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Genome-Wide Small RNA Sequencing Identifies MicroRNAs Deregulated in Non-Small Cell Lung Carcinoma Harboring Gain-of-Function Mutant p53

1
Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
2
Human Genetics Unit, Indian Statistical Institute, 203 B. T. Road, Kolkata 700108, India
3
Saroj Gupta Cancer Centre and Research Institute, Mahatma Gandhi Road, Thakurpukur, Kolkata 700063, India
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Genes 2019, 10(11), 852; https://doi.org/10.3390/genes10110852
Received: 24 August 2019 / Revised: 11 October 2019 / Accepted: 12 October 2019 / Published: 28 October 2019
(This article belongs to the Section Human Genomics and Genetic Diseases)
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. View Full-Text
Keywords: microRNA; non-small cell lung carcinoma; mutant p53; gain of function; small RNA sequencing; TCGA; novel miRNA; node metastasis; survival microRNA; non-small cell lung carcinoma; mutant p53; gain of function; small RNA sequencing; TCGA; novel miRNA; node metastasis; survival
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Datta, A.; Das, P.; Dey, S.; Ghuwalewala, S.; Ghatak, D.; Alam, S.K.; Chatterjee, R.; Roychoudhury, S. Genome-Wide Small RNA Sequencing Identifies MicroRNAs Deregulated in Non-Small Cell Lung Carcinoma Harboring Gain-of-Function Mutant p53. Genes 2019, 10, 852.

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