BackgroundBreast cancer (BC) is the leading cause of cancer‐related death among women. One of the hallmarks of cancer is sustained angiogenesis. YAP/STAT3 may promote angiogenesis and driving BC progression. This study aimed to investigate how YAP/STAT3 affects the immune microenvironment in BC and understand the underlying mechanism.MethodsTo establish a tumor‐associated macrophages (TAMs) model, macrophages were cultured in the 4T1 cell culture medium. A BC mouse model was created by injecting 4T1 cells. The expression of YAP, STAT3, p‐STAT3, VEGF, VEGFR‐2, and PD‐L1 was analyzed using immunofluorescence, western blotting, and quantitative real‐time PCR. Flow cytometry was used to identify M1 and M2 macrophages, CD4+ T, CD8+ T, and Treg cells. Levels of iNOS, IL‐12, IL‐10, TGF‐β, Arg‐1, and CCL‐22 were measured using enzyme‐linked immunosorbent assay. Co‐IP was used to verify whether YAP binds to STAT3. Hematoxylin–eosin staining was used to observe tumor morphology. Cell counting kit‐8 was selected to detect T‐cell proliferation.ResultsYAP, STAT3, P‐STAT3, VEGF, VEGFR‐2, and PD‐L1 were highly expressed in BC tissues. The M2/M1 macrophages ratio increased in the TAMs group compared with the control group. Inhibiting of YAP and STAT3 decreased the M2/M1 macrophages ratio. YAP was found to bind with STAT3. T‐cell proliferation was enhanced after YAP inhibition, and overexpression of STAT3 reversed the regulation of YAP on T‐cell proliferation. In animal studies, inhibiting YAP inhibited tumor weight and volume development. After YAP inhibition, inflammatory infiltration, M2/M1 macrophage ratio, and Treg cell ratio declined, while CD8+ and CD4+ T‐cell ratio increased.ConclusionIn conclusion, this study suggested inhibition of YAP/STAT3 reversed M2 polarization of TAMs and suppressed CD8+ T‐cell activity in the BC immune microenvironment. These findings open up new avenues for the development of innovative therapies in the treatment of BC.
Glioma is a brain tumor that originated from brain or spine glial cells. Despite utilizing alternative treatments, the overall survival remains poor. Oridonin (ORI) is purified from the Chinese herb Rabdosia rubescens which exhibited anti-cancer effects on human tumorigenesis. The aim of this study was to investigate the effect of ORI on U87MG glioblastoma cells and whether Hippo/YAP-related signaling pathway was involved in. Here, we found that ORI inhibited cell proliferation and promoted cell apoptosis in a dose-dependent manner in U87MG cells. Moreover, ORI inhibited Bcl-2, YAP, c-Myc protein expression but increased Bax, caspase-3, p-YAP protein expression. Furthermore, these anti-cancer effects of ORI were also confirmed in a mouse model bearing glioma. Further study suggested that the YAP inhibitor Verteporfin (VP) showed the similar effect of ORI, but ORI reversed the effect of over-expression of YAP. Collectively, Oridonin suppressed glioblastoma oncogenesis via the Hippo/YAP signaling pathway and could be a potential therapeutic target in the treatment of glioblastoma.
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