Biology subjects

Karunagaran, D.

Publications and source records attributed to Karunagaran, D..

4 recordsLinked to original sources

bioRxiv2023

In Vitro Validation of Computationally Predicted Oncogenic Driver Mutations in EGFR Tyrosine Kinase Domain

Epidermal Growth Factor Receptor (EGFR) signaling is known to play essential roles in growth and development; nevertheless, overexpression and mutation of EGFR have been reported in several cancers. Non-small cell lung cancer (NSCLC), the most observed type of lung cancer, harbors the highest number of EGFR tyrosine kinase mutations and therefore, EGFR has become an important therapeutic target for treatment of these tumors. Tyrosine Kinase Inhibitors (TKIs) are found to be effective in patients whose tumors contain activating mutations in the tyrosine kinase region of the receptor. This would seem to be beneficial in the treatment of EGFR mutation-positive NSCLC patients but the activating mutations should be sensitive to TKIs. Earlier, a machine learning approach was developed to classify single amino acid polymorphisms (SAPs) in EGFR into driver (cancer-causing) and passenger (neutral) mutations using structural and functional features (Anoosha et al., 2015). This study screened all possible point mutations in EGFR and predicted a list of mutations with high probability of being a driver or a passenger. From this list, we selected 2 mutations (G729E and G719F) with high evolutionary conservation score for in vitro validation. If proven to be oncogenic drivers and sensitive to EGFR TKIs, these mutations can aid in the early diagnosis and successful therapy of EGFR mutation-positive NSCLC.

cancer biology↗

bioRxiv2020

Non-coding RNAs in fluid shear stress-driven and reactive oxygen species-mediated colon cancer metastasis

BackgroundColon adenocarcinoma (COAD) is the third most common cancer in the world. Fluid shear stress (FSS) and intracellular reactive oxygen species (ROS) levels are known to mediate COAD metastasis. The present work was performed to explore the role of regulatory non-coding RNA molecules associated with FSS and ROS in COAD metastasis. MethodsThe interactions between the mRNAs associated with FSS and ROS, the corresponding miRNAs, lncRNAs and circRNAs in COAD metastasis were used to generate the mRNA-miRNA-lncRNA-circRNA network. The expression levels of the RNAs in the network were also considered besides the identification of RNA hubs and modules. Further, functional enrichment and survival analysis of the significant miRNAs together with the OncoPrint as well as survival analysis of the selected mRNAs were performed. Subsequently, their functional role was also corroborated with existing literature. ResultsTen significant miRNA hubs were identified, out of which hsa-miR-17-5p and hsa-miR-20a-5p were found to interact with a lncRNA, CCAT2 and hsa-miR-335 was found to interact with four circRNAs. 60% of the FSS and ROS associated mRNAs and 90% of the top 10 miRNA-enriched pathways that emerged from the functional analysis were reported to be involved in COAD metastasis. 15 significant miRNAs were identified in ten different modules suggesting their importance in FSS and ROS mediated COAD metastasis. Finally, ten miRNAs and three mRNAs associated with FSS and/or ROS were identified as significant overall survival markers; 33 mRNAs were also identified as metastasis-free survival markers whereas 15 mRNAs showed >10% gene alterations in TCGA-COAD data and hence emerged as significant molecular markers in the process. ConclusionWe hypothesize that the biologically significant RNAs identified in this integrated analysis may provide valuable insights to understand the molecular mechanism of the FSS driven and ROS mediated COAD metastasis and to design efficient treatment strategies.

systems biology↗

bioRxiv2019

Silver nanoparticle induced oxidative stress augments anticancer gut bacterial metabolites production

Colorectal cancer (CRC) is the fourth leading cause of mortality, world-wide. Gut bacterial dysbiosis being one of the major causes of CRC onset. Gut microbiota produced metabolites, e.g. folate and butyrate play crucial roles in cancer progression and treatment, and thus, need to be considered for effective CRC management. A potential cancer therapy, i.e., use of silver nanoparticles (AgNPs), imparts cytotoxic effects by inducing high intracellular reactive oxygen species (ROS) levels. However, the simultaneous interactions of AgNPs with gut microbiota to aid CRC treatment has not been reported thus far. Therefore, in this study, variation of intracellular ROS concentrations, in Enterococcus durans (E. durans), a representative gut microbe, was studied in the presence of low AgNP concentrations (25 ppm). Increases were observed in intracellular hydroxyl radical and extracellular folic acid concentrations by 48% and 52%, respectively, at the 9thhour of microbial growth. To gain a systems level understanding of ROS metabolism in E. durans, genome scale metabolic network reconstruction and modeling was adopted. In silico modeling reconfirmed the critical association between ROS and folate metabolism. Further, amino acids, energy metabolites, nucleotides, and butyrate were found to be important key players. Consequently, the anticancer effect of folic acid was experimentally studied on HCT116 (i.e., colon cancer cell line), wherein, its viability was reduced to 79% via folate present in the supernatants from AgNP treated E. durans cultures. Thus, we suggest that the inter-relationship between gut bacteria and AgNP-based cancer treatment can be used to design robust and effective cancer therapies.

systems biology↗

bioRxiv2018

A feedback loop between miRNA-155, Programmed cell death 4 and Activation Protein-1 modulates the expression of miR-155 and tumorigenesis in tongue cancer

miR-155 is an oncomir, generated as a non-coding RNA from BIC gene whose promoter activity is mainly controlled via AP-1 and NF-{kappa}B transcription factors. We found that the expression levels of miR-155 and Pdcd4 exhibit inverse relationship in tongue cancer cells (SAS and AWL) and tumor tissues compared to normal FBM cells and normal tongue tissues, respectively. Insilco and In-vitro studies with 3UTR of Pdcd4 via luciferase reporter assays, qPCR and western blots show that miR-155 directly targets Pdcd4 mRNA and blocks its expression. Ectopic expression of Pdcd4 or knockdown of miR-155 in tongue cancer cells predominantly reduces AP-1 dependent transcriptional activity of BIC promoter and decreases miR-155 expression. In this study, we demonstrate that miR-155 expression is modulated by a feedback loop between Pdcd4, AP-1 and miR-155 which results in enhanced expression of miR-155 with a consequent progression of tongue tumorigenesis. Further, miR-155 knockdown increases apoptosis, arrests cell cycle, regresses tumor size in xenograft nude mice and reduces cell viability and colony formation in soft agar and clonogenic assays. Thus, the restoration of Pdcd4 levels by the use of molecular manipulation such as using miR-155 sponge have important role in the therapeutic intervention of cancers, including tongue cancer.

cancer biology↗