAS1 promotes proliferation and metastasis of clear cell renal cell carcinoma via targeting miR-10a/SKA1 pathway.
Biomed Pharmacother. 2019; 111:917-925 [PubMed
] Related Publications
BACKGROUND: LncRNA ZFAS1 (ZNFX1 antisense RNA1) plays key roles in the occurrence and progression of various cancers, including colorectal cancer, glioma, lung cancer, gastric cancer, and so on. To date, relatively little is known about its potential role in development and/or progression of clear cell renal cell carcinoma (ccRCC).
METHODS: Expression level of ZFAS1 and miR-10a in 60 ccRCC and 20 adjacent non-tumor tissues were determined by using qRT-PCR. The effect of knockdown of ZFAS1 on cell proliferation, migration and invasion were measured by CCK-8 assay, transwell migration and invasion assay, respectively. The correlation of ZFAS1 and miR-10a was analyzed by bioinformatics DIANA TOOLS. Protein and mRNA expression of spindle and kinetochore-associated protein 1(SKA1) were determined by western blot and qRT-PCR analysis, respectively. Interactions between ZFAS1 and miR-10a were verified by luciferase reporter assay and RNA immunoprecipitation (RIP) assay, and interactions between miR-10a and SKA1 was verified by a luciferase reporter assay.
RESULTS: We observed that high-level expression of ZFAS1 is positively correlated with poor prognosis and shorter overall survival (OS) in patients with ccRCC. Knockdown of ZFAS1 significantly suppressed proliferation, migration and invasion of ccRCC cells. Furthermore, miR-10a was identified as a target of ZFAS1. Silencing miR-10a could attenuate the ability of ZFAS1 in promoting proliferation and metastasis of ccRCC. Subsequently, our studies validated that SKA1, as a key downstream target protein for miR-10a, is responsible for the biological role of ZFAS1. ZFAS1 positively regulated SKA1 expression via sponging miR-10a.
CONCLUSIONS: Taken together, our findings suggest that ZFAS1 promotes growth and metastasis of ccRCC via targeting miR-10a/SKA1 pathway, which may represent a novel therapeutic target or biomarker for ccRCC.
Zhang L, Liu SK, Song L, Yao HRSP1-induced up-regulation of lncRNA LUCAT1 promotes proliferation, migration and invasion of cervical cancer by sponging miR-181a.
Artif Cells Nanomed Biotechnol. 2019; 47(1):556-564 [PubMed
] Related Publications
Long noncoding RNA lung cancer associated transcript 1 (LUCAT1) has been shown to be a lncRNA that facilitates the development and progression of several tumours. However, the evidence of LUCAT1 modulating the growth and metastasis of cervical cancer (CC) were still lacking. The present study aimed to explore the expression pattern, biological function and potential mechanism of LUCAT1 in CC. In this study, we, first, confirmed that LUCAT1 acted as an up-regulated lncRNA by analyzing the data from GCTA dataset and RT-PCR in both CC tissues and cell lines. We also showed that TINCR overexpression is induced by nuclear transcription factor SP1. Then, clinical assays showed that LUCAT1 was associated with advanced clinical progression and poor prognosis of CC patients. Importantly, multivariate Cox model confirmed that LUCAT1 expression was an independent prognostic factor for both 5-year overall survival in CC. Then, lost-function assays revealed that knockdown of LUCAT1 significantly suppressed CC cells proliferation, colony formation, migration, invasion and EMT by a series of cells experiments. Mechanistically, Bioinformatic tools predicted that miR-181a may target LUCAT1, which was confirmed using luciferase reporter assay and RNA immunoprecipitation (RIP) assays. Overall, our findings showed that SP1-activated LUCAT1 exerts an oncogenic function in CC by binding to miR-181a, suggesting that miR-181a may be a ponderable and promising therapeutic target for CC.
BACKGROUND: The long non-coding RNA PVT1 (lncRNA PVT1) has been reported to act as an oncogenic regulator of several cancers. However, its expression and function in gallbladder cancer (GBC) remain largely unknown.
