Elevated Kir2.1/nuclear N2ICD defines a highly malignant subtype of non-WNT/SHH medulloblastomas

Wang, Yanxia; Wu, Haibo; Ren, Yong; Lv, Sheng‐Qing; Ji, Chao; Xiang, Dongfang; Zhang, Mengsi; Lu, Huimin; Fu, Wen-Juan; Liu, Qing; Yan, Zexuan; Ma, Qinghua; Miao, Jingya; Cai, Ruili; Lan, Xi; Wu, Bin; Wang, Wenying; Liu, Yinhua; Wang, Daizhong; Cao, Mianfu; He, Zhicheng; Shi, Yu; Ping, Yi‐Fang; Yao, Xiaohong; Zhang, Xia; Zhang, Peng; Wang, Ji Ming; Wang, Yan; Cui, You‐Hong; Bian, Xiu‐Wu

doi:10.1038/s41392-022-00890-7

Cited by 4 publications

(1 citation statement)

References 78 publications

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“…The genetic features of Group 3 and Group 4 MB subgroups remain unclear [6,7,10]. Our previous study revealed Kir2.1 and the Notch pathway as potential targets for Group 3 and Group 4 MB [11]. Several inhibitors targeting molecular subtypes of MB have shown antitumor efficacy in preclinical and clinical trials, but none have so far been applied in the clinic [12].…”

Section: Introductionmentioning

confidence: 99%

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

Zhou,

Wang,

et al. 2024

The Journal of Pathology

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Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single‐cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene (FANCD2) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK‐8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2‐related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe2+). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH‐MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH‐MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH‐MB cells and sensitized SHH‐MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH‐MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH‐MB cell‐derived tumors in vivo. Our study revealed FANCD2 as a potential therapeutic target in SHH‐MB and silencing FANCD2 could sensitize SHH‐MB cells to radiotherapy via inducing ferroptosis. © 2024 The Pathological Society of Great Britain and Ireland.

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Section: Introductionmentioning

confidence: 99%

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

Zhou,

Wang,

et al. 2024

The Journal of Pathology

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Potassium channels, tumorigenesis and targeted drugs

Xia¹,

Liu²,

Ren³

et al. 2023

Biomedicine & Pharmacotherapy

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Differential Signaling Pathways in Medulloblastoma: Nano-biomedicine Targeting Non-coding Epigenetics to Improve Current and Future Therapeutics

Sokolov,

Sharda,

Banerjee

et al. 2024

CPD

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Background: Medulloblastomas (MDB) are malignant, aggressive brain tumors that primarily affect children. The survival rate for children under 14 is approximately 72%, while for ages 15 to 39, it is around 78%. A growing body of evidence suggests that dysregulation of signaling mechanisms and noncoding RNA epigenetics play a pivotal role in this disease. Methodology: This study conducted an electronic search of articles on websites like PubMed and Google. The current review also used an in silico databases search and bioinformatics analysis and an extensive comprehensive literature search for original research articles and review articles as well as retrieval of current and future medications in clinical trials. Results: This study indicates that several signaling pathways, such as sonic hedgehog, WNT/β-catenin, unfolded protein response mediated ER stress, notch, neurotrophins and TGF-β and ERK, MAPK, and ERK play a crucial role in the pathogenesis of MDB. Gene and ncRNA/protein are also involved as an axis long ncRNA to sponge micro-RNAs that affect downstream signal proteins expression and translation affection disease pathophysiology, prognosis and present potential target hit for drug repurposing. Current treatment options include surgery, radiation, and chemotherapy; unfortunately, the disease often relapses, and the survival rate is less than 5%. Therefore, there is a need to develop more effective treatments to combat recurrence and improve survival rates. Conclusion: This review describes various MDB disease hallmarks, including the signaling mechanisms involved in pathophysiology, related-causal genes, epigenetics, downstream genes/epigenes, and possibly the causal disease genes/non-protein coding (nc)RNA/protein axis. Additionally, the challenges associated with MDB treatment are discussed, along with how they are being addressed using nano-technology and nano-biomedicine, with a listing of possible treatment options and future potential treatment modalities.

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Elevated Kir2.1/nuclear N2ICD defines a highly malignant subtype of non-WNT/SHH medulloblastomas

Cited by 4 publications

References 78 publications

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

Potassium channels, tumorigenesis and targeted drugs

Differential Signaling Pathways in Medulloblastoma: Nano-biomedicine Targeting Non-coding Epigenetics to Improve Current and Future Therapeutics

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