STAT3 is required for Smo‐dependent signaling and mediates Smo‐targeted treatment resistance and tumorigenesis in Shh medulloblastoma

Yuan, Liangping; Zhang, Hongying; Liu, Jingbo; Malhotra, Anshu; Dey, Abhinav; Yu, Bing; Jella, Kishore Kumar; Schniederjan, Matthew; MacDonald, Tobey J.

doi:10.1002/1878-0261.13097

Cited by 10 publications

(6 citation statements)

References 69 publications

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“…STAT3 activity, in turn, represses p21 expression and fosters the formation of colonies in SHH-MB cells. However, the combined treatment with inhibitors targeting both Smo and STAT3 leads to a marked synergistic effect, effectively overcoming drug resistance in Smo antagonist-resistant SHH-MB cells [32]. Our current study further establishes that celastrol induces apoptosis in ONS-76 cells, with notable increases in ROS levels following celastrol treatment.…”

Section: Discussionsupporting

confidence: 65%

Celastrol can inhibit the growth of SHH medulloblastoma: In vitro and in vivo studies

王,

徐,

余

et al. 2024

Preprint

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Celastrol is a naturally occurring compound with a range of pharmacological properties derived from the traditional Chinese herb Tripterygium wilfordii. To develop a new therapeutic strategy for medulloblastoma (MB), this study will investigate the inhibitory effect of celastrol on MB and its underlying signaling pathway. We evaluated the effects of celastrol on cell proliferation using the CCK-8 assay and colony formation assay. Scratch assays and transwell invasion assays were used to assess the effects of celastrol on metastasis. The flow cytometry method was used to detect apoptosis and reactive oxygen species (ROS) levels in the cells. The potential signaling pathways were detected by transcriptomics and quantitative PCR. To study the anticancer effect of celastrol on MB in vivo using a mouse xenograft model. Cell proliferation and metastasis of the SHH subgroup MB cell line can be inhibited by celastrol, and the effect of the drug on apoptosis is associated with its proliferation inhibition effect. Animal experiments showed that celastrol inhibited the growth of MB in vivo. In addition, the pro-apoptotic effect of celastrol on ONS-76 cells may be caused by ROS. Our findings indicate that celastrol inhibits the progression of MB both in vitro and in vivo, and this effect is associated with the induction of ROS in cells by celastrol in vitro studies.

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Section: Discussionsupporting

confidence: 65%

Celastrol can inhibit the growth of SHH medulloblastoma: In vitro and in vivo studies

王,

徐,

余

et al. 2024

Preprint

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“…Several studies have shown a link between IGFBP2 and STAT3 activity, and STAT3 is known to regulate cell proliferation and EMT phenotypes [ 7 , 33 , 34 , 61 , 71 ]. STAT3 is phosphorylated at tyrosine705 by Janus Kinase family members, which stimulates its homodimerization and nuclear localization, and transcription of EMT-promoting genes.…”

Section: Discussionmentioning

confidence: 99%

IGFBP2 promotes proliferation and cell migration through STAT3 signaling in Sonic hedgehog medulloblastoma

Kunhiraman

Shahab

Gershon

et al. 2023

acta neuropathol commun

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Medulloblastoma (MB) is the most common pediatric brain malignancy and is divided into four molecularly distinct subgroups: WNT, Sonic Hedgehog (SHHp53mut and SHHp53wt), Group 3, and Group 4. Previous reports suggest that SHH MB features a unique tumor microenvironment compared with other MB groups. To better understand how SHH MB tumor cells interact with and potentially modify their microenvironment, we performed cytokine array analysis of culture media from freshly isolated MB patient tumor cells, spontaneous SHH MB mouse tumor cells and mouse and human MB cell lines. We found that the SHH MB cells produced elevated levels of IGFBP2 compared to non-SHH MBs. We confirmed these results using ELISA, western blotting, and immunofluorescence staining. IGFBP2 is a pleiotropic member of the IGFBP super-family with secreted and intracellular functions that can modulate tumor cell proliferation, metastasis, and drug resistance, but has been understudied in medulloblastoma. We found that IGFBP2 is required for SHH MB cell proliferation, colony formation, and cell migration, through promoting STAT3 activation and upregulation of epithelial to mesenchymal transition markers; indeed, ectopic STAT3 expression fully compensated for IGFBP2 knockdown in wound healing assays. Taken together, our findings reveal novel roles for IGFBP2 in SHH medulloblastoma growth and metastasis, which is associated with very poor prognosis, and they indicate an IGFBP2-STAT3 axis that could represent a novel therapeutic target in medulloblastoma.

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“…Furthermore, it was reported that tumor-derived SHH directly acts on TAMs to promote M2 polarization, mediated by the transcription factor Krüppel-like factor 4 (Klf4) ( 28 ). In addition, other signaling pathways are also involved, such as signal transducer and activator of transcription 3 (STAT3), which is necessary to maintain SHH signaling and can enhance macrophage proliferation and survival through multiple pathways ( 29 , 30 ). Augmented M1 recruitment in SHH subgroup was not observed.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Associated Macrophages Correlate With Prognosis in Medulloblastoma

et al. 2022

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PurposeMacrophage polarization plays an essential role in the tumor microenvironment of brain tumors. However, the role of tumor-associated macrophages (TAMs) in medulloblastoma still remains controversial. Thus, we investigated the distribution of macrophages in medulloblastoma tissues and analyzed the association of TAM recruitment and medulloblastoma patients’ outcomes.MethodsWe obtained a total of 71 paraffin sections from patients with medulloblastoma, and detected the activated phenotype (M1/M2) by monoclonal antibodies for CD68, HLA-DR and CD163 with multiple fluorescence immunohistochemistry method. The number of polarized macrophages was quantified using the InForm software. Outcomes were analyzed according to clinical data and quantified macrophage data.ResultsThe study revealed that TAMs were significantly higher in sonic hedgehog (SHH) medulloblastoma than in other subgroups, and M1 macrophages in metastatic group were significantly higher than those in non-metastatic group. A Kaplan-Meier survival analysis and multivariate Cox regression model showed the correlation of high percentage of total macrophages (P = 0.038, HR = 0.241) and M1 macrophages (P = 0.034, HR = 0.333) with good 5-year progression-free survival (PFS); however, M2 macrophages had no correlation with survival of medulloblastoma patients (P> 0.05).ConclusionHigh percentage of total macrophages and M1 macrophages are correlated with good outcome of medulloblastoma patients. TAMs might be a target of therapy.

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STAT3 is required for Smo‐dependent signaling and mediates Smo‐targeted treatment resistance and tumorigenesis in Shh medulloblastoma

Cited by 10 publications

References 69 publications

Celastrol can inhibit the growth of SHH medulloblastoma: In vitro and in vivo studies

Celastrol can inhibit the growth of SHH medulloblastoma: In vitro and in vivo studies

IGFBP2 promotes proliferation and cell migration through STAT3 signaling in Sonic hedgehog medulloblastoma

Tumor-Associated Macrophages Correlate With Prognosis in Medulloblastoma

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