Myeloid-derived suppressor cells (MDSCs) were one of the major components of the immune suppressive network. STAT3 has an important role in regulating the suppressive potential of MDSCs. In this study, we found that the expression of STAT3 could be modulated by both miR-17-5p and miR-20a. The transfection of miR-17-5p or miR-20a remarkably reduces the expression of reactive oxygen species and the production of H2O2, which are regulated by STAT3. MDSCs transfected with miR-17-5p or miR-20a are less able to suppress Ag-specific CD4 and CD8 T cells. Importantly, both miR-17-5p and miR-20a alleviate the suppressive function of MDSCs in vivo. The expression of miR-17-5p and miR-20a in tumor-associated MDSCs was found to be lower than in Gr1+CD11b+ cells isolated from the spleens of disease-free mice. Tumor-associated factor downregulates the expression of both miR-17-5p and miR-20a. The modulation of miR-17-5p and miR-20a expression may be important for the process by which patients with a tumor can overcome the immune tolerance mediated by MDSCs. Our results suggest that miR-17-5p and miR-20a could potentially be used for immunotherapy against diseases, especially cancer, by blocking STAT3 expression.
MicroRNAs (miRNAs) have been recognized as significantly involved in prostate cancer (PCa). Since androgen receptor (AR) plays a central role in PCa carcinogenesis and progression, it is imperative to systematically elucidate the causal association between AR and miRNAs, focusing on the molecular mechanisms by which miRNAs mediate AR signalling. In this study, we performed a series of time-course microarrays to observe the dynamic genome-wide expressions of mRNAs and miRNAs in parallel in hormone-sensitive prostate cancer LNCaP cells stimulated by androgen. Accordingly, we introduced Response Score to identify AR target miRNAs, as well as Modulation Score to identify miRNA target mRNAs. Based on theoretical identification and experimental validation, novel mechanisms addressing cell viability in PCa were unravelled for 3 miRNAs newly recognized as AR targets. (1) miR-19a is directly up-regulated by AR, and represses SUZ12, RAB13, SC4MOL, PSAP and ABCA1, respectively. (2) miR-27a is directly up-regulated by AR, and represses ABCA1 and PDS5B. (3) miR-133b is directly up-regulated by AR, and represses CDC2L5, PTPRK, RB1CC1, and CPNE3, respectively. Moreover, we found miR-133b is essential to PCa cell survival. Our study gives certain clues on miRNAs mediated AR signalling to cell viability by influencing critical pathways, especially by breaking through androgen’s growth restriction effect on normal prostate tissue.
Gyroid scaffold has superior mechanical properties to mimic human bone; Gyroid scaffold has adjustable permeability properties to match human bone; SLM-produced gyroid scaffold has good consistency with its designing CAD model.
Loss of Hippo tumor-suppressor activity and hyperactivation of YAP are commonly observed in cancers. Inactivating mutations of Hippo kinases MST1/2 are uncommon, and it remains unclear how their activity is turned off during tumorigenesis. We identified STRN3 as an essential regulatory subunit of protein phosphatase 2A (PP2A) that recruits MST1/2 and promotes its dephosphorylation, which results in YAP activation. We also identified STRN3 upregulation in gastric cancer correlated with YAP activation and poor prognosis. Based on this mechanistic understanding and aided by structure-guided medicinal chemistry, we developed a highly selective peptide inhibitor, STRN3-derived Hippo-activating peptide, or SHAP, which disrupts the STRN3-PP2Aa interaction and reactivates the Hippo tumor suppressor, inhibits YAP activation, and has antitumor effects in vivo.
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