Abstract
Among solid tumors, hepatocellular carcinoma (HCC) emerges as a prototypical therapy-resistant tumor. Considering the emerging sorafenib resistance crisis in HCC, future studies are urgently required to overcome resistance. Recently noncoding RNAs (ncRNAs) have emerged as significant regulators in signalling pathways involved in cancer drug resistance and pharmacologically targeting these ncRNAs might be a novel stratagem to reverse drug resistance. In the current study, using a hybrid Petri net based computational model, we have investigated the harmonious effect of miR-17-92 cluster inhibitors/mimics and circular RNAs on sorafenib resistant HCC cells in order to explore potential resistance mechanisms and to identify putative targets for sorafenib-resistant HCC cells. An integrated model was developed that incorporates seven miRNAs belonging to miR-17-92 cluster (hsa-miR-17-5p, hsa-miR-17-3p, hsa-miR-19a, hsa-miR-19b, hsa-miR-18a, hsa-miR-20a and hsa-miR-92) and crosstalk of two signaling pathways (EGFR and IL-6) that are differentially regulated by these miRNAs. The mechanistic connection was proposed by the correlation between members belonging to miR-17-92 cluster and corresponding changes in the protein levels of their targets in HCC, specifically those targets that have verified importance in sorafenib resistance. Current findings uncovered potential pathway features, underlining the significance of developing modulators of this cluster to combat drug resistance in HCC.
Highlights
Chemotherapy serves as a cornerstone in the development of current cancer therapy and is widely used in the treatment of cancer[1]
Further investigation and exploration of the crosstalk of miRNAs and their associated pathways may lead to future breakthroughs in the treatment of Hepatocellular carcinoma (HCC) and will hopefully increase our understanding of the mechanisms implicated in sorafenib resistance
In the current study, using a hybrid Petri net (HPN)-based computational approach, we have investigated the dynamics of several signaling molecules
Summary
Chemotherapy serves as a cornerstone in the development of current cancer therapy and is widely used in the treatment of cancer[1]. This cluster has been validated as an oncogenic as well as tumor suppressive regulator This dual role of miR-17-92 cluster is due to the diverse spectrum of targeted mRNAs as well as intricate cascade of miRNAs and their targets involved in distinct pathways[20]. Further investigation and exploration of the crosstalk of miRNAs and their associated pathways may lead to future breakthroughs in the treatment of HCC and will hopefully increase our understanding of the mechanisms implicated in sorafenib resistance. By comparing experimental data with the model simulations, we have uncovered potential pathway features as well as putative targets for sorafenib resistant signaling in HCC cells. Current study was carried out with an objective of making correlation among miR-17-92 cluster, EGFR/IL-6 signaling pathway and sorafenib resistance through step wise simulation, validation of the proposed model and analysis of sorafenib resistant HCC cells. We expect that the current association between miR-17-92 cluster and sorafenib resistance in HCC will attract experimental research community to verify their role in resistance mechanism
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
