Genome-wide small RNA sequencing identifies micrornas deregulated in non-small cell lung carcinoma harboring gain-of-function mutant P53

Arindam Datta, Pijush Das, Sanjib Dey, Sangeeta Ghuwalewala, Dishari Ghatak, Sk Kayum Alam, Raghunath Chatterjee, Susanta Roychoudhury

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Mutations in the TP53 gene are one of the most frequent events in cancers. Certain missense mutant p53 proteins gain oncogenic functions (gain-of-functions) and drive tumorigenesis. Apart from the coding genes, a few non-coding microRNAs (miRNAs) are implicated in mediating mutant p53-driven cancer phenotypes. Here, we identified miRNAs in mutant p53R273H bearing non-small cell lung carcinoma (NSCLC) cells while using small RNA deep sequencing. Differentially regulated miRNAs were validated in the TCGA lung adenocarcinoma patients with p53 mutations and, subsequently, we identified specific miRNA signatures that are associated with lymph node metastasis and poor survival of the patients. Pathway analyses with integrated miRNA-mRNA expressions further revealed potential regulatory molecular networks in mutant p53 cancer cells. A possible contribution of putative mutant p53-regulated miRNAs in epithelial-to-mesenchymal transition (EMT) is also predicted. Most importantly, we identified a novel miRNA from the unmapped sequencing reads through a systematic computational approach. The newly identified miRNA promotes proliferation, colony-forming ability, and migration of NSCLC cells. Overall, the present study provides an altered miRNA expression profile that might be useful in biomarker discovery for non-small cell lung cancers with TP53 mutations and discovers a hitherto unknown miRNA with oncogenic potential.

Original languageEnglish (US)
Article number852
JournalGenes
Volume10
Issue number11
DOIs
StatePublished - Nov 2019
Externally publishedYes

Bibliographical note

Funding Information:
Funding: This work was supported by CSIR—Mayo Clinic Collaboration for Innovation and Translational Research Grant CMPP-08, CSIR-NMITLI project TLP 0007 and J C Bose Fellowship (JCB/2017/000005) awarded to S. Roychoudhury. R. Chatterjee is supported by the intramural funding from Indian Statistical Institute and extramural funding from CSIR Grant 27(0306)/14//EMR-II.

Funding Information:
This work was supported by CSIR-Mayo Clinic Collaboration for Innovation and Translational Research Grant CMPP-08, CSIR-NMITLI project TLP 0007 and J C Bose Fellowship (JCB/2017/000005) awarded to S. Roychoudhury. R. Chatterjee is supported by the intramural funding from Indian Statistical Institute and extramural funding from CSIR Grant 27(0306)/14//EMR-II. We thank Varda Rotter (Weizmann Institute of Science, Rehovot, Israel) for kindly providing us with the H1299/EV cell line. We thank David Callen (Centre for Personalized Cancer Medicine, School of Medicine, The University of Adelaide, Australia) for kindly providing us with the mutant p53R273H transcriptome dataset in the H1299 cell line. We thank Atreyee Saha (Life Technologies, India) for helping us with Ion PGM? sequencing facility. We thank Neha Garg (Life Technologies, India) Joyeeta Chakraborty and Sayantan Laha (Indian Statistical Institute, Kolkata, India) for their valuable suggestions in data analysis.

Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Gain of function
  • MicroRNA
  • Mutant p53
  • Node metastasis
  • Non-small cell lung carcinoma
  • Novel miRNA
  • Small RNA sequencing
  • Survival
  • TCGA

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