METHODS: In situ hybridization (ISH) and quantitative real-time PCR (qPCR) were performed to detect the expression of PVT1 and miR-143 in GBC tissues and cell lines. Immunohistochemistry (IHC) assays were performed to assess the expression of the hexokinase 2 (HK2) protein. The relationships among PVT1, miR-143 and HK2 were evaluated using dual-luciferase reporter, RNA immunoprecipitation (RIP) and biotin pull-down assays. The biological functions of PVT1, miR-143 and HK2 in GBC cells were explored with cell counting kit 8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU), colony formation, transwell, wound healing and glucose metabolism assays in vitro. For in vivo experiments, a xenograft model was used to investigate the effects of PVT1 and HK2 on GBC.
RESULTS: PVT1 was upregulated in GBC tissues and cells and was positively associated with malignancies and worse overall survival. PVT1 knockdown inhibited cell proliferation, migration, and invasion in vitro and restrained tumor growth in vivo. Further studies demonstrated that PVT1 positively regulated HK2 expression via its competing endogenous RNA (ceRNA) activity on miR-143. Additionally, HK2 expression and function were positively correlated with PVT1. Furthermore, we observed that the PVT1/miR-143/HK2 axis promoted cell proliferation and metastasis by regulating aerobic glucose metabolism in GBC cells.
CONCLUSIONS: The results of our study reveal a potential ceRNA regulatory pathway in which PVT1 modulates HK2 expression by competitively binding to endogenous miR-143 in GBC cells, which may provide new insights into novel molecular therapeutic targets for GBC.
Gao R, Zhang N, Yang J, et al.Long non-coding RNA ZEB1-AS1 regulates miR-200b/FSCN1 signaling and enhances migration and invasion induced by TGF-β1 in bladder cancer cells.
J Exp Clin Cancer Res. 2019; 38(1):111 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: The effect of competing endogenous RNA (ceRNA) can regulate gene expression by competitively binding microRNAs. Fascin-1 (FSCN1) plays an important role in the regulation of cellular migration and invasion during tumor progression, but how its regulatory mechanism works through the ceRNA effect is still unclear in bladder cancer (BLCA).
METHODS: The role of fascin-1, miR-200b, and ZEB1-AS1 in BLCA was investigated in vitro and in vivo. The interaction between fascin-1, miR-200b, and ZEB1-AS1 was identified using bioinformatics analysis, luciferase activity assays, RNA-binding protein immunoprecipitation (RIP), quantitative PCR, and western blotting. Loss (or gain)-of-function experiments were performed to investigate the biological roles of miR-200b and ZEB1-AS1 on migration, invasion, proliferation, cell apoptosis, and cell cycle.
RESULTS: ZEB1-AS1 functions as a competing endogenous RNA in BLCA to regulate the expression of fascin-1 through miR-200b. Moreover, the oncogenic long non-coding RNA ZEB1-AS1 was highly expressed in BLCA and positively correlated with high tumor grade, high TNM stage, and reduced survival of patients with BLCA. Moreover, ZEB1-AS1 downregulated the expression of miR-200b, promoted migration, invasion, and proliferation, and inhibited apoptosis in BLCA. Furthermore, we found TGF-β1 induced migration and invasion in BLCA by regulating the ZEB1-AS1/miR-200b/FSCN1 axis.
CONCLUSION: The observations in this study identify an important regulatory mechanism of fascin-1 in BLCA, and the TGF-β1/ZEB1-AS1/miR-200b/FSCN1 axis may serve as a potential target for cancer therapeutic purposes.
