RESUMEN
Detectable in biopsies and body fluids, the measurement of a single or panels of microRNAs have been reported to be quite sensitive and specific for the prediction, diagnosis, and prognosis of many diseases. Interest in the use of microRNAs as biomarkers and eventual therapeutic targets has increased exponentially in the last decade. However, in the field of graft-versus-host disease (GVHD), the discovery of their involvement in biological processes and their predictive value is only emerging. With 30-75% of patients developing GVHD following allogeneic hematopoietic cell transplant and the absence of routinely used predictive biomarkers, microRNAs are promising for early detection and follow-up of this condition. We aim to summarize the current knowledge on the involvement of these small RNAs in the pathophysiology of this disease. We also review studies investigating the potential of miRNAs as biomarkers for early detection, follow-up, and prognosis of GVHD.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , MicroARNs , Biomarcadores , Humanos , MicroARNs/genética , PronósticoRESUMEN
The discovery of miRNAs in the mid-90s has changed the dogma of gene expression regulation. Currently, miRNAs are the main theme of thousands of publications each year and their involvement in human diseases is everyday more deeply understood. With that being known, what are the actual clinical applications of miRNAs and how far are they truly from the patients? To address this question, we reviewed the miRNA diagnostic and therapeutic market. With many companies developing miRNA panels, the activity is high in the diagnostic area. Some products, notably for thyroid cancer (Interpace Diagnostic), are already available to clinician and covered by major insurance companies. In comparison, the therapeutic market, mainly driven by miRNA mimics and antagomiR products, is less advanced. Miravirsen (produced by Roche/Santaris) and RG-101 (produced by Regulus Therapeutics), designed to treat hepatitis C, are considered the flagship products of this class of future drugs. All of the miRNA-based drugs are currently in clinical trials and none have yet reached the pharmaceutical breakthrough. However, acquisition of miRNA-based companies by major pharmas is sending a positive feedback on their potentials. With multiple initiatives on their way, the next years will definitely be determinant for the miRNA market that is still in his infancy.
RESUMEN
The three PRL (phosphatases of regenerating liver) protein tyrosine phosphatases (PRL-1, -2 and -3) have been identified as key contributors to metastasis in several human cancers, yet the molecular basis of their pro-oncogenic property is unclear. Among the subfamily of PRL phosphatases, overexpression of PRL-2 in breast cancer cells has been shown to promote tumor growth by a mechanism that remains to be uncovered. Here we show that PRL-2 regulates intracellular magnesium levels by forming a functional heterodimer with the magnesium transporter CNNM3. We further reveal that CNNM3 is not a phosphorylated substrate of PRL-2, and that the interaction occurs through a loop unique to the CBS pair domains of CNNM3 that exists only in organisms having PRL orthologs. Supporting the role of PRL-2 in cellular magnesium transport is the observation that PRL-2 knockdown results in a substantial decrease of cellular magnesium influx. Furthermore, in PRL-2 knockout mice, serum magnesium levels were significantly elevated as compared with control animals, indicating a pivotal role for PRL-2 in regulating cellular magnesium homeostasis. Although the expression levels of CNNM3 remained unchanged after magnesium depletion of various cancer cell lines, the interaction between endogenous PRL-2 and CNNM3 was markedly increased. Importantly, xenograft tumor assays with CNNM3 and a mutant form that does not associate with PRL-2 confirm that CNNM3 is itself pro-oncogenic, and that the PRL-2/CNNM3 association is important for conferring transforming activities. This finding is further confirmed from data in human breast cancer tissues showing that CNNM3 levels correlate positively with both PRL-2 expression and the tumor proliferative index. In summary, we demonstrate that oncogenic PRL-2 controls tumor growth by modulating intracellular magnesium levels through binding with the CNNM3 magnesium transporter.