Prognostic microRNAs as biomarkers for prostate cancer.

OBJECTIVE: Prostate cancer is the second largest cancer, most commonly diagnosed in men. Several studies reveal that miRNAs (microRNAs) are involved in various stages of prostate cancer. miRNAs are a family of small non-coding RNA species that have been implicated in the post-transcriptional regulation of gene expression. The present in silico study aims at identifying miRNA biomarkers that are significantly associated with the regulation of genes involved in prostate cancer. METHODS: Dataset of miRNA and mRNA of prostate adenocarcinoma patients and controls was downloaded from The Cancer Genome Atlas (TCGA), and differential gene expression analysis was carried out. ROC and Kaplan-Meier survival analyses were performed on differentially expressed miRNAs. Pathway analysis was carried out for significant miRNAs, and protein-protein interaction of involved genes and miRNAs was examined. RESULTS: A total of 185 miRNAs were differentially expressed between the patients and the control. ROC and Kaplan-Meier survival analysis showed that the two miRNAs hsa-mir-133b and hsa-mir-17-5p were found to be significantly associated with prostate cancer prognosis. HAS2 and EPHA10 gene targets of identified miRNA were also differentially expressed. A protein-protein interaction (PPI) network was constructed, and the HAS2 gene was found to be interacting with the epidermal growth factor receptor (EGFR). CONCLUSION: This study highlights the potential of hsa-mir-133b and hsa-mir-17-5p miRNAs as biomarkers for the prognosis of prostate cancer. However, further experimental studies are required to validate this finding.

Overcoming multi drug resistance mediated by ABC transporters by a novel acetogenin- annonacin from Annona muricata L.

ETHNOPHARMACOLOGICAL RELEVANCE: Multi-Drug Resistance (MDR), mediated by P-glycoprotein (P-gp) is one of the barriers to successful chemotherapy in colon cancer patients. Annona muricata L. (A.muricata), commonly known as soursop/Graviola, is a medicinal plant that has been traditionally used in treating diverse diseases including cancer. Phytochemicals of A.muricata (Annonaceous Acetogenins-AGEs) have been well-reported for their anti-cancer effects on various cancers. AIM OF THE STUDY: The study aimed to examine the effect of AGEs in reversing MDR in colorectal cancer cells. METHODS: Based on molecular docking and molecular dynamic simulation, the stability of annonacin upon P-gp was investigated. Further in vitro studies were carried in oxaliplatin-resistant human colon cancer cells (SW480R) to study the biological effect of annonacin, in reversing drug resistance in these cells. RESULTS: Molecular docking and simulation studies have indicated that annonacin stably interacted at the drug binding site of P-gp. In vitro analysis showed that annonacin was able to significantly reduce the expression of P-gp by 2.56 folds. It also induced apoptosis in the drug-resistant colon cancer cells. Moreover, the intracellular accumulation of P-gp substrate (calcein-AM) was observed to increase in resistant cells upon treatment with annonacin. CONCLUSION: Our findings suggest that annonacin could inhibit the efflux of chemotherapeutic drugs mediated by P-gp and thereby help in reversing MDR in colon cancer cells. Further in vivo studies are required to decipher the underlying mechanism of annonacin in treating MDR cancers.

The genomic landscape associated with resistance to aromatase inhibitors in breast cancer.

Aromatase inhibitors (AI) are drugs that are widely used in treating estrogen receptor (ER)-positive breast cancer patients. Drug resistance is a major obstacle to aromatase inhibition therapy. There are diverse reasons behind acquired AI resistance. This study aims at identifying the plausible cause of acquired AI resistance in patients administered with non-steroidal AIs (anastrozole and letrozole). We used genomic, transcriptomic, epigenetic, and mutation data of breast invasive carcinoma from The Cancer Genomic Atlas database. The data was then separated into sensitive and resistant sets based on patients' responsiveness to the non-steroidal AIs. A sensitive set of 150 patients and a resistant set of 172 patients were included for the study. These data were collectively analyzed to probe into the factors that might be responsible for AI resistance. We identified 17 differentially regulated genes (DEGs) among the two groups. Then, methylation, mutation, miRNA, copy number variation, and pathway analyses were performed for these DEGs. The top mutated genes (FGFR3, CDKN2A, RNF208, MAPK4, MAPK15, HSD3B1, CRYBB2, CDC20B, TP53TG5, and MAPK8IP3) were predicted. We also identified a key miRNA - hsa-mir-1264 regulating the expression of CDC20B. Pathway analysis revealed HSD3B1 to be involved in estrogen biosynthesis. This study reveals the involvement of key genes that might be associated with the development of AI resistance in ER-positive breast cancers and hence may act as a potential prognostic and diagnostic biomarker for these patients.