The globo-series glycosphingolipids (GSLs) SSEA3, SSEA4, and Globo-H specifically expressed on cancer cells are found to correlate with tumor progression and metastasis, but the functional roles of these GSLs and the key enzyme β1,3-galactosyltransferase V (β3GalT5) that converts Gb4 to SSEA3 remain largely unclear. Here we show that the expression of β3GalT5 significantly correlates with tumor progression and poor survival in patients, and the globo-series GSLs in breast cancer cells form a complex in membrane lipid raft with caveolin-1 (CAV1) and focal adhesion kinase (FAK) which then interact with AKT and receptor-interacting protein kinase (RIP), respectively. Knockdown of β3GalT5 disrupts the complex and induces apoptosis through dissociation of RIP from the complex to interact with the Fas death domain (FADD) and trigger the Fas-dependent pathway. This finding provides a link between SSEA3/SSEA4/Globo-H and the FAK/CAV1/AKT/RIP complex in tumor progression and apoptosis and suggests a direction for the treatment of breast cancer, as demonstrated by the combined use of antibodies against Globo-H and SSEA4.
BACKGROUND: Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. PD-L1 could promote the expression of stemness markers (OCT4 and Nanog) in breast cancer stem cells. However, the mechanisms by which PD-L1 regulates the stemness of breast cancer cells and PD-L1 is regulated in breast cancer cells are still unclear.
METHODS: Lentivirus infection was used to construct stable cell lines. The correlation between PD-L1 and stemness markers expression was evaluated in clinical samples. Additionally, luciferase reporter assay combined with RNA-Fluorescence in situ hybridization (RNA-FISH) and RNA-binding protein immunoprecipitation (RIP) assays were used to verify the direct binding of miR-873 on PD-L1. Furthermore, flow cytometry, mammosphere formation combined with nude mouse tumor xenograft model were carried out to examine the effects of miR-873/PD-L1 axis on the stemness of breast cancer cells. Finally, MTT assay was performed to determine the effects of miR-873/PD-L1 axis on drug resistance.
FINDINGS: PD-L1 expression was positively correlated with the expression of stemness markers, and overexpression of PD-L1 contributed to chemoresistance and stemness-like properties in breast cancer cells via activating PI3K/Akt and ERK1/2 pathways. Mechanistically, miR-873 inhibited PD-L1 expression through directly binding to its 3'-untranslated region (UTR), and miR-873 attenuated the stemness and chemoresistance of breast cancer cells which was dependent on PD-L1 and the downstream PI3K/Akt and ERK1/2 signaling. Notably, the promotion of PD-L1 on the stemness and chemoresistance was enhanced by recombinant PD-1 (rPD-1), this effect was attenuated by PD-1/PD-L1 inhibitor.
INTERPRETATION: miR-873/PD-L1 regulatory axis might serve as a therapeutic target to enhance the chemo-sensitivity and eliminate the stemness of breast cancer cells. FUND: This work was supported by the National Nature Science Foundation of China, No. 81702957, China Postdoctoral Science Foundation, No. 2017M620230, the Postdoctoral Research Funding Scheme of Jiangsu Province (2017), No. 1701197B, and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.
BACKGROUND: The cross-talk between RNA binding proteins (RBPs) and microRNAs (miRNAs) in the regulation of gene expression is a complex process. Here, we describe a new mode of regulation of TRIM25 expression mediated by an antagonistic interplay between IGF2BP3 and miR-3614-3p.
METHODS: The expression level of TRIM25, IGF2BP3, pri-miR-3614 and miR-3614-3p in breast cancer (BC) tissues, non-tumor tissues and BC cell lines were detected by qRT-PCR, Western blot and Immunohistochemistry (IHC). Binding of miR-3614-3p and IGF2BP3 to TRIM25 RNA was verified using luciferase activation assays, RNA immunoprecipitation (RIP) and biotin pull-down assays. In vitro and in vivo loss- and gain-of-function studies were performed to reveal the effects and related mechanism of IGF2BP3-miR-3614-3p-TRIM25 axis in in breast cancer cells proliferation.
FINDINGS: We found that an intragenic miRNA-3614-3p inhibits the expression of its host gene TRIM25 by binding to its 3'- untranslated region (UTR). Interestingly, IGF2BP3 can competitively occupy this binding site and inhibit miRNA-3614 maturation, thereby protecting TRIM25 mRNA from miR-3614-mediated degradation. The overexpression of miR-3614-3p dramatically inhibited breast cancer cell growth through the downregulation of TRIM25. Furthermore, the silencing of IGF2BP3 reduced TRIM25 expression, suppressed cell proliferation, and exhibited a synergistic effect with miR-3614-3p overexpression.
