ABSTRACT
Overwhelming evidence indicates that cancer is a genetic disease caused by the accumulation of mutations in oncogenes and tumor suppressor genes. It is also increasingly apparent, however, that cancer depends not only on mutations in these coding genes but also on alterations in the large class of non-coding RNAs. Here, we report that one such long non-coding RNA, TRPM2-AS, an antisense transcript of TRPM2, which encodes an oxidative stress-activated ion channel, is overexpressed in prostate cancer (PCa). The high expression of TRPM2-AS and its related gene signature were found to be linked to poor clinical outcome, with the related gene signature working also independently of the patient's Gleason score. Mechanistically, TRPM2-AS knockdown led to PCa cell apoptosis, with a transcriptional profile that indicated an unbearable increase in cellular stress in the dying cells, which was coupled to cell cycle arrest, an increase in intracellular hydrogen peroxide and activation of the sense TRPM2 gene. Moreover, targets of existing drugs and treatments were found to be consistently associated with high TRPM2-AS levels in both targeted cells and patients, ultimately suggesting that the measurement of the expression levels of TRPM2-AS allows not only for the early identification of aggressive PCa tumors, but also identifies a subset of at-risk patients who would benefit from currently available, but mostly differently purposed, therapeutic agents.
Subject(s)
Biomarkers, Tumor/genetics , Prostatic Neoplasms/genetics , RNA, Antisense/genetics , TRPM Cation Channels/genetics , Apoptosis/genetics , Cell Cycle Checkpoints/genetics , Cell Line, Tumor , Endoplasmic Reticulum Stress/genetics , Humans , Hydrogen Peroxide/metabolism , Male , Oxidative Stress/genetics , Prognosis , Prostatic Neoplasms/mortality , RNA Interference , RNA, Antisense/biosynthesis , RNA, Small Interfering , TRPM Cation Channels/biosynthesis , Transcription, GeneticABSTRACT
We report on the expression pattern of a novel EGF- containing gene named Maeg. RNA in situ studies indicate that Maeg is first activated during specification of the early lateral dermatome, and continues to be expressed in all the dermatome derivatives as the dermis of the trunk, the hair follicles, and the mesenchyme of the cranio-facial region.
Subject(s)
Embryonic and Fetal Development/genetics , Epidermal Growth Factor/genetics , Glycoproteins , Growth Substances , Neoplasm Proteins , Peptides , Animals , Base Sequence , Calcium-Binding Proteins , Cell Adhesion Molecules , DNA Primers/genetics , Gene Expression Regulation, Developmental , Genetic Markers , In Situ Hybridization , Mice , RNA, Messenger/genetics , RNA, Messenger/metabolism , Somites/metabolismABSTRACT
Epidermal growth factor (EGF) repeat-containing proteins constitute an expanding family of proteins involved in several cellular activities such as blood coagulation, fibrinolysis, cell adhesion, and neural and vertebrate development. By using a bioinformatic approach, we have identified a new member of this family named MAEG (MAM- and EGF-containing gene; HGMW-approved gene symbol and gene name). Sequence analysis indicates that MAEG encodes a secreted protein characterized by the presence of five EGF repeats, three of which display a Ca(2+)-binding consensus sequence. In addition, a MAM domain is also present at the C-terminus of the predicted protein product. The human and murine full-length cDNAs were identified and mapped to human Xp22 and to the mouse syntenic region. Northern analysis indicates that MAEG is expressed early during development. Taken together, these data render MAEG a candidate for human and murine developmental disorders.
