1 rotein staining, respectivelyWang et al. not too long ago demonstrated that also miRNAs can
1 rotein staining, respectivelyWang et al. not too long ago demonstrated that also miRNAs can be oxidatively modified by ROS, altering their binding properties from native targets to new ones, as inside the case of miR-18425. It can be worth noting that the duplex structure of pri-miRNAs precursor may represent the favorite target of APE1 activity17. Consequently, we should reinterpret the roles of APE1 in modulating cellular responses to genotoxic stresses and within the pathogenesis of human ailments, in light with the new function of this multifunctional protein in RNA biology. miR-221 and miR-222 are two highly homologous miRNAs, tandemly encoded on the X-chromosome, whose LILRB4/CD85k/ILT3, Human (Biotinylated, HEK293, His-Avi) overexpression has been lately described in several human malignancies, including thyroid papillary carcinomas, glioblastoma, prostate carcinoma, gastric carcinoma and others50. They both act as oncogenic miRNAs typically targeting a cluster of genes with a important part in tumor inhibition, for instance PTEN in tumor suppression, PUMA in apoptosis, TRPS1 in epithelial to mesenchymal transition and also the cell cycle inhibitors p27Kip1 and CDKN1C/p57 50, 51. Upregulation of miR-221/222 has been shown to confer radioresistance, cell growth and invasion capabilities to unique cancer cell kinds by suppressing the action of PTEN and their other essential target29, 31, 52, 53. Furthermore, upregulation of miR-221/ 222 has been connected with the improvement of multidrugNATURE COMMUNICATIONS | 8:resistance and altered response to chemotherapy546. Consequently, restoring these anti-cancer genes expression by inhibiting miR-221/222 levels has been considered as a possible therapeutic strategy50. Interestingly, we noticed that the different pri-miR-221 and pri-miR-222 expression levels we measured, may possibly be suggestive for independent expression by various promoters, as also confirmed by experimental data obtained in the FANTOM5 project57. The truth is, inside the 1174 human samples analyzed, the RLE-normalized promoter activity of miR-222 is on average 3.8-fold greater than that of miR-221. For that reason, as well as a generally thought polycistronic nature, miR-221 and miR-222 may possibly be independently transcribed (Supplementary Fig. 9). Relating to the crucial function of apoptosis-resistance and EMT in acquired resistance to radiotherapy, chemotherapy, and targeted therapy, our outcome that APE1-endonuclease activity can interfere with miR-221/222 biogenesis represents, for the finest of our understanding, a novel combinational therapeutic approach by way of utilizing APE1 inhibitors to improve efficacy of current cancer treatment. PTEN is really a well-known tumor suppressor gene that negatively regulates the key cell survival PI3K/AKT signaling pathway. Downregulation of PTEN, as a consequence of miR-221/222 overexpression, results in a constitutive activation in the PI3K/ AKT pathway, which in turn promotes cell transformation580.| DOI: 10.1038/s41467-017-00842-8 | nature.com/naturecommunicationsARTICLEaRPLNATURE COMMUNICATIONS | DOI: 10.1038/s41467-017-00842-HNRNPH1 PABPCSNRPD1 HNRNPULHNRNPK SFPQ SUMO1 HNRNPU RPS3 THRAP3 NME1 BASP1 HMGB2 MSM CDK5 HOXC9 TCEB1 LGALS1 SUMO2 SET TCF21 TXN SRPK2 HMGA2 Transcription NPM1 APP TERF2 TDG OGG1 XRCC6 PRPF19 NAE1 Processing of RNAHNRNPF MPGCDKN1AHUS1 LIG1 RAD9ARepair of DNA HNRNPL Excision repair SRPKTPNCLTRAF2 TEAP4 EP300 ASCL2 ANP32A MDM2 RNF4 STAT3 TERF2IP ESRXRCC1 XRCC5 YBX1 FEN1 APEX1 SIRT1 PRDX6 HMGA1 CD162/PSGL-1, Mouse (266a.a, HEK293, Fc) PCNARADUBE2I HDAC1 HSPA1A/HSPA1B WDR77 PRPS1 TCP1 POLR3D RPSA TERF1 PRPS2 AICDA SPHKMYO1C ARIH2 RPL4 CCD.