INTERPRETATION: Collectively, these results demonstrate that control of TRIM25 RNA by an interplay between IGF2BP3 and miR-3614-3p represents a mechanism for breast cancer cell proliferation. FUND: The scientific research and sharing platform construction project of Shaanxi Province, Opening Project of Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, China Postdoctoral Science Foundation and The National Natural Science Foundation of China.
Zheng S, Jiang F, Ge D, et al.LncRNA SNHG3/miRNA-151a-3p/RAB22A axis regulates invasion and migration of osteosarcoma.
Biomed Pharmacother. 2019; 112:108695 [PubMed
] Related Publications
To elucidate the potential function of lncRNA SNHG3 in the development of osteosarcoma. Quantitative real-time polymerase chain reaction was conducted for detection of SNHG3, miRNA-151a-3p and RAB22 A in osteosarcoma tissues and cells. Receiver operating characteristic curve was introduced to analyze the diagnostic potential of SNHG3 in osteosarcoma. Correlation between SNHG3 expression and the overall survival of osteosarcoma patients was evaluated using Kaplan-Meier method. Invasive and migratory potentials of osteosarcoma cells were examined by Transwell assay. Furthermore, dual-luciferase reporter gene assay, RNA-pull down and RIP assay were used to verify the binding of SNHG3/RAB22 A to miRNA-151a-3p. The function of SNHG3/miRNA-151a-3p/RAB22 A axis in osteosarcoma was finally confirmed by rescue experiments. SNHG3 and RAB22 A were highly expressed in osteosarcoma patients, while miRNA-151a-3p was lowly expressed. The overall survival of osteosarcoma patients with high expression of SNHG3 was shorter than those with low expression. SNHG3 overexpression markedly promoted invasive and migratory potentials of osteosarcoma cells. Through dual-luciferase reporter gene assay, both SNHG3 and RAB22 A could bind to miRNA-151a-3p. RAB22 A expression was positively regulated by SNHG3, but negatively regulated by miRNA-151a-3p. Finally, rescue experiments confirmed that RAB22 A overexpression could reverse the promotive effects of miRNA-151a-3p knockdown on invasive and migratory potentials of osteosarcoma cells. SNHG3 is highly expressed in osteosarcoma, and promotes the invasive and migratory potentials of osteosarcoma cells by absorbing miRNA-151a-3p to upregulate RAB22 A expression.
BACKGROUND It is well documented that long non-coding RNAs (lncRNAs) are involved in the progression of multiple human tumors by sponging microRNAs (miRNAs). However, whether lncRNA TFAP2A-AS1 plays a role in the tumorigenesis of breast cancer (BC) remains undetermined. MATERIAL AND METHODS Real-time PCR (qRT-PCR) assay was performed to detect the relative mRNA expression of TFAP2A-AS1 and miR-933. Flow cytometry analysis, CCK-8 assay, and Transwell assay were applied to detect the effects of TFAP2A-AS1 overexpression on cell cycle, apoptosis, viability, and invasion of BC cells. In vivo proliferation assay was performed to evaluate the effects of TFAP2A-AS1 overexpression on tumor growth. Bioinformatics methods, dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays were used to predict and validate the interaction between TFAP2A-AS1 and miR-933, as well as SMAD2 and miR-933. Western blot assay was performed to examine the protein expression of SMAD2 in treated BC cells. RESULTS TFAP2A-AS1 expression was significantly lower in BC tissues and cell lines, and patients with high TFAP2A-AS1 expression exhibited a better prognosis than those with low TFAP2A-AS1 expression. Overexpression of TFAP2A-AS1 in BC cells caused cell cycle arrest, promoted cell apoptosis, suppressed cell ability, and attenuated cell invasion in vitro, and inhibited tumor growth in vivo. TFAP2A-AS1 was revealed to act as a miRNA sponge for miR-933 and then regulated the expression of Smad2. CONCLUSIONS Results from the present study suggest that TFAP2A-AS1 acts as a tumor suppressor in BC via the miR-933/SMAD2 axis.
BACKGROUND: Nearly 25% of long intergenic non-coding RNAs (lincRNAs) recruit chromatin-modifying proteins (e.g., EZH2) to silence target genes. HOX antisense intergenic RNA (HOTAIR) is deregulated in diverse cancers and could be an independent and powerful predictor of eventual metastasis and death. Yet, it is challenging to develop small molecule drugs to block activity of HOTAIR with high specificity in a short time.
RESULTS: Our previous study proved that the 5' domain, but not its 3' domain, was the function domain of HOTAIR responsible for tumorigenesis and metastasis in glioblastoma and breast cancer, by recruiting and binding EZH2. Here, we targeted to establish a structure-based methodology to identify lead compounds of HOTAIR, by abrogating scaffold interactions with EZH2. And a small compound AC1NOD4Q (ADQ) was identified by high-throughput molecular docking-based virtual screening of the PubChem library. Our analysis revealed that ADQ was sufficiently and specifically interfering HOTAIR/EZH2 interaction, thereby impairing the H3K27-mediated tri-methylation of NLK, the target of HOTAIR gene, and consequently inhibiting tumor metastasis through Wnt/β-catenin pathway in vitro and in orthotopic breast cancer models. The results of RIP and EMSA further revealed that 36G46A of 5' domain was the essential binding site for ADQ exerted its inhibitory effect, further narrowed the structure and function of HOTAIR from the 5' functional domain to the micro-domain.
CONCLUSIONS: Our findings suggest of a potential new strategy to discover the lead compound for targeted lincRNA therapy and potentially pave the way for exploiting ADQ as a scaffold for more effective small molecule drugs.
Wang Y, Liang Z, Li H, et al.NSPc1 polycomb protein complex binds and cross‑talks to lncRNAs in glioma H4 cells.
Oncol Rep. 2019; 41(4):2575-2584 [PubMed
] Related Publications
Recently, emerging evidence shows that a number of long non‑coding RNAs (lncRNAs) recruit polycomb group (PcG) proteins to specific chromatin loci to silence relevant gene expression. In the present study, we provided evidence that lncRNA candidates, selected by bioinformatic analysis and nervous system polycomb 1 (NSPc1), a key polycomb repressive complex 1 (PRC1) member, were highly expressed in glioma H4 cells in contrast to that noted in non‑cancerous cells. RNA binding protein immunoprecipitation (RIP) assays demonstrated that metastasis associated lung adenocarcinoma transcript 1 (MALAT1), SOX2 overlapping transcript (SOX2OT) and maternally expressed 3 (MEG3) among the 8 candidates bound to the NSPc1 protein complex in glioma H4 cells. Furthermore, overexpression of NSPc1 caused a decrease in the expression of MALAT1 and MEG3 and increased expression of SOX2OT, while NSPc1 downregulation caused the levels of all three genes to increase. Meanwhile, suppression of the expression of MALAT1 increased the expression levels of mRNA and protein of NSPc1, whereas downregulation of the expression of SOX2OT decreased NSPc1 expression. Moreover, a significant decrease in cell growth and increased cell apoptosis were observed in the transfected H4 cells by MTT assay and flow cytometric analysis. The results showed that the reduced co‑expression between NSPc1 and MALAT1/SOX2OT decreased the proliferation and promoted the death of H4 cells more obviously than the respectively decrease in expression of NSPc1, MALAT1 and SOX2OT. Remarkably, the influence of a simultaneously decreased expression of NSPc1 and SOX2OT on promoting cell apoptosis was more obvious than the total effect of the separate downregulation of NSPc1 and SOX2OT on accelerating cell death. However, that impact was partially counteracted in the silencing of the co‑expression of MALAT1 and NSPc1. Furthermore, they cooperated to affect transcription of p21 and OCT4.Briefly, these data suggest NSPc1 polycomb protein complex binding and cross‑talk to lncRNAs in glioma H4 cells, offering new insight into the important function of polycomb protein complex and lncRNA interactions in glioma cells and provide a novel view of potential biomarkers and targets for the diagnosis and therapy of glioma.
