Melatonin and cancer: Exploring gene networks and functional categories

Abstract

While melatonin is known for its multifaceted properties and its potential to combat cancer, there has been limited exploration of the cancer-melatonin interaction at the gene network level. One of the ways to better understand the molecular mechanisms of melatonin’s anti-cancer effects is to use text-mining strategies to extract relevant information that creates knowledge networks of entities and their associations. In this study, we mined gene-publication associations to search for genes most relevant to the terms of “melatonin” and “cancer”. A total of 152 genes were identified and ranked, among which 15 were kinase-related and three G-protein coupled receptor genes. The hub genes (STAT3, JUN, TP53, MAPK3, EP300, SRC, HSP90AA1, AKT1, ESR1, and IL6) were involved with several pathways in cancer. After examining the melatonin-treated cancers, we mapped 25 upregulated and 51 downregulated genes; these were strongly associated with cancer hallmarks such as resisting cell death, sustaining proliferative signaling, and inducing invasion and metastasis. Upregulated genes showed molecular functions including apoptotic protease activator, caspase activator, enzyme regulator, and protein binding, whereas the downregulated genes affected protein kinase activities, transcription factor binding, protein, enzyme, DNA, and promoter bindings. By connecting gene subsets, we detected a closer relationship among breast, hepatocellular, prostate, and oral cancers, in addition to neuroblastoma and osteosarcoma in terms of changes in melatonin-related signaling pathways. TCGA data were analyzed to understand the impact of gene signatures on survival of patients, and melatonin-downregulated genes were associated with longer survival of patients with glioblastoma, bladder, breast, colon, stomach, liver, lung, and ovarian carcinomas. These results provide a global view of gene interaction networks in melatonin-treated cancers and their functional value, opening new opportunities to consider melatonin for cancer therapy.