RNA-Interference-Mediated miR-122-Based Gene Regulation in Colon Cancer, a Structural In Silico Analysis

Harsha Ganesan; Suman K Nandy; Antara Banerjee; Surajit Pathak; Hong Zhang; Xiao-Feng Sun

doi:10.3390/ijms232315257

RNA-Interference-Mediated miR-122-Based Gene Regulation in Colon Cancer, a Structural In Silico Analysis

Int J Mol Sci. 2022 Dec 3;23(23):15257. doi: 10.3390/ijms232315257.

Authors

Harsha Ganesan¹, Suman K Nandy², Antara Banerjee¹, Surajit Pathak^{1

3}, Hong Zhang⁴, Xiao-Feng Sun³

Affiliations

¹ Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai 603103, Tamil Nadu, India.
² BioNEST Bioincubator Facility, North-Eastern Hill University, Tura Campus, Chasingre, Tura 793022, Meghalaya, India.
³ Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden.
⁴ School of Medical Sciences, Faculty of Medicine and Health, Orebro University, 702 81 Örebro, Sweden.

Abstract

The role of microRNA 122 (miR-122) in colorectal cancer (CRC) has not been widely investigated. In the current study, we aimed to identify the prominent gene and protein interactors of miR122 in CRC. Based on their binding affinity, these targets were chosen as candidate genes for the creation of miR122-mRNA duplexes. Following this, we examined the miRNA-mediated silencing mechanism using the gene-silencing complex protein Argonaute (AGO). Public databases, STRING, and GeneMANIA were utilized to identify major proteins and genes interacting with miR-122. DAVID, PANTHER, UniProt, FunRich, miRwalk, and KEGG were used for functional annotation, pathway enrichment, binding affinity analysis, and expression of genes in different stages of cancer. Three-dimensional duplexes of hub genes and miR-122 were created using the RNA composer, followed by molecular interaction analysis using molecular docking with the AGO protein. We analyzed, classified, and scrutinized 93 miR-122 interactors using various bioinformatic approaches. A total of 14 hub genes were categorized as major interactors of miR-122. The study confirmed the role of various experimentally documented miR-122 interactors such as MTDH (Q86UE4), AKT1 (P31749), PTPN1 (P18031), MYC (P01106), GSK3B (P49841), RHOA (P61586), and PIK3CG (P48736) and put forth several novel interactors, with AKT3 (Q9Y243), NCOR2 (Q9Y618), PIK3R2 (O00459), SMAD4 (P61586), and TGFBR1 (P36897). Double-stranded RNA duplexes of the strongest interactors were found to exhibit higher binding affinity with AGO. In conclusions, the study has explored the role of miR-122 in CRC and has identified a closely related group of genes influencing the prognosis of CRC in multiple ways. Further, these genes prove to be targets of gene silencing through RNA interference and might serve as effective therapeutic targets in understanding and treating CRC.

Keywords: Argonaute protein; RNA interference; colorectal cancer; gene silencing; miR-122; network biology; signaling pathways.

MeSH terms

Colonic Neoplasms* / genetics
Colorectal Neoplasms* / genetics
Computational Biology / methods
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Humans
Membrane Proteins / metabolism
MicroRNAs* / genetics
MicroRNAs* / metabolism
Molecular Docking Simulation
RNA Interference
RNA-Binding Proteins / metabolism

Substances

MicroRNAs
MTDH protein, human
Membrane Proteins
RNA-Binding Proteins
MIRN122 microRNA, human

Grants and funding

This research was funded by Department of Science and Technology (DST)–Science and Engineering Research Board (SERB), grant number (EMR/2017/001877) sanctioned to S.P. Article processing charges were covered through the fund from Cancerfonden (19 0322 Pj) sanctioned to X.-F.S.