BACKGROUND: CircRNA has emerged as a new non-coding RNA that plays crucial roles in tumour initiation and development. 'MiRNA sponge' is the most reported role played by circRNAs in many tumours. The AKT/mTOR axis is a classic signalling pathway in cancers that sustains energy homeostasis through energy production activities, such as the Warburg effect, and blocks catabolic activities, such as autophagy. Additionally, the AKT/mTOR axis exerts a positive effect on EMT, which promotes tumour metastasis.
METHODS: We detected higher circNRIP1 expression in gastric cancer by performing RNA-seq analysis. We verified the tumour promotor role of circNRIP1 in gastric cancer cells through a series of biological function assays. We then used a pull-down assay and dual-luciferase reporter assay to identify the downstream miR-149-5p of circNRIP1. Western blot analysis and immunofluorescence assays were performed to demonstrate that the circNRIP1-miR-149-5p-AKT1/mTOR axis is responsible for the altered metabolism in GC cells and promotes GC development. We then adopted a co-culture system to trace circNRIP1 transmission via exosomal communication and RIP experiments to determine that quaking regulates circNRIP1 expression. Finally, we confirmed the tumour suppressor role of microRNA-133a-3p in vivo in PDX mouse models.
RESULTS: We discovered that knockdown of circNRIP1 successfully blocked proliferation, migration, invasion and the expression level of AKT1 in GC cells. MiR-149-5p inhibition phenocopied the overexpression of circNRIP1 in GC cells, and overexpression of miR-149-5p blocked the malignant behaviours of circNRIP1. Moreover, it was proven that circNRIP1 can be transmitted by exosomal communication between GC cells, and exosomal circNRIP1 promoted tumour metastasis in vivo. We also demonstrated that quaking can promote circNRIP1 transcription. In the final step, the tumour promotor role of circNRIP1 was verified in PDX models.
CONCLUSIONS: We proved that circNRIP1 sponges miR-149-5p to affect the expression level of AKT1 and eventually acts as a tumour promotor in GC.
Cheng X, Xu Q, Zhang Y, et al.miR-34a inhibits progression of neuroblastoma by targeting autophagy-related gene 5.
Eur J Pharmacol. 2019; 850:53-63 [PubMed
] Related Publications
Neuroblastoma (NB) is a common pediatric malignancy with high mortality in childhood. Although many attentions have been gained, novel biomarkers for NB diagnosis and prognosis are still needed. microRNAs (miRNAs) played important roles in NB progression and miR-34a is a tumor suppressor in NB. However, the mechanism that underlies miR-34a regulating proliferation, migration, invasion and autophagy in NB remains poorly understood. In this study, cell proliferation was investigated by MTT and colony assay. Cell apoptosis was measured by caspase 3 activity assay. Cell migration and invasion were detected by trans-well analysis. Autophagy was measured via GFP-LC3 puncta fluorescence assay and western blots (WB). The expression of miR-34a was examined by quantitative real-time PCR (qRT-PCR). The regulatory effect of miR-34a on autophagy-related gene 5 (ATG5) was detected by qRT-PCR and WB. The interaction between miR-34a and ATG5 was probed by luciferase activity and RNA immunoprecipitation (RIP) assay. Results showed that miR-34a expression was inhibited in NB tissues and cells with low survival rate. Addition of miR-34a suppressed cell proliferation, migration, invasion and autophagy but promoted apoptosis in NB cells, whereas miR-34a deficiency played opposite roles in NB progression. Intriguingly, ATG5 was directly targeted by miR-34a. Moreover, ATG5 restoration attenuated miR-34a-mediated inhibitory effect on proliferation, apoptosis, migration, invasion and autophagy. These results indicated miR-34a suppressed proliferation, apoptosis, migration, invasion and autophagy in NB cells by targeting ATG5, providing a novel therapeutic avenue for NB treatment.
