Non-Coding RNAs as Mediators of Epigenetic Changes in Malignancies

Non-coding RNAs (ncRNAs) are untranslated RNA molecules that regulate gene expressions. NcRNAs include small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), circular RNAs (cRNAs) and piwi-interacting RNAs (piRNAs). This review focuses on two types of ncRNAs: microRNAs (miRNAs) or short interfering RNAs (siRNAs) and long non-coding RNAs (lncRNAs). We highlight the mechanisms by which miRNAs and lncRNAs impact the epigenome in the context of cancer. Both miRNAs and lncRNAs have the ability to interact with numerous epigenetic modifiers and transcription factors to influence gene expression. The aberrant expression of these ncRNAs is associated with the development and progression of tumors. The primary reason for their deregulated expression can be attributed to epigenetic alterations. Epigenetic alterations can cause the misregulation of ncRNAs. The experimental evidence indicated that most abnormally expressed ncRNAs impact cellular proliferation and apoptotic pathways, and such changes are cancer-dependent. In vitro and in vivo experiments show that, depending on the cancer type, either the upregulation or downregulation of ncRNAs can prevent the proliferation and progression of cancer. Therefore, a better understanding on how ncRNAs impact tumorigenesis could serve to develop new therapeutic treatments. Here, we review the involvement of ncRNAs in cancer epigenetics and highlight their use in clinical therapy.

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HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01066-6 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Fengjie Jiang ◽

Xiaozhu Tang ◽

Chao Tang ◽

Zhen Hua ◽

Mengying Ke ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Proliferation ◽

Cellular Proliferation ◽

Aberrant Expression ◽

The Stability ◽

Induced Apoptosis ◽

Proliferation In Vitro

AbstractN6-methyladenosine (m6A) modification is the most prevalent modification in eukaryotic RNAs while accumulating studies suggest that m6A aberrant expression plays an important role in cancer. HNRNPA2B1 is a m6A reader which binds to nascent RNA and thus affects a perplexing array of RNA metabolism exquisitely. Despite unveiled facets that HNRNPA2B1 is deregulated in several tumors and facilitates tumor growth, a clear role of HNRNPA2B1 in multiple myeloma (MM) remains elusive. Herein, we analyzed the function and the regulatory mechanism of HNRNPA2B1 in MM. We found that HNRNPA2B1 was elevated in MM patients and negatively correlated with favorable prognosis. The depletion of HNRNPA2B1 in MM cells inhibited cell proliferation and induced apoptosis. On the contrary, the overexpression of HNRNPA2B1 promoted cell proliferation in vitro and in vivo. Mechanistic studies revealed that HNRNPA2B1 recognized the m6A sites of ILF3 and enhanced the stability of ILF3 mRNA transcripts, while AKT3 downregulation by siRNA abrogated the cellular proliferation induced by HNRNPA2B1 overexpression. Additionally, the expression of HNRNPA2B1, ILF3 and AKT3 was positively associated with each other in MM tissues tested by immunohistochemistry. In summary, our study highlights that HNRNPA2B1 potentially acts as a therapeutic target of MM through regulating AKT3 expression mediated by ILF3-dependent pattern.

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Exosomes derived from mmu_circ_0000623-modified ADSCs prevent liver fibrosis via activating autophagy

Human & Experimental Toxicology ◽

10.1177/0960327120931152 ◽

2020 ◽

Vol 39 (12) ◽

pp. 1619-1627 ◽

Cited By ~ 1

Author(s):

M Zhu ◽

X Liu ◽

W Li ◽

L Wang

Keyword(s):

Liver Fibrosis ◽

Expression Profiles ◽

Parenchymal Cell ◽

Hepatic Tissue ◽

Circular Rnas ◽

In Vivo Experiments ◽

Matrix Accumulation ◽

Inhibitor Treatment

Prolonged parenchymal cell death leads to activation of fibrogenic cells, extracellular matrix accumulation, and eventually liver fibrosis. Increasing evidence shows that exosomes (Exos) secreted by adipose-derived mesenchymal stem cells (ADSCs) can be used to deliver circular RNAs (circRNAs) to treat liver fibrosis. To explore the uses of circRNA, circRNA expression profiles of hepatic tissue from normal and CCl4-induced mice were analyzed using high-throughput circRNA microarrays. The result showed that mmu_circ_0000623 expression was downregulated in CCl4-induced mice. Bioinformatics analysis and luciferin reporter experiments showed that mmu_circ_0000623 interacted with and regulated miR-125/ATG4D. In vitro and in vivo experiments showed that Exos from ADSCs, especially from mmu_circ_0000623-modified ADSCs, significantly suppressed CCl4-induced liver fibrosis by promoting autophagy activation. Autophagy inhibitor treatment significantly reversed the treatment effects of Exos. Proteins involved in autophagy and autophagy plaques positive for ATG4D expression were regulated by mmu_circ_0000623/miR-125. Our study found that Exos derived from mmu_circ_0000623-modified ADSCs prevented liver fibrosis via activating autophagy.

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CircRNA_0092516 regulates chondrocyte proliferation and apoptosis in osteoarthritis through the miR-337-3p/PTEN axis

The Journal of Biochemistry ◽

10.1093/jb/mvaa119 ◽

2020 ◽

Author(s):

Zhihui Huang ◽

Wenming Ma ◽

Jinhuai Xiao ◽

Xiaoyu Dai ◽

Weiqi Ling

Keyword(s):

Cell Apoptosis ◽

Luciferase Reporter ◽

Circular Rnas ◽

Mechanism Analysis ◽

Potential Mechanism ◽

Luciferase Reporter Gene ◽

Chondrocyte Proliferation ◽

In Vivo Experiments

Abstract The dysregulation of circular RNAs (circRNAs) has been identified in various human diseases. Here, we probed into the potential mechanism of circRNA_0092516 in osteoarthritis (OA). The expression of circRNA_0092516 was tested by quantitative real-time PCR. MTT, flow cytometry and western blot were applied to confirm the functions of circRNA_0092516 in vitro. Besides, RNA pull-down and dual-luciferase reporter gene experiments were applied to probe into the mechanism. circRNA_0092516 was raised in the tissues of OA patients and chondrocytes stimulated by IL-1β. The potential mechanism analysis expounded that circRNA_0092516 bound to miR-337-3p, and the interference with circRNA_0092516 boosted chondrocyte proliferation and restrained cell apoptosis through the miR-337-3p/phosphatase and tensin homolog (PTEN) axis, thereby improving OA. In-vivo experiments expounded that circRNA_0092516 regulated cartilage production through miR-337-3p. Overall, our data expounded that the interference with circRNA_0092516 boosted chondrocyte proliferation and restrained cell apoptosis through the miR-337-3p/PTEN axis, eventually slowed down the progress of OA.

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The TWIST1-centered competing endogenous RNA network promotes proliferation, invasion, and migration of lung adenocarcinoma

Oncogenesis ◽

10.1038/s41389-019-0167-6 ◽

2019 ◽

Vol 8 (11) ◽

Cited By ~ 4

Author(s):

Wenjie Xia ◽

Qixing Mao ◽

Bing Chen ◽

Lin Wang ◽

Weidong Ma ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Migration And Invasion ◽

Circular Rnas ◽

Messenger Rnas ◽

Competing Endogenous Rna ◽

Invasion And Migration ◽

Non Coding Rnas ◽

And Migration

Abstract The proposed competing endogenous RNA (ceRNA) mechanism suggested that diverse RNA species, including protein-coding messenger RNAs and non-coding RNAs such as long non-coding RNAs, pseudogenes and circular RNAs could communicate with each other by competing for binding to shared microRNAs. The ceRNA network (ceRNET) is involved in tumor progression and has become a hot research topic in recent years. To date, more attention has been paid to the role of non-coding RNAs in ceRNA crosstalk. However, coding transcripts are more abundant and powerful than non-coding RNAs and make up the majority of miRNA targets. In this study, we constructed a mRNA-mRNA related ceRNET of lung adenocarcinoma (LUAD) and identified the highlighted TWIST1-centered ceRNET, which recruits SLC12A5 and ZFHX4 as its ceRNAs. We found that TWIST1/SLC12A5/ZFHX4 are all upregulated in LUAD and are associated with poorer prognosis. SLC12A5 and ZFHX4 facilitated proliferation, migration, and invasion in vivo and in vitro, and their effects were reversed by miR-194–3p and miR-514a-3p, respectively. We further verified that SLC12A5 and ZFHX4 affected the function of TWIST1 by acting as ceRNAs. In summary, we constructed a mRNA-mRNA related ceRNET for LUAD and highlighted the well-known oncogene TWIST1. Then we verified that SLC12A5 and ZFHX4 exert their oncogenic function by regulating TWIST1 expression through a ceRNA mechanism.

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Biogenesis of mature piRNAs in Caenorhabditis elegans is dependent on orchestration between multiple ribonucleases and PRG-1

10.1101/2021.12.29.474424 ◽

2021 ◽

Author(s):

Aniruddha Samajdar ◽

Tamoghna Chowdhury ◽

Saibal Chatterjee

Keyword(s):

Caenorhabditis Elegans ◽

Specific Class ◽

Genomic Integrity ◽

Selfish Genetic Elements ◽

In Vivo Experiments ◽

Non Coding Rnas ◽

Precursor Molecules ◽

Endoribonuclease Activity

Piwi-interacting RNAs (piRNAs) are an animal-specific class of germline-enriched small non-coding RNAs that shape transcriptome, as well as ensure genomic integrity and fertility by regulating transposons and other selfish genetic elements. In Caenorhabditis elegans mature piRNAs are 21-nucleotides long, begin with a monophosphorylated uridine, and they associate with PRG-1 to form piRISCs that scan the transcriptome for non-self sequences. However, these piRNAs are born as longer 5-capped transcripts, where PARN-1, a 3-5 exoribonuclease, contributes to the formation of the mature 3-end. But, till date, the 5-processing events remain elusive. We demonstrate that the recently identified endoribonuclease activity of XRN-2 is involved in the processing of the 5-end of precursor piRNAs in worms. Depletion of XRN-2 results in reduced mature piRNA levels, with concomitant increase in levels of the 5-capped precursors. We also reveal that the piRNAs born as longer precursor molecules (>60 nt), prior to 5-end processing, undergo ENDU-1-mediated endoribonucleolytic processing of their 3-ends. Our in vitro RNA-protein interaction studies unravel the mechanistic interactions between XRN-2 and PRG-1 towards the formation of mature 5-ends of piRNAs. In vivo experiments employing prg-1 mutant worms indicate that XRN-2 has the potential to perform clearance of precursors that are not bound and protected by PRG-1. Finally, we also demonstrate that XRN-2 is not only important for the generation of mature piRNAs and piRNA-dependent endo-siRNAs, but through yet unknown pathways, it also affects piRNA-independent endo-siRNAs that shape transcriptome, as well as contribute to genomic integrity via regulation of transposable elements.

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Circular RNA UBE2Q2 promotes malignant progression of gastric cancer by regulating signal transducer and activator of transcription 3-mediated autophagy and glycolysis

Cell Death and Disease ◽

10.1038/s41419-021-04216-3 ◽

2021 ◽

Vol 12 (10) ◽

Author(s):

Jing Yang ◽

Xing Zhang ◽

Jiacheng Cao ◽

Penghui Xu ◽

Zetian Chen ◽

...

Keyword(s):

Gastric Cancer ◽

Rna Binding ◽

Synergistic Effects ◽

Circular Rna ◽

Circular Rnas ◽

In Vivo Experiments ◽

Series Of Experiments ◽

Transcription 3

AbstractGastric cancer remains the third leading cause of cancer-related mortality worldwide. Emerging evidence has shown that circular RNAs (circRNAs) play a critical regulatory role in the occurrence and development of various cancers through sponging miRNAs or acting as RNA-binding protein (RBP) sponges. We found that circUBE2Q2 was significantly upregulated in GC tissues and cell lines. Knockdown of circUBE2Q2 inhibited proliferation, migration, invasion, and glycolysis, and increased autophagy in vitro. In addition, knockdown of circUBE2Q2 inhibited GC tumorigenicity and metastasis potential in vivo. A series of experiments were performed to confirm that circUBE2Q2 regulates GC progression via the circUBE2Q2-miR-370-3p-STAT3 axis and promotes tumor metastasis through exosomal communication. Further in vivo experiments confirmed that, combination treatment of circUBE2Q2 knocking down and STAT3 inhibitor has synergistic effects on the gastric cancer growth inhibition, which provides a possibility to enhance the sensitivity of targeted drugs to gastric cancer through targeting circUBE2Q2. Our findings revealed that circUBE2Q2 may serve as a new proliferation-promoting factor and prognostic marker in gastric cancer.

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The lncRNA ADAMTS9-AS2 Regulates RPL22 to Modulate TNBC Progression via Controlling the TGF-β Signaling Pathway

Frontiers in Oncology ◽

10.3389/fonc.2021.654472 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kan Ni ◽

Zhiqi Huang ◽

Yichun Zhu ◽

Dandan Xue ◽

Qin Jin ◽

...

Keyword(s):

Signaling Pathway ◽

Functional Role ◽

Cancer Type ◽

Cycle Arrest ◽

Transcriptomic Sequencing ◽

Non Coding Rnas ◽

Functional Relevance

BackgroundLong non-coding RNAs (lncRNAs) are key regulators of triple-negative breast cancer (TNBC) progression, but further work is needed to fully understand the functional relevance of these non-coding RNAs in this cancer type. Herein, we explored the functional role of the lncRNA ADAMTS9-AS2 in TNBC.MethodsNext-generation sequencing was conducted to compare the expression of different lncRNAs in TNBC tumor and paracancerous tissues, after which ADAMTS9-AS2differential expression in these tumor tissues was evaluated via qPCR. The functional role of this lncRNA was assessed by overexpressing it in vitro and in vivo. FISH and PCR were used to assess the localization of ADAMTS9-AS2within cells. Downstream targets of ADAMTS9-AS2 signaling were identified via RNA pulldown assays and transcriptomic sequencing.ResultsThe expression ofADAMTS9-AS2 was decreased in TNBC tumor samples (P < 0.05), with such downregulation being correlated with TNM stage, age, and tumor size. Overexpressing ADAMTS9-AS2 promoted the apoptotic death and cell cycle arrest of tumor cells in vitro and inhibited tumor growth in vivo. From a mechanistic perspective, ADAMTS9-AS2 was found to control the expression of RPL22 and to thereby modulate TGF-β signaling to control TNBC progression.ConclusionADAMTS9-AS2 controls the expression of RPL22 and thereby regulates TNBC malignancy via the TGF-β signaling pathway.

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Circular RNA Hsa_Circ_0002483 Promotes Growth and Invasion of Lung Adenocarcinoma by Sponging miR-125a-3p

10.21203/rs.3.rs-742632/v1 ◽

2021 ◽

Author(s):

Jun Wan ◽

Guanggui Ding ◽

Min Zhou ◽

Xiean Ling ◽

ZhanPeng Rao

Keyword(s):

Lung Adenocarcinoma ◽

Colony Formation ◽

Molecular Mechanisms ◽

Specific Binding ◽

Tumor Model ◽

Circular Rnas ◽

Aberrant Expression ◽

Tissue Samples

Abstract Background: Increasing evidence indicates that the aberrant expression of circular RNAs (circRNAs) is involved in the pathogenesis and progression of lung adenocarcinoma (LUAC). However, the function and molecular mechanisms of hsa_circ_0002483 (circ_0002483) in LUAC remain unclear. Methods: The association between circ_0002483 expression and clinicopathological characteristics and prognosis in patients with LUAC was analyzed by fluorescence in situ hybridization. The functional experiments such as MTT, colony formation and Transwell assays and a subcutaneous tumor model were conducted to determine the role of circ_0002483 in LUAC cells. The specific binding between circ_0002483 and miR-125a-3p was validated by RNA immunoprecipitation, luciferase gene report and qRT-PCR assays. The effects of circ_0002483 on miR-125a-3p-mediated C-C motif chemokine ligand 4 (CCL4)-CCR5 axis were assessed by Western blot analysis.Results: We found that circ_0002483 was upregulated in LUAC tissue samples and associated with TNM stage and poor survival in patients with LUAC. Knockdown of circ_0002483 inhibited proliferation, colony formation and invasion of A549 and PC9 cells in vitro, whereas overexpression of circ_0002483 harbored the opposite effects. Furthermore, circ_0002483 sponged miR-125a-3p and negatively modulated its expression. CCL4 was identified as a direct target of miR-125a-3p. The rescue experiments showed that miR-125a-3p mimics reversed the tumor-promoting effects of circ_0002483 by targeting CCL4-CCR5 axis in A549 and PC9 cells. In addition, the in vivo experiment further validated that knockdown of circ_0002483 repressed tumor growth. Conclusions: Our findings demonstrated that circ_0002483 could act as a sponge of miR-125a-3p to upregulate CCL4-CCR5 axis, contributing to the tumorigenesis of LUAC, and represent a potential therapeutic target for LUAC.

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Circular RNA circRPPH1 promotes breast cancer progression via circRPPH1-miR-512-5p-STAT1 axis

Cell Death Discovery ◽

10.1038/s41420-021-00771-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yixiang Huang ◽

Wenfang Zheng ◽

Changle Ji ◽

Xuehui Wang ◽

Yunhe Yu ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Underlying Mechanism ◽

Circular Rna ◽

Gene Expression Omnibus ◽

Circular Rnas ◽

In Vivo Experiments

AbstractBreast cancer (BC) is one of the most fatal diseases among women all over the world. Non-coding RNAs including circular RNAs (circRNAs) have been reported to be involved in different aspects during tumorigenesis and progression. In this study, we aimed to explore the biological functions and underlying mechanism of circRPPH1 in BC. Candidate circRNAs were screened in dataset GSE101123 from Gene Expression Omnibus (GEO) database and a differentially expressed circRNA, circRPPH1, was discovered in BC. CircRPPH1 expression was higher in the cancerous tissue compared to paired adjacent tissue. Further in vitro and in vivo experiments indicated that circRPPH1 acted as an oncogene in BC. In addition, circRPPH1 was mainly localized in cytoplasm and played the role of miR-512-5p sponge. By sequestering miR-512-5p from the 3′-UTR of STAT1, circRPPH1 inhibited the suppressive role of miR-512-5p, stabilized STAT1 mRNA in BC and finally affected BC progression. In conclusion, these findings indicated that circRPPH1 acted as an oncogene and regulated BC progression via circRPPH1-miR-512-5p-STAT1 axis, which might provide a potential therapeutic target for BC treatment.

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SAT-315 CircVPS13c Promotes Tumor Growth and Invasiveness in Pituitary Adenoma by Downregulating IFITM1

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1249 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Xiaobing Jiang ◽

weiyu zhang ◽

piaopiao zhang

Keyword(s):

Pituitary Adenoma ◽

Tumor Growth ◽

Transmembrane Protein ◽

Circular Rnas ◽

Tumor Invasiveness ◽

In Vivo Experiments ◽

Wide Range ◽

Associated Proteins

Abstract Background and objectives Invasive nonfunctioning pituitary adenoma (NFPA) remains the major cause of hypopituitarism and infertility. Increasing evidences suggest that circular RNAs (circRNAs) exert crucial functions in regulating gene expression in a wide range of tumors. The present study was designed to explore the role of circRNAs in proliferation and invasion of NFPAs. Methods The expression profile of circRNAs was compared with circRNA array between NFPA (n=10) and normal pituitary tissues (n=4), invasive (n=5) and noninvasive (n=5) NFPA samples. A total of 249 circRNAs were shown to be significantly upregulated in human invasive NFPA tissues, comparing to the noninvasive ones. CircVPS13C was identified for further study, whose oncogenic effect were explored with in vitro and in vivo experiments. Results CircVPS13C was markedly upregulated in NFPA samples and positively correlated with NFPA invasiveness. Silencing of circVPS13C effectively suppressed NFPA cell proliferation, invasiveness and promoted apoptosis, in vitro, and suppressed tumor growth, in vivo. The oncogenic effects were significantly enhanced when circVPS13C was overexpressed. By whole exome sequencing, interferon induced transmembrane protein 1 (IFITM1) was found significantly increased in cells with circVPS13C knockout. Decreased level of IFITM1 protein was confirmed in NFPAs samples, and negatively correlated with the level of circVPS13C and tumor invasiveness. Upregulation of IFITM1 could partly reverse the effect of IFITM1 on tumor cells, and IFITM1 downregulating enhanced the oncogenic effect of circVPS13C. CHIRP analysis suggested that circVPS13C may inhibit the IFITM1 transcription by competitively binding the RNA-associated proteins. Conclusions CircVPS13C promotes NFPA growth and invasiveness by regulating tumor suppressor IFITM1, revealing a therapeutic target in preventing the tumorigenesis of NFPA.

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