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LNRRIL6, a novel long noncoding RNA, protects colorectal cancer cells by activating the IL-6-STAT3 pathway.

ABSTRACT: Long noncoding RNAs (lncRNAs) are emerging as critical regulators of cancer. There is a comparable number of lncRNAs to protein-coding genes, but the expression patterns, functions, and molecular mechanisms of most lncRNAs in colorectal cancer (CRC) remain unclear. In this study, we report the identification of a novel lncRNA, named long noncoding RNA regulating IL-6 transcription (LNRRIL6), which is upregulated in CRC tissues and cell lines. Increased LNRRIL6 expression is associated with aggressive clinicopathological characteristics and poor prognosis of CRC patients. Functional experiments showed that enhanced expression of LNRRIL6 promotes CRC cell proliferation and survival in vitro and CRC tumor growth in vivo. Conversely, depletion of LNRRIL6 inhibits CRC cell proliferation and survival in vitro and CRC tumor growth in vivo. Mechanistically, we revealed that LNRRIL6 physically binds to the IL-6 promoter, thereby increasing IL-6 transcription, inducing IL-6 autocrine signaling, and activating the IL-6/STAT3 pathway. The expression of IL-6 is positively associated with that of LNRRIL6 in CRC tissues. Blocking the IL-6/STAT3 pathway using the FDA-approved IL-6-receptor antagonist antibody, tocilizumab, abolished the oncogenic role of LNRRIL6 in CRC. Taken together, these findings identify a novel lncRNA, LNRRIL6, that promotes CRC cell survival through activation of the IL-6/STAT3 pathway and suggest that LNRRIL6 may be a potential prognostic biomarker and therapeutic target for CRC.

SUBMITTER: Wang J

PROVIDER: S-EPMC6822249 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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LNRRIL6, a novel long noncoding RNA, protects colorectal cancer cells by activating the IL-6-STAT3 pathway.

Wang Jiaxing J Zhou Junfeng J Jiang Caiyun C Zheng Jing J Namba Hiroki H Chi Pan P Asakawa Tetsuya T

Molecular oncology 20190930 11

Long noncoding RNAs (lncRNAs) are emerging as critical regulators of cancer. There is a comparable number of lncRNAs to protein-coding genes, but the expression patterns, functions, and molecular mechanisms of most lncRNAs in colorectal cancer (CRC) remain unclear. In this study, we report the identification of a novel lncRNA, named long noncoding RNA regulating IL-6 transcription (LNRRIL6), which is upregulated in CRC tissues and cell lines. Increased LNRRIL6 expression is associated with aggre ...[more]

PMID: 31246342

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Project description:BackgroundGallbladder cancer (GBC) is a highly malignant cancer with poor prognosis. Several long noncoding RNAs (lncRNAs) have been reported to be involved in the tumorigenesis and progression of GBC. However, the expressions, clinical significances, and roles of most other lncRNAs in GBC are still unknown.MethodsThe differentially expressed lncRNAs in GBC were screened through re-analyzing the public available microarray datasets. The expression of lncRNA high expressed in gallbladder cancer (lncRNA-HEGBC) in GBC was measured by qRT-PCR. The correlations between HEGBC with clinicopathological characteristics and prognosis were analyzed by Pearson chi-square test and log-rank test. A series of in vitro and in vivo, gain-of and loss-of function assays were performed to investigate the roles of HEGBC in GBC cell proliferation, apoptosis, migration, tumor growth and metastasis. The interactions between HEGBC and IL-11/STAT3 signaling were explored using chromatin isolation by RNA purification (ChIRP), chromatin immunoprecipitation (ChIP), enzyme linked immunosorbent assay (ELISA), qRT-PCR, western blot, and luciferase reporter assays.ResultsWe identified a novel lncRNA HEGBC, which is upregulated in GBC and positively associated with advanced TNM stages and poor prognosis of GBC patients. Overexpression of HEGBC increased GBC cell viability, inhibited GBC cell apoptosis, promoted GBC cell migration, and promoted GBC tumor growth and metastasis in vivo. Conversely, depletion of HEGBC decreased GBC cell viability, promoted GBC cell apoptosis, inhibited GBC cell migration, and inhibited GBC tumor growth and metastasis in vivo. Mechanistic investigations showed that HEGBC bound to the promoter of IL-11, increased IL-11 transcription, induced IL-11 autocrine, and activated IL-11/STAT3 signaling pathway. Furthermore, STAT3 also bound to the promoter of HEGBC and activated HEGBC expression. Thus, HEGBC/IL-11/STAT3 formed a positive regulatory loop in GBC. Depletion of IL-11 attenuated the oncogenic roles of HEGBC in GBC.ConclusionsOur findings identified a novel lncRNA HEGBC, which is upregulated and indicts poor prognosis of GBC. HEGBC exerts oncogenic roles in GBC via forming a positive regulatory loop with IL-11/STAT3 signaling. Our data suggested that HEGBC could be a potential prognostic biomarker and therapeutic target for GBC.

Project description:The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodelling. An estimated 70% of mouse genes undergo antisense transcription, including myosin heavy chain 7 (Myh7), which encodes molecular motor proteins for heart contraction. Here we identify a cluster of lncRNA transcripts from Myh7 loci and demonstrate a new lncRNA-chromatin mechanism for heart failure. In mice, these transcripts, which we named myosin heavy-chain-associated RNA transcripts (Myheart, or Mhrt), are cardiac-specific and abundant in adult hearts. Pathological stress activates the Brg1-Hdac-Parp chromatin repressor complex to inhibit Mhrt transcription in the heart. Such stress-induced Mhrt repression is essential for cardiomyopathy to develop: restoring Mhrt to the pre-stress level protects the heart from hypertrophy and failure. Mhrt antagonizes the function of Brg1, a chromatin-remodelling factor that is activated by stress to trigger aberrant gene expression and cardiac myopathy. Mhrt prevents Brg1 from recognizing its genomic DNA targets, thus inhibiting chromatin targeting and gene regulation by Brg1. It does so by binding to the helicase domain of Brg1, a domain that is crucial for tethering Brg1 to chromatinized DNA targets. Brg1 helicase has dual nucleic-acid-binding specificities: it is capable of binding lncRNA (Mhrt) and chromatinized--but not naked--DNA. This dual-binding feature of helicase enables a competitive inhibition mechanism by which Mhrt sequesters Brg1 from its genomic DNA targets to prevent chromatin remodelling. A Mhrt-Brg1 feedback circuit is thus crucial for heart function. Human MHRT also originates from MYH7 loci and is repressed in various types of myopathic hearts, suggesting a conserved lncRNA mechanism in human cardiomyopathy. Our studies identify a cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodelling factors, and establish a new paradigm for lncRNA-chromatin interaction.

Dataset Information

LNRRIL6, a novel long noncoding RNA, protects colorectal cancer cells by activating the IL-6-STAT3 pathway.

Publications

LNRRIL6, a novel long noncoding RNA, protects colorectal cancer cells by activating the IL-6-STAT3 pathway.

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