ABSTRACT
Cancer of the head and neck are the most common cancers in India and account for 30% of all cancers. At molecular level, it could be attributed to the overexpression of growth factors like IGF1-R, EGFR, VEGF-R and deregulation of cell cycle regulators and tumor suppressors. IGF1-R is an emerging target in head and neck cancer treatment, because of its reported role in tumor development, progression and metastasis. IGF1R targeted agents are in advanced stages of clinical development. Nevertheless, these agents suffer from several disadvantages including acquired resistance and toxic side effects. Hence there is a need for developing newer agents targeting not only the receptor but also its downstream signaling. miRNAs are considered as master regulators of gene expression of multiple genes and has been widely reported to be a promising therapeutic strategy. This review discusses the present status of research in both these arenas and emphasizes the role of miRNA as a promising agent for biologic therapy.
Subject(s)
Antineoplastic Agents/pharmacology , MicroRNAs/genetics , Neoplasms/genetics , Receptors, Somatomedin/metabolism , Antineoplastic Agents/therapeutic use , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , MicroRNAs/drug effects , Molecular Targeted Therapy , Receptor, IGF Type 1 , Receptors, Somatomedin/genetics , Signal Transduction/drug effectsABSTRACT
In this study, we have identified one microRNA, microRNA 493 (miR-493), which could simultaneously and directly regulate multiple genes downstream of the insulin-like growth factor 1 receptor (IGF1R) pathway, including IGF1R, by binding with complementary sequences in the 3' untranslated region (UTR) of mRNAs of IGF1R, insulin receptor substrate 1 (IRS1), and mitogen-activated protein kinase 1 (MAPK1), thereby potentiating their inhibitory function at multiple levels in development and progression of cancers. This binding was further confirmed by pulldown of miR with AGO-2 antibody. Further, results from head and neck samples showed that miR-493 levels were significantly downregulated in tumors, with a concomitant increase in the expression of IGF1R and key downstream effectors. Functional studies from miR-493 overexpression cells and nude-mouse models revealed the tumor suppressor functions of miR-493. Regulation studies revealed that Snail binds to the miR-493 promoter and represses it. We found the existence of a dynamic negative feedback loop in the regulation of IGF1R and miR-493 mediated via Snail. Our study showed that nicotine treatment significantly decreases the levels of miR-493-with a concomitant increase in the levels of Snail-an indication of progression of cells toward tumorigenesis, reestablishing the role of tobacco as a major risk factor for head and neck cancers and elucidating the mechanism behind nicotine-mediated tumorigenesis.
Subject(s)
Carcinogenesis/pathology , Feedback, Physiological , MicroRNAs/metabolism , Receptor, IGF Type 1/metabolism , Signal Transduction , Snail Family Transcription Factors/metabolism , Animals , Binding Sites , Carcinogenesis/drug effects , Carcinogenesis/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation/drug effects , Down-Regulation/genetics , Epithelial-Mesenchymal Transition/drug effects , Feedback, Physiological/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Genes, Tumor Suppressor , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/pathology , Humans , Kinetics , Mice, Nude , MicroRNAs/genetics , Models, Biological , Nicotine/pharmacology , Signal Transduction/drug effects , Snail Family Transcription Factors/genetics , Xenograft Model Antitumor AssaysABSTRACT
Parkinson disease (PD) is a neurodegenerative disorder with loss of dopaminergic neurons of the brain, which results in insufficient synthesis and action of dopamine. Metastasis-associated protein 1 (MTA1) is an upstream modulator of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, and hence MTA1 plays a significant role in PD pathogenesis. To impart functional and clinical significance to MTA1, we analyzed MTA1 and TH levels in the substantia nigra region of a large cohort of human brain tissue samples by Western blotting, quantitative PCR, and immunohistochemistry. Our results showed that MTA1 and TH levels were significantly down-regulated in PD samples as compared with normal brain tissue. Correspondingly, immunohistochemistry analysis for MTA1 in substantia nigra sections revealed that 74.1% of the samples had a staining intensity of <6 in the PD samples as compared with controls, 25.9%, with an odds ratio of 8.54. Because of the clinical importance of MTA1 established in PD, we looked at agents to modulate MTA1 expression in neuronal cells, and granulocyte colony-stimulating factor (G-CSF) was chosen, due to its clinically proven neurogenic effects. Treatment of the human neuronal cell line KELLY and acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model with G-CSF showed significant induction of MTA1 and TH with rescue of phenotype in the mouse model. Interestingly, the observed induction of TH was compromised on silencing of MTA1. The underlying molecular mechanism of MTA1 induction by G-CSF was proved to be through induction of c-Fos and its recruitment to the MTA1 promoter.
