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Application of comprehensive bioinformatics approaches to reconnoiter crucial genes and pathways underpinning hepatocellular carcinoma: a drug repurposing endeavor

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Abstract

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm in the world. Chronic inflammation of liver and associated wound healing processes collectively contribute to the development of cirrhosis which further progresses to dysplastic nodule and then to HCC. Etiological mediators and ongoing manipulations at cellular level in HCC are well established; however, key protein interactions and genetic alterations involved in stepwise hepatocarcinogenic pathways are seldom explored. This study aims to unravel novel targets of HCC and repurpose the FDA-approved drugs against the same. Genetic data pertinent to different stages of HCC were retrieved from GSE6764 dataset and analyzed via GEO2R. Subsequently, protein–protein interaction network analysis of differentially expressed genes was performed to identify the hub genes with significant interaction. Hub genes displaying higher interactions were considered as potential HCC targets and were validated thorough UALCAN and GEPIA databases. These targets were screened against FDA-approved drugs through molecular docking and dynamics simulation studies to capture the drugs with potential activity against HCC. Finally, cytotoxicity of the shortlisted drug was confirmed in vitro by MTT assay. CDC20 was identified as potential druggable target. Docking, binding energy calculations, and dynamic studies revealed significant interaction exhibited by Labetalol with CDC20. Further, in MTT assay, Labetalol demonstrated an IC50 of 200.29 µg/ml in inhibiting the cell growth of HepG2 cell line. In conclusion, this study discloses a series of key genetic underpinnings of HCC and recommends the pertinence of labetalol as a potential repurposable drug against HCC.

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Abbreviations

rGyr:

Radius of Gyration

ASPM:

Assembly Factor for Spindle Microtubules

BCLC:

Barcelona Clinic Liver Cancer

BUB1:

BUB1 Mitotic Checkpoint Serine/Threonine Kinase

BUB1B:

BUB1 Mitotic Checkpoint Serine/Threonine Kinase B

CCL19:

Chemokine (C–C Motif) Ligand 19

CCNB1:

Cyclin B1

CCNB1:

Cyclin B1

CCNB2:

Cyclin B2

CDC20:

Cell Division Cycle 20

CDK1:

Cyclin-Dependent Kinase 1

CDKN3:

Cyclin-Dependent Kinase Inhibitor 3

CENPF:

Centromere Protein F

CFTR:

Cystic Fibrosis Transmembrane Conductance Regulator

CXCL11:

C-X-C Motif Chemokine 11

DEG:

Differentially Expressed Genes

DN:

Dysplastic Nodule

FDA:

Food and Drug Administration

GEPIA:

Gene Expression Profiling Interactive Analysis

GO:

Gene Ontology

HBV:

Hepatitis-B Virus

HCC:

Hepatocellular Carcinoma

HCV:

Hepatitis-C Virus

HMMR:

Hyaluronan-Mediated Motility Receptor

IGF1:

Insulin-Like Growth Factor 1

IL7R:

Interleukin 7 Receptor

KEGG:

Kyoto Encyclopedia of Genes and Genomes

KIF20A:

Kinesin Family Member 20A

KIF2C:

Kinesin Family Member 2C

KIF4A:

Kinesin Family Member 4A

KRT19:

Keratin 19

MAD2L1:

Mitotic Arrest Deficient 2 Like 1

MELK:

Maternal Embryonic Leucine Zipper Kinase

MM/GBSA:

Molecular Mechanics energies combined with the Generalized Born and Surface Area continuum Solvation

MX1:

MX Dynamin Like GTPase 1

NCAPG:

Non-SMC Condensin I Complex Subunit G

NEK2:

NIMA-Related Kinase 2

PBK:

PDZ Binding Kinase

PDB:

Protein Data Bank

PROM1:

Prominin 1

RMSD:

Root Mean Square Deviation

RMSF:

Root-Mean-Square Fluctuation

STAT1:

Signal Transducer and Activator of Transcription 1

TCGA:

The Cancer Genome Atlas

TOP2A:

DNA Topoisomerase II Alpha

TPX2:

TPX2 Microtubule Nucleation Factor

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Pharmacy, M. S. Ramaiah University of Applied Sciences, Bangalore, Karnataka, India

    Gouri Nair

  2. Department of Pharmacy Practice, Faculty of Pharmacy, M. S. Ramaiah University of Applied Sciences, Bangalore, India, Karnataka

    G. N. S. Hema Sree, Ganesan Rajalekshmi Saraswathy & V. Lakshmi Prasanna Marise

  3. Department of Biotechnology, M. S. Ramaiah Institute of Technology, Bengaluru, Karnataka, 560054, India

    T. P. Krishna Murthy

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Nair, G., Hema Sree, G.N.S., Saraswathy, G.R. et al. Application of comprehensive bioinformatics approaches to reconnoiter crucial genes and pathways underpinning hepatocellular carcinoma: a drug repurposing endeavor. Med Oncol 38, 145 (2021). https://doi.org/10.1007/s12032-021-01576-w

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