RESUMEN
BACKGROUND: Patients with brain tumors, especially pediatric brain tumors such as cerebellar medulloblastoma, always suffer from the severe side effects of radiotherapy. Regeneration of neural cells in irradiation-induced cerebellar injury has been reported, but the underlying mechanism remains elusive. METHODS: We established an irradiation-induced developing cerebellum injury model in neonatal mice. Microarray, KEGG analysis and semi in vivo slice culture were performed for mechanistic study. RESULTS: Nestin-expressing progenitors (NEPs) but not granule neuron precursors (GNPs) were resistant to irradiation and able to regenerate after irradiation. NEPs underwent less apoptosis but similar DNA damage following irradiation compared with GNPs. Subsequently, they started to proliferate and contributed to granule neurons regeneration dependent on the sonic hedgehog (Shh) pathway. In addition, irradiation increased Shh ligand provided by Purkinje cells. And microglia accumulated in the irradiated cerebellum producing more IFN-γ, which augmented Shh ligand production to promote NEP proliferation. CONCLUSIONS: NEP was radioresistant and regenerative. IFN-γ was increased post irradiation to upregulate Shh ligand, contributing to NEP regeneration. Our study provides insight into the mechanisms of neural cell regeneration in irradiation injury of the developing cerebellum and will help to develop new therapeutic targets for minimizing the side effects of radiotherapy for brain tumors.
Asunto(s)
Neoplasias Cerebelosas , Proteínas Hedgehog , Humanos , Niño , Ratones , Animales , Nestina/metabolismo , Ligandos , Ratones Transgénicos , Proteínas Hedgehog/metabolismo , Cerebelo , Regeneración Nerviosa , Neoplasias Cerebelosas/radioterapia , Neoplasias Cerebelosas/metabolismoRESUMEN
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide. This complex and often fatal disease has a high mortality rate. The Hedgehog (Hh) signaling pathway is crucial in CRC. Many studies have indicated that Shh is overexpressed in cancer stem cells (CSCs), and shh overexpression is positively correlated with CRC tumorigenesis. New drugs that kill CRC cells through the Hh pathway are needed. Toosendanin (TSN), a natural triterpenoid saponin extracted from the bark or fruit of Melia toosendan Sieb. et Zucc, can inhibit various tumors. Here, we investigated the effects of TSN in CRC and explored the possible targets and mechanisms. Shh-Light â ¡ cells were treated with TSN and tested by dual luciferase reporter assays to determine the relationship with the Hh pathway. Cell Counting Kit-8 (CCK-8) assays were used to test the inhibitory effects of TSN on CRC cells. The expression of Hh components after TSN treatment was detected using western blots and quantitative reverse transcription polymerase chain reaction. Cellular thermal shift assays confirmed the targets of TSN. The same effects of TSN on xenograft tumor growth were investigated in vivo. The average weight, volume of the finally resected tumor, and the expression of Shh in the TSN-treated groups were significantly lower than those of the control group. This result strongly suggested that TSN administration inhibited CRC growth in vivo. Our research preliminarily demonstrated that the target of TSN was Shh and that TSN inhibits CRC cell growth by inhibiting the Hh pathway, identifying a new anticancer molecular mechanism of TSN in CRC.