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Abstract Introduction Glioblastoma (GBM) poses a significant challenge in oncology, with median survival times barely extending beyond a year due to resistance to standard therapies like temozolomide (TMZ). This study introduces a novel therapeutic strategy combining progesterone (Prog) and abiraterone (Abi) aimed at enhancing GBM treatment efficacy by modulating the tumor microenvironment and augmenting NK cell-mediated immunity. Methods We employed in vitro and in vivo GBM models to assess the effects of Prog and Abi on cell viability, proliferation, apoptosis, and the immune microenvironment. Techniques included cell viability assays, Glo-caspase 3/7 apoptosis assays, RNA-seq and qPCR for gene expression, Seahorse analysis for mitochondrial function, HPLC-MS for metabolomics analysis, and immune analysis by flow cytometry to quantify NK cell infiltration. Results Prog significantly reduced the IC50 of Abi in TMZ-resistant GBM cell, suggesting the enhanced cytotoxicity. Treatment induced greater apoptosis than either agent alone, suppressed tumor growth, and prolonged survival in mouse models. Notably, there was an increase in CD3−/CD19−/CD56+/NK1.1+ NK cell infiltration in treated tumors, indicating a shift towards an anti-tumor immune microenvironment. The combination therapy also resulted in a reduction of MGMT expression and a suppression of mitochondrial respiration and glycolysis in GBM cells. Conclusion The combination of Prog and Abi represents a promising therapeutic approach for GBM, showing potential in suppressing tumor growth, extending survival, and modulating the immune microenvironment. These findings warrant further exploration into the clinical applicability of this strategy to improve outcomes for GBM patients.

Mild traumatic brain injury (mTBI) is a prevalent health concern with variable recovery trajectories, necessitating reliable prognostic markers. Insulin-like growth factor 1 (IGF-1) emerges as a potential candidate because of its role in cellular growth, repair, and neuroprotection. However, limited studies investigate IGF-1 as a prognostic marker in mTBI patients. This study aimed to explore the correlation of IGF-1 with cognitive functions assessed using the Wisconsin Card Sorting Test (WCST) in mTBI patients. We analyzed data from 295 mTBI and 200 healthy control participants, assessing demographic characteristics, injury causes, and IGF-1 levels. Cognitive functions were evaluated using the WCST. Correlation analyses and regression models were used to investigate the associations between IGF-1 levels, demographic factors, and WCST scores. Significant differences were observed between mTBI and control groups in the proportion of females and average education years. Falls and traffic accidents were identified as the primary causes of mTBI. The mTBI group demonstrated worse cognitive outcomes on the WCST, except for the ?Learning to Learn? index. Correlation analyses revealed significant relationships between IGF-1 levels, demographic factors, and specific WCST scores. Regression models demonstrated that IGF-1, age, and education years significantly influenced various WCST scores, suggesting their roles as potential prognostic markers for cognitive outcomes in mTBI patients. We provide valuable insights into the potential correlation of IGF-1 with cognitive functions in mTBI patients, particularly in tasks requiring cognitive flexibility and problem solving.

Abstract Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with limited treatment options, such as the chemotherapeutic agent, temozolomide (TMZ). