The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has a master control role in various cancer-related biological processes as cell growth, proliferation, differentiation, migration, and apoptosis. It also regulates many transcription factors that control microRNAs (miRNAs) and their biosynthetic machinery. To investigate on the still poorly characterised global involvement of miRNAs within the pathway, we profiled the expression of 745 miRNAs in three colorectal cancer (CRC) cell lines after blocking the pathway with three different inhibitors. This allowed the identification of two classes of post-treatment differentially expressed (DE) miRNAs: (1) common DE miRNAs in all CRC lines after treatment with a specific inhibitor (class A); (2) DE miRNAs in a single CRC line after treatment with all three inhibitors (class B). By determining the molecular targets, biological roles, network position of chosen miRNAs from class A (miR-372, miR-663b, miR-1226*) and class B (miR-92a-1*, miR-135b*, miR-720), we experimentally demonstrated that they are involved in cell proliferation, migration, apoptosis, and globally affect the regulation circuits centred on MAPK/ERK signaling. Interestingly, the levels of miR-92a-1*, miR-135b*, miR-372, miR-720 are significantly higher in biopsies from CRC patients than in normal controls; they also are significantly higher in CRC patients with mutated KRAS than in those with wild-type genotypes (Wilcoxon test, p < 0.05): the latter could be a downstream effect of ERK pathway overactivation, triggered by KRAS mutations. Finally, our functional data strongly suggest the following miRNA/target pairs: miR-92a-1*/PTEN-SOCS5; miR-135b*/LATS2; miR-372/TXNIP; miR-663b/CCND2. Altogether, these results contribute to deepen current knowledge on still uncharacterized features of MAPK/ERK pathway, pinpointing new oncomiRs in CRC and allowing their translation into clinical practice and CRC therapy.
Studies on oocyte transcriptome are important to understand the biological pathways involved in oogenesis, totipotence and early embryonic development. Moreover, genes regulating physiological pathways in gametes could represent potential candidates for reproductive disorders. In addition to oocyte specific transcription factors, also the members of the p53 family could be etiologically involved due to their biological functions. In fact, their role in the control of cell cycle, apoptosis and germ-line genome stability is well known. Female reproductive aging is one of the causes of fertility reduction and it is often associated with egg aneuploidy increase. In order to verify the potential involvement of p73 in reproductive aging, we determined its expression in single mature MII oocytes from two groups of women, younger than 35 or older than 38 y, respectively. We found that TAp73 isoforms are downregulated in oocytes from women older than 38 y. We confirmed these data in pools of mouse oocytes. TAp73 downregulation in oocytes from women of advanced reproductive age could explain both the reduction of fertility and the increase of newborns with chromosomal abnormalities.
The aim of the study was to investigate the release of endothelin-1 (ET-1) in normal and varicose saphenous veins at baseline and after venous stasis test. Ten patients (eight women and two men, mean age 43 +/- 4) with primarily varicose great saphenous veins and ten controls (eight women and two men, mean age 42 +/- 6) were recruited. After 30 minutes of resting in supine position, venous occlusion in a leg was performed with a sphygmomanometer provided to keep the pressure in the cuff intermediate between systolic and diastolic blood pressure for 10 minutes. Blood samples were taken from the great saphenous vein just above the medial malleolus at baseline and 10 minutes after venous stasis was begun. Plasma ET-1 was determined by a radioimmunoassay system. Results are expressed as mean +/- SD. Plasma ET-1 concentration was higher in varicose than in normal saphenous veins (4 +/- 0.1 pmol/L vs 2.6 +/- 0.1 pmol/L, P < 0.001), and it significantly increased (P < 0.001) in both groups after venous stasis when compared with baseline (6.8 +/- 0.9 pmol/L and 3.6 +/- 0.1 pmol/L in varicose and normal saphenous veins, respectively). Absolute increase in plasma ET-1 was significantly greater in varicose than in normal saphenous veins (2.8 +/- 0.9 pmol/L vs 1.0 +/- 0.2 pmol/L, P < 0.01). In conclusion, increased local ET-1 release in varicose saphenous veins could be a marker for venous endothelial activation/damage and/or contribute to promote the morphologic alterations of the varicose vein wall by stimulating smooth muscle cell proliferation. On the other hand, increased ET-1 release could contribute to counterbalancing the varicose venous relaxation and to increasing preload in varicose patients via ET-1-induced venoconstriction.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.