Zhao W, Zhang D, Qin P, et al.Long non-coding RNA EPIC1 inhibits viability and invasion of osteosarcoma cells by promoting MEF2D ubiquitylation.
Int J Biol Macromol. 2019; 128:566-573 [PubMed
] Related Publications
BACKGROUND: Long non-coding RNAs (lncRNAs) can modulate gene expression through different mechanisms, but the fundamental molecular mechanism behind EPIC1 and osteosarcoma (OS) was poorly understood.
METHODS: Bone tumor tissues and the matched normal tissues were obtained from 36 OS patients who received tumor resection from 2014 to 2018. The expression of EPIC1 and MEF2D was determined by quantitative real-Time PCR and western blotting. Cell viability and invasion were evaluated by MTT assay and transwell assay. The animal xenograft model was also established.
RESULTS: EPIC1 was down-regulated, but MEF2D was up-regulated in OS tissues and OS cell lines. Overexpression of EPIC1 inhibited cell viability and invasion of OS cells. Targeting relationship between EPIC1 and MEF2D was confirmed by RNA pull-down and RNA immunoprecipitation (RIP). The MEF2D protein binding to ubiquitin was significantly increased in OS cells overexpressing EPIC1. The co-transfection with pcDNA-EPIC1 and pcDNA-MEF2D rescued the inhibition of cell viability and invasion caused by the overexpression of EPIC1. Overexpression of EPIC1 suppressed tumor growth in the OS xenograft model.
CONCLUSION: Our findings indicated that overexpression of EPIC1 inhibited cell viability and invasion of OS cells by promoting MEF2D ubiquitylation, which provided innovative lncRNA and protein targets for treating OS.
BACKGROUND: Accumulating evidence has highlighted the potential role of RNA binding proteins (RBPs) in the biological behaviors of glioblastoma cells. Herein, the expression and function of RNA binding proteins FXR1 were investigated in human glioma cells.
METHODS: Quantitative real-time PCR were conducted to evaluate the expression of MIR17HG and miR-346, miRNA-425-5p in glioma tissues and cells. Western blot were used to explore the expression of FXR1, TAL1 and DEC1 in glioma tissues and cells. Stable knockdown of FXR1 and MIR17HG in glioma cells were established to explore the function of FXR1, MIR17HG in glioma cells. Further, RIP and RNA pull-down assays were used to investigate the correlation between FXR1 and MIR17HG. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate the function of FXR1 and MIR17HG in malignant biological behaviors of glioma cells. ChIP assays were employed to ascertain the correlations between TAL1 and MIR17HG.
RESULTS: FXR1and MIR17HG were upregulated in glioma tissues and cell lines. Downregulation of FXR1 or MIR17HG resulted in inhibition of glioma cells progression. We also found that FXR1 regulates the biological behavior of glioma cells via stabilizing MIR17HG. In addition, downregulated MIR17HG increased miR-346/miR-425-5p expression and MIR17HG acted as ceRNA to sponge miR-346/miR-425-5p. TAL1 was a direct target of miR-346/miR-425-5p, and played oncogenic role in glioma cells. More importantly, TAL1 activated MIR17HG promoter and upregulated its expression, forming a feedback loop. Remarkably, FXR1 knockdown combined with inhibition of MIR17HG resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo.
CONCLUSIONS: FXR1/MIR17HG/miR-346(miR-425-5p)/TAL1/DEC1 axis plays a novel role in regulating the malignant behavior of glioma cells, which may be a new potential therapeutic strategy for glioma therapy.
Dai W, Mu L, Cui Y, et al.Berberine Promotes Apoptosis of Colorectal Cancer via Regulation of the Long Non-Coding RNA (lncRNA) Cancer Susceptibility Candidate 2 (CASC2)/AU-Binding Factor 1 (AUF1)/B-Cell CLL/Lymphoma 2 (Bcl-2) Axis.
Med Sci Monit. 2019; 25:730-738 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND Berberine, a natural isoquinoline alkaloid derived from Berberis genus plants, has been reported to have anti-cancer effects. While cell behavior can be modulated by long non-coding RNAs (lncRNAs), the contributions of lncRNAs in progression and berberine effects on colorectal cancer are largely unknown. Therefore, the present study investigated the involvement and regulatory function of lncRNA cancer susceptibility candidate 2 (CASC2) during the treatment of human colorectal cancer using berberine. MATERIAL AND METHODS Reverse transcription-quantitative PCR (RT-qPCR) was performed to detect the expression levels of lncRNA CASC2 and Bcl-2 mRNA in colorectal cancer cells. MTT assay was performed to evaluate cell viability. Flow cytometry and TUNEL assay were used to analyze the apoptosis of cancer cells. RNA immunoprecipitation (RIP) assay was done to verify the interaction between lncRNA CASC2 and (AU-binding factor 1) AUF1, or AUF1 and B-cell CLL/lymphoma 2 (Bcl-2). RESULTS Treatment with berberine suppressed cell viability of colorectal cancer by promoting apoptosis level. LncRNA CASC2 was upregulated in cells treated with berberine, and knockdown of lncRNA CASC2 reversed the berberine-induced apoptosis. In addition, anti-apoptotic gene Bcl-2 was suppressed by berberine treatment and lncRNA CASC2, inducing the pro-apoptotic effects. Moreover, lncRNA CASC2 binds to AUF1, which sequestered AUF1 from binding to Bcl-2 mRNA, thus inducing the inactivation of Bcl-2 translation. CONCLUSIONS Our study reveals that lncRNA CASC2 mediates the berberine-induced pro-apoptotic effect via inhibition of Bcl-2 expression at the post-transcriptional level.
Sun ZY, Jian YK, Zhu HY, Li BlncRNAPVT1 targets miR-152 to enhance chemoresistance of osteosarcoma to gemcitabine through activating c-MET/PI3K/AKT pathway.
Pathol Res Pract. 2019; 215(3):555-563 [PubMed
] Related Publications
BACKGROUND: LncRNA PVT1 has been reported to be involved in a variety of biological processes, including cell proliferation, cell differentiation and cancer progression. However, the mechanism by which LncRNA PVT1 contributes to chemoresistance of osteosarcoma cell, has not been fully elucidated.
METHODS: We first generatedLncRNA PVT1-overexpressed MG63 cells and LncRNA PVT1 knockdown MG63/DOX cells. Then, we examined the effect of LncRNA PVT1 on cell viability and colony formation ability by MTT assay and soft agar assay, respectively. In addition, we performed flow cytometry analysis to detect apoptosis induced by GEM. Dual luciferase reporter assay and RIP were used to confirmed the interaction between LncRNA PVT1 and miR-152. Finally, we determined protein level of c-MET, p-PI3K, and p-AKT by westernblot.
RESULTS: LncRNA PVT1 overexpression promoted cell proliferation and exhibited the anti-apoptotic property in LncRNA PVT1-overexpressing MG63 cells treated with gemcitabine. While, LncRNA PVT1-depleted MG63/DOX cells treated with gemcitabine exhibited significant lower survival rate and high percentage of apoptosis. Next, we found that LncRNA PVT1 could target and downregulated the level of miR-152. Interestingly, miR-152 greatly rescued the biological outcomes of LncRNA PVT1 not only in MG63 but also in MG63/DOX cells. We observed that LncRNA PVT1 markedly induced PI3K/AKT pathway activation, which was abolished by miR-152 mimics overexpression. Finally, c-MET inhibitor was used to confirm the essential role of c-MET in LncRNA PVT1 and miR-152-regulated PI3K/AKT signaling.
CONCLUSION: We showed thatlncRNA PVT1 played a contributory role in chemoresistance of osteosarcoma cells through c-MET/PI3K/AKT pathway activation, which was largely dependent on miR-152. Our findings advance our understanding of how lncRNA PVT1 promotes chemoresistance of osteosarcoma cells and facilitate development of novel strategies for treating osteosarcoma.