The Long Noncoding RNA MEG3 Retains Epithelial-Mesenchymal Transition by Sponging miR-146b-5p to Regulate SLFN5 Expression in Breast Cancer Cells

More and more studies have shown that long noncoding RNAs (lncRNAs) play essential roles in malignant tumors. The lncRNA MEG3 serves as a crucial molecule in breast cancer development, but the specific molecular mechanism needs to be further explored. We previously reported that Schlafen family member 5 (SLFN5) inhibits breast cancer malignant development by regulating epithelial-mesenchymal transition (EMT), invasion, and proliferation/apoptosis. Herein, we demonstrated that MEG3 was downregulated in pan-cancers and correlated with SLFN5 expression positively in breast cancer by bioinformatics analysis of TCGA and UCSC Xena data. Intervention with MEG3 positively affected SLFN5 expression in breast cancer cells. MEG3 repressed EMT and migration/invasion, similar to our previously reported functions of SLFN5 in breast cancer. Through bioinformatics analysis of starBase and LncBase data, 12 miRNAs were found to regulate both SLFN5 and MEG3, in which miR-146b-5p was confirmed to be regulated by MEG3 using MEG3 siRNA and overexpression method. MiR-146b-5p could bind to both SLFN5 3′UTR and MEG3, and inhibit their expression in a competing endogenous RNA mechanism, assayed by luciferase reporter and RNA pull down methods. Therefore, we conclude that MEG3 positively modulates SLFN5 expression by sponging miR-146b-5p and inhibits breast cancer development.

[1]  Changlian Lu,et al.  Prognostic Ferroptosis-Related lncRNA Signatures Associated With Immunotherapy and Chemotherapy Responses in Patients With Stomach Cancer , 2022, Frontiers in Genetics.

[2]  Wei Wei,et al.  Long noncoding RNA Meg3 sponges miR-708 to inhibit intestinal tumorigenesis via SOCS3-repressed cancer stem cells growth , 2021, Cell Death & Disease.

[3]  G. Christofori,et al.  Distinct contributions of partial and full EMT to breast cancer malignancy. , 2021, Developmental cell.

[4]  Qing Liu,et al.  Long Noncoding RNA MIR100HG Knockdown Attenuates Hepatocellular Carcinoma Progression by Regulating MicroRNA-146b-5p/Chromobox 6 , 2021, Gastroenterology research and practice.

[5]  X. Zuo,et al.  LncRNA MEG3 regulates breast cancer proliferation and apoptosis through miR-141-3p/RBMS3 axis. , 2021, Genomics.

[6]  Lizhen Qu,et al.  The miR-146b-5p promotes Ewing’s sarcoma cells progression via suppressing the expression of BTG2 , 2021, Science progress.

[7]  E. Weiderpass,et al.  The Global Breast Cancer Initiative: a strategic collaboration to strengthen health care for non-communicable diseases. , 2021, The Lancet. Oncology.

[8]  Q. Fan,et al.  Long non-coding RNA SNHG7 facilitates pancreatic cancer progression by regulating the miR-146b-5p/Robo1 axis , 2021, Experimental and therapeutic medicine.

[9]  Xiangdong Li,et al.  lncRNA MEG3 inhibits pituitary tumor development by participating in cell proliferation, apoptosis and EMT processes , 2021, Oncology reports.

[10]  Haifeng Zhang,et al.  miR-146b-5p inhibits tumorigenesis and metastasis of gallbladder cancer by targeting Toll-like receptor 4 via the nuclear factor-κB pathway , 2021, Oncology reports.

[11]  Wenling Zhang,et al.  Colorectal cancer prompted adipose tissue browning and cancer cachexia through transferring exosomal miR‐146b‐5p , 2020, Journal of cellular physiology.

[12]  Changlian Lu,et al.  SLFN5 influences proliferation and apoptosis by upregulating PTEN transcription via ZEB1 and inhibits the purine metabolic pathway in breast cancer. , 2020, American journal of cancer research.

[13]  Weijun Huang,et al.  Long Non-Coding RNA NEAT1 Promotes the Proliferation, Migration, and Metastasis of Human Breast-Cancer Cells by Inhibiting miR-146b-5p Expression , 2020, Cancer management and research.

[14]  Hailong Wu,et al.  Human Schlafen 5 regulates reversible epithelial and mesenchymal transitions in breast cancer by suppression of ZEB1 transcription , 2020, British Journal of Cancer.

[15]  A. Giuliani,et al.  Deregulated expression of the imprinted DLK1-DIO3 region in glioblastoma stemlike cells: tumor suppressor role of lncRNA MEG3 , 2020, Neuro-oncology.

[16]  C. Erzik,et al.  Response Assessment With Molecular Characterization of Circulating Tumor Cells and Plasma MicroRNA Profiling in Patients With Locally Advanced Breast Cancer During Neoadjuvant Chemotherapy. , 2020, Clinical breast cancer.

[17]  F. Naya,et al.  The long noncoding RNA Meg3 regulates myoblast plasticity and muscle regeneration through epithelial-mesenchymal transition , 2020, Development.

[18]  Xing-ming Jiang,et al.  LncRNA‐MEG3 inhibits cell proliferation and invasion by modulating Bmi1/RNF2 in cholangiocarcinoma , 2019, Journal of cellular physiology.

[19]  Saugata Hazra,et al.  The basics of epithelial–mesenchymal transition (EMT): A study from a structure, dynamics, and functional perspective , 2019, Journal of cellular physiology.

[20]  Xian-fu Sun,et al.  LncRNA SNHG7 contributes to tumorigenesis and progression in breast cancer by interacting with miR-34a through EMT initiation and the Notch-1 pathway. , 2019, European journal of pharmacology.

[21]  Changlian Lu,et al.  SLFN5 suppresses cancer cell migration and invasion by inhibiting MT1-MMP expression via AKT/GSK-3β/β-catenin pathway. , 2019, Cellular signalling.

[22]  Lin Lv,et al.  Construction and analysis of a lncRNA‑miRNA‑mRNA network based on competitive endogenous RNA reveals functional lncRNAs in diabetic cardiomyopathy. , 2019, Molecular medicine reports.

[23]  R. Chakrabarti,et al.  Consequences of EMT-Driven Changes in the Immune Microenvironment of Breast Cancer and Therapeutic Response of Cancer Cells , 2019, Journal of clinical medicine.

[24]  Y. Bidet,et al.  New Insights into the Implication of Epigenetic Alterations in the EMT of Triple Negative Breast Cancer , 2019, Cancers.

[25]  Jia Qian Wu,et al.  Invited Review: Long non‐coding RNAs: important regulators in the development, function and disorders of the central nervous system , 2019, Neuropathology and applied neurobiology.

[26]  S. Dimmeler,et al.  Long non-coding RNAs in vascular biology and disease. , 2019, Vascular pharmacology.

[27]  Y. Mo,et al.  Emerging roles of lncRNAs in the post-transcriptional regulation in cancer , 2019, Genes & diseases.

[28]  Wei Wu,et al.  New Insights into the Interplay between Non-Coding RNAs and RNA-Binding Protein HnRNPK in Regulating Cellular Functions , 2019, Cells.

[29]  Shouming Xu,et al.  Long noncoding RNA MEG3 inhibits breast cancer growth via upregulating endoplasmic reticulum stress and activating NF‐κB and p53 , 2018, Journal of cellular biochemistry.

[30]  R. Weinberg,et al.  New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer , 2018, Nature reviews. Molecular cell biology.

[31]  A. Jemal,et al.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries , 2018, CA: a cancer journal for clinicians.

[32]  Qing Tang,et al.  HOTAIR: An Oncogenic Long Non-Coding RNA in Human Cancer , 2018, Cellular Physiology and Biochemistry.

[33]  C. Dang,et al.  MEG3/miR-21 axis affects cell mobility by suppressing epithelial-mesenchymal transition in gastric cancer , 2018, Oncology reports.

[34]  Zhongming Zhao,et al.  Decoding critical long non-coding RNA in ovarian cancer epithelial-to-mesenchymal transition , 2017, Nature Communications.

[35]  L. Platanias,et al.  Human SLFN5 is a Transcriptional Co-repressor of STAT1-Mediated Interferon Responses and Promotes the Malignant Phenotype in Glioblastoma , 2017, Oncogene.

[36]  Jingwu Jiang,et al.  LncRNA MEG3 inhibits cell epithelial-mesenchymal transition by sponging miR-421 targeting E-cadherin in breast cancer. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[37]  L. D. White,et al.  EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells , 2017, Nature Communications.

[38]  F. Portillo,et al.  LOXL2 drives epithelial-mesenchymal transition via activation of IRE1-XBP1 signalling pathway , 2017, Scientific Reports.

[39]  A. Chinnaiyan,et al.  Long noncoding RNAs in cancer: from function to translation. , 2015, Trends in cancer.

[40]  A. Verma,et al.  Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells , 2015, Molecular and Cellular Biology.

[41]  Wei Gao,et al.  Long non-coding RNA GAS5 functions as a tumor suppressor in renal cell carcinoma. , 2013, Asian Pacific journal of cancer prevention : APJCP.

[42]  Marian Hajduch,et al.  MEG3: a novel long noncoding potentially tumour-suppressing RNA in meningiomas , 2013, Journal of Neuro-Oncology.

[43]  Yunli Zhou,et al.  MEG3 noncoding RNA: a tumor suppressor. , 2012, Journal of molecular endocrinology.

[44]  L. Platanias,et al.  Role of Interferon α (IFNα)-inducible Schlafen-5 in Regulation of Anchorage-independent Growth and Invasion of Malignant Melanoma Cells* , 2010, The Journal of Biological Chemistry.

[45]  A. Ferguson-Smith,et al.  Genomic imprinting at the mammalian Dlk1-Dio3 domain. , 2008, Trends in genetics : TIG.

[46]  Yi Li,et al.  Inhibition of lncRNA PANDAR reduces cell proliferation, cell invasion and suppresses EMT pathway in breast cancer. , 2019, Cancer biomarkers : section A of Disease markers.

[47]  C. González,et al.  SCHLAFEN 5 expression correlates with intestinal metaplasia that progresses to gastric cancer , 2016, Journal of Gastroenterology.