Integrative analyses of noncoding RNAs reveal the potential mechanisms augmenting tumor malignancy in lung adenocarcinoma: Nucleic acids research

J.-H. Shih, H.-Y. Chen, S.-C. Lin, Y.-C. Yeh, R. Shen, Y.-D. Lang, D.-C. Wu, C.-Y. Chen, R.-H. Chen, T.-Y. Chou, Y.-S. Jou

Research output: Contribution to journalArticle

Abstract

Precise noncoding RNA (ncRNA)-based network prediction is necessary to reveal ncRNA functions and pathological mechanisms. Here, we established a systemic pipeline to identify prognostic ncRNAs, predict their functions and explore their pathological mechanisms in lung adenocarcinoma (LUAD). After in silico and experimental validation based on evaluations of prognostic value in multiple LUAD cohorts, we selected the PTTG3P pseudogene from among other prognostic ncRNAs (MIR497HG, HSP078, TBX5-AS1, LOC100506990 and C14orf64) for mechanistic studies. PTTG3P upregulation in LUAD cells shortens the metaphase to anaphase transition in mitosis, increases cell viability after cisplatin or paclitaxel treatment, facilitates tumor growth that leads to poor survival in orthotopic lung models, and is associated with a poor survival rate in LUAD patients in the TCGA cohort who received chemotherapy. Mechanistically, PTTG3P acts as an ncRNA that interacts with the transcription factor FOXM1 to regulate the transcriptional activation of the mitotic checkpoint kinase BUB1B, which augments tumor growth and chemoresistance and leads to poor outcomes for LUAD patients. Overall, we established a systematic strategy to uncover prognostic ncRNAs with functional prediction methods suitable for pan-cancer studies. Moreover, we revealed that PTTG3P, due to its upregulation of the PTTG3P/FOXM1/BUB1B axis, could be a therapeutic target for LUAD patients. © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
Original languageEnglish
Pages (from-to)1175-1191
Number of pages17
JournalNucleic Acids Research
Volume48
Issue number3
DOIs
Publication statusPublished - 2020

Keywords

  • BUB1B protein, human
  • cell cycle protein
  • forkhead box protein M1
  • protein serine threonine kinase
  • untranslated RNA
  • adenocarcinoma
  • animal
  • cell proliferation
  • chromatin
  • computer simulation
  • drug resistance
  • genetics
  • human
  • lung tumor
  • male
  • metabolism
  • mitosis
  • mortality
  • mouse
  • pathology
  • prognosis
  • signal transduction
  • tumor cell line
  • Adenocarcinoma
  • Animals
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatin
  • Computer Simulation
  • Drug Resistance, Neoplasm
  • Forkhead Box Protein M1
  • Humans
  • Lung Neoplasms
  • Male
  • Mice
  • Mitosis
  • Prognosis
  • Protein-Serine-Threonine Kinases
  • RNA, Untranslated
  • Signal Transduction

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  • Cite this

    Shih, J-H., Chen, H-Y., Lin, S-C., Yeh, Y-C., Shen, R., Lang, Y-D., Wu, D-C., Chen, C-Y., Chen, R-H., Chou, T-Y., & Jou, Y-S. (2020). Integrative analyses of noncoding RNAs reveal the potential mechanisms augmenting tumor malignancy in lung adenocarcinoma: Nucleic acids research. Nucleic Acids Research, 48(3), 1175-1191. https://doi.org/10.1093/nar/gkz1149