ABSTRACT
Background and Objectives@#Glioblastoma (GBM) is an aggressive primary brain tumor characterized by its hetero-geneity and high recurrence and lethality rates. Glioblastoma stem cells (GSCs) play a crucial role in therapy resistance and tumor recurrence. Therefore, targeting GSCs is a key objective in developing effective treatments for GBM. The role of Parathyroid hormone-related peptide (PTHrP) in GBM and its impact on GSCs remains unclear. This study aimed to investigate the effect of PTHrP on GSCs and its potential as a therapeutic target for GBM. @*Methods@#and Results: Using the Cancer Genome Atlas (TCGA) database, we found higher expression of PTHrP in GBM, which correlated inversely with survival. GSCs were established from three human GBM samples obtained after surgical resection. Exposure to recombinant human PTHrP protein (rPTHrP) at different concentrations significantly enhanced GSCs viability. Knockdown of PTHrP using target-specific siRNA (siPTHrP) inhibited tumorsphere formation and reduced the number of BrdU-positive cells. In an orthotopic xenograft mouse model, suppression of PTHrP expression led to significant inhibition of tumor growth. The addition of rPTHrP in the growth medium counteracted the antiproliferative effect of siPTHrP. Further investigation revealed that PTHrP increased cAMP concentration and activated the PKA signaling pathway. Treatment with forskolin, an adenylyl cyclase activator, nullified the antiproliferative effect of siPTHrP. @*Conclusions@#Our findings demonstrate that PTHrP promotes the proliferation of patient-derived GSCs by activating the cAMP/PKA signaling pathway. These results uncover a novel role for PTHrP and suggest its potential as a therapeutic target for GBM treatment.
ABSTRACT
Objective To study the dynamic expression and distribution of high mobility group box 1 (HMGB-1)in diffuse axonal injury (DAI)in rats and to clarify its involvement in the inflammatory reaction after DAI in rats,in order to provide new targets for the clinical treatment of DAI.Methods A DAI model was established using a coronal rotation device and evaluated by HE,Glees-Marsland silver staining,and Mallory phosphotungstic acid hematoxylin staining.Immunohistochemistry,Western blot and RT-PCR were used to detect the expression and distribution of HMGB-1 in the cortex of DAI rats at 6 h,1 d,3 d and 7 d.And TUNEL was used to examine the apoptosis of neurons in DAI rats.Results Immunohistochemical results showed that at 6 h and 1 d after DAI,the number of HMGB-1-positive cells decreased,but at 3 and 7 d it began to increase.Western blot also showed that during the early stage after DAI (6 h and 1 d),the level of HMGB-1 protein in the cortex was significantly lower than that in the control group,but at the late stage (3 and 7 d)after DAI it significantly increased compared with that in the control group until 7 d.RT-PCR showed that at 6 h after DAI there was no significant increase in the level of HMGB-1mRNA,but at 1 d there was a slight increase compared with the control group;at 3 and 7 d,it showed an obvious significance.TUNEL staining indicated that the significant neuronal apoptosis appeared as early as 6 h after DAI,and reached the peak at 3 d;it started to decrease at 7 d but still remained at a relatively high level.Conclusion The dynamic expression and distribution of HMGB-1 showed significant changes with the time course after DAI in rats.They decreased at the early stage but increased at the late stage.At the early stage, HMGB-1 is mainly passively released by the necrotic neurons,and at the late stage it may be actively secreted by the active inflammatory cells.HMGB-1 may mediate the post-DAI neural cell apoptosis by inducing the inflammatory reaction.