A Boolean Model of the Proliferative Role of the lncRNA XIST in Non-Small Cell Lung Cancer Cells

Author(s)

Gupta, Shantanu ; Silveira, Daner A. ; Hashimoto, Ronaldo E. ; Mombach, Jose Carlos M.

• Document type: Journal article
• Source: BIOLOGY-BASEL; v. 11, n. 4, p. 14-pg., 2022-04-01.

Abstract

Simple Summary The lncRNA XIST has been verified as an oncogenic gene in non-small cell lung cancer (NSCLC), whereas the tumor suppressors miR-34a, miR-449a, and miR-16 were downregulated in NSCLC. The lncRNA XIST is known to bind to the miR-449a and miR-34a sponges, however, the biological functions linking all these non-coding RNAs (ncRNAs) are still unknown in NSCLC. This study aims to perform dynamic analysis of the gene regulation between these two ncRNAs in NSCLC. Thus, we presented a Boolean model of the plausible network connecting the lncRNA XIST/miR-34a/miR-449a and miR-16 in NSCLC. We observed that miR-449a/miR-34a regulates miR-16 and p21 expression by targeting HDAC1, c-Myc, and the lncRNA XIST. Our results demonstrate that the lncRNA XIST is an attractive target of drug development in NSCLC and that favorable outcomes can be achieved through tumor suppressor miRNAs. The long non-coding RNA X inactivate-specific transcript (lncRNA XIST) has been verified as an oncogenic gene in non-small cell lung cancer (NSCLC) whose regulatory role is largely unknown. The important tumor suppressors, microRNAs: miR-449a and miR-16 are regulated by lncRNA XIST in NSCLC, these miRNAs share numerous common targets and experimental evidence suggests that they synergistically regulate the cell-fate regulation of NSCLC. LncRNA XIST is known to sponge miR-449a and miR-34a, however, the regulatory network connecting all these non-coding RNAs is still unknown. Here we propose a Boolean regulatory network for the G1/S cell cycle checkpoint in NSCLC contemplating the involvement of these non-coding RNAs. Model verification was conducted by comparison with experimental knowledge from NSCLC showing good agreement. The results suggest that miR-449a regulates miR-16 and p21 activity by targeting HDAC1, c-Myc, and the lncRNA XIST. Furthermore, our circuit perturbation simulations show that five circuits are involved in cell fate determination between senescence and apoptosis. The model thus allows pinpointing the direct cell fate mechanisms of NSCLC. Therefore, our results support that lncRNA XIST is an attractive target of drug development in tumor growth and aggressive proliferation of NSCLC, and promising results can be achieved through tumor suppressor miRNAs. (AU)

• FAPESP's process: 15/22308-2 - Intermediate representations in Computational Science for knowledge discovery
• Grantee: Roberto Marcondes Cesar Junior
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/09070-8 - Modeling, analysis, and inference of biological networks
• Grantee: Shantanu Gupta
• Support Opportunities: Scholarships in Brazil - Post-Doctoral