Shizhu Yu

Glioblastoma (GBM) is the most frequent and lethal subtype of glioma that leads to unsatisfactory clinical outcomes. Hypoxia-induced chemoresistance exacerbates therapy. S100 calcium-binding protein A10 (S100A10) plays a crucial role in the oncogenesis of multiple human tumors. However, its role in to hypoxia-driven GBM progression and chemoresistance remains unclear. S100A10 was identified as a key gene because of its significant upregulation in GBM, hypoxia-treated GBM cells and temozolomide (TMZ)-resistant GBM cells. Public datasets, quantitative PCR (qPCR) and Western blot were performed to determine the levels of S100A10 in gliomas and cell lines. The clinical relevance, prognostic significance, and functional enrichment of S100A10 were fully assessed using open resources from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). CCK8, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, colony formation, annexin V staining, and flow cytometry assays were used to measure the proliferation, cell cycle, and apoptosis of GBM cells in vitro. Glycolysis potential was examined by determining lactate and pyruvate production. The interaction between hypoxia and S100A10 was assessed by qPCR and Western blot. Our study suggests that hypoxia-induced S100A10 expression facilitates proliferation and glycolysis and inhibits apoptosis by regulating the PI3K-AKT signaling pathway, which enhances TMZ resistance in GBM cells.

Improving glioma treatment effectiveness requires a thorough understanding of gliomagenesis. Emerging evidences have proved that zinc and ring finger 2 (ZNRF2) contributes to development of various human malignancies. Nevertheless, a comprehensive study of ZNRF2’s role in glioma is absent currently. Utilizing open resources from Chinese Glioma Genome Atlas (CGGA), Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), Connectivity Map (cMap) and other bioinformatic tools, we systematically examined the expression, clinical significance, prognostic value, regulated biological processes, immune infiltration, and potential inhibitors of ZNRF2 in gliomas. Functional experiments were also performed to validate its oncogenic roles in glioblastoma (GBM) cells. Our findings revealed that ZNRF2 expression was elevated in gliomas compared to normal brains, and its higher levels were correlated with increased grades and worse patient prognosis. The immune analysis suggested that immunotherapies targeting immune checkpoint genes could be beneficial for glioma patients with elevated ZNRF2 expression. Endogenous ZNRF2 knockdown impaired GBM cell proliferation, G2/M cell cycle progression and glycolysis, which was revealed by reduced ATP, pyruvic acid, lactic acid levels and less glucose uptake. Finally, we identified methylprednisolone (MP) as a potential ZNRF2 inhibitor and validated its anti-glioma effects in vitro. MP also enhanced the sensitization of GBM cells to temozolomide (TMZ), the primary chemotherapeutic agent for GBM in clinic. Taken together, our study demonstrated ZNRF2 as an essential tumor-promoting factor by favoring GBM cell proliferation and glycolysis. Our findings suggested that ZNRF2 might serve as a novel independent prognostic biomarker and promising therapeutic target for glioma patients.

Neurolymphomatosis (NL) is an uncommon malignant lymphoma characterized by selective infiltration of the central and peripheral nervous system. In this case report, we present a patient diagnosed with diffuse large B-cell lymphoma who initially manifested with peripheral neuropathy, primarily characterized by weakness of the left lower limb. By exploring its clinical manifestations, ancillary tests, and reviewing the relevant literature, we aim to deepen our understanding, diagnosis, and treatment of this disease. A 48-year-old male patient presented to the Department of Neurology, Hematology, and Neurosurgery with complaint of left lower limb weakness that had persisted for over 11 months. Initial laboratory tests and cerebrospinal fluid analysis yielded negative results. Electromyography examination indicated damage to the left lumbar plexus and iliac plexus nerves raising suspicions of nerve root involvement. Enhanced MRI of the lumbosacral plexus nerves revealed thickening and enhanced signals in left nerve roots at T12-L1, L1-2, and L3-4 levels. Additionally, local thickening and enhancement of signals were observed in the left erector spine muscle, psoas major, and iliopsoas muscles compared to the contralateral side. PEC/CT imaging displayed multiple soft tissue density shadows in the left foraminal area at the T12-1 and L1-2 levels. Bone marrow examination excluded hematological disease. Subsequent biopsy of the left foraminal nerve root at T12-L1 and the vertebral muscle at L3 level confirmed a diagnosis of diffuse large B-cell malignant lymphoma, indicating PNSL due to the involvement of multiple nerve roots. Following diagnosis, the patient underwent chemotherapy, resulting in the alleviation of his symptoms. Diagnosing PNSL can be challenging due to the nonspecific clinical manifestations and often inconclusive laboratory test results. Misdiagnosis and delayed diagnosis are common pitfalls. Electromyography may reveal damage to the affected peripheral nerves, while MR imaging might show nerve root thickening, and PET/CT can demonstrate increased lesion uptake. However, the definitive diagnosis relies on a biopsy of the lesion. Treatment for PNSL typically involves chemotherapy.

Collision tumors are rarely reported in patients with von Hippel-Lindau (VHL) disease, even though VHL patients often present with multi-organ tumor syndromes, like hemangioblastoma and renal cell carcinoma (RCC). Hemangioblastoma is rarely located in a supratentorial location, and intracranial lateral ventricular is also not a common site of metastasis for RCC. It is extremely rare for the two tumors to collide in the supratentorial area. We report a 64-year-old man with a history of clear cell RCC who presented with a sudden headache. The brain magnetic resonance imaging revealed that there was a cystic-solid mass in the intracranial lateral ventricular trigone. Histopathologically, the tumor consisted of two distinct components, most of which showed the typical morphology of hemangioblastoma. However, there were a few acinar structures composed of clear cells scattered in hemangioblastoma, and these acinar structures were subsequently confirmed as clear cell RCC. The genetic testing confirmed that the patient had VHL disease with de novo somatic mutation. Based on our case report, we systematically reviewed the characteristics of collision tumor composed of hemangioblastoma and metastatic RCC in VHL patients. The special growth site of our case is the first report of this kind of collision tumor, and can also help enrich our understanding of VHL disease and collision tumor.

Synergies of transcription factors, chromatin modifiers and their target genes are vital for cell fate determination in human cancer. Although the importance of numerous epigenetic machinery for regulating gliomagenesis has been previously recognized, how chromatin modifiers collaborate with specific transcription factors remains largely elusive. Herein we report that Pontin chromatin remodelling factor acts as a coactivator for LEF1 to activate TGFβ/SMAD signalling, thereby contributing to gliomagenesis. Pontin is highly expressed in gliomas, and its overexpression paralleled the grade elevation and poor prognosis of patients. Functional studies verified its oncogenic roles in GBM cells by facilitating cell proliferation, survival and invasion both in vitro and in vivo. RNA sequencing results revealed that Pontin regulated multiple target genes involved in TGFβ/SMAD signalling. Intriguingly, we found that Pontin amplified TGFβR2 gene transcription by recruiting LEF1, thereby activating TGFβ/SMAD signalling and facilitating gliomagenesis. Furthermore, higher TGFβR2 expression conferred worse patient outcomes in glioma. To conclude, our study revealed that the Pontin-LEF1 module plays a crucial role in driving TGFβR2 gene transcription, which could be exploited to target TGFβ/SMAD signalling for anti-glioma therapy.

Pontin (RUVBL1) is a highly conserved ATPase of the AAA + (ATPases Associated with various cellular Activities) superfamily and is implicated in various biological processes crucial for oncogenesis. Its overexpression is observed in multiple human cancers, whereas the relevance of Pontin to gliomagenesis remains obscure. To gain insights into Pontin involvement in glioma, we performed bioinformatics analyses of Pontin co-expressed genes, Pontin-affected genes, and carried out experimental studies. The results verified that Pontin was upregulated in gliomas. Its higher levels might predict the worse prognosis of glioma patients. The Pontin co-expressed genes were functionally enriched in cell cycle progression and RNA processing. In the nucleus, Pontin promoted cell growth via facilitating cell cycle progression. Using RNA-seq, we found that Pontin knockdown resulted in altered expression of multiple genes, among which the E2F1 targets accounted for a large proportion. Mechanistic studies found that Pontin interacted with E2F1 and markedly amplified the E2F1 transcription response in an ATPase domain-dependent manner. By analyzing the RNA-seq data, we also found that Pontin could impact on the alternative splicing (AS). Both differential expressed genes and AS events affected by Pontin were associated with cell cycle regulation. Taken together, our findings provide novel insights of the importance of Pontin in gliomagenesis by regulating cell cycle and AS, and shed light on the possible application of Pontin as an antineoplastic target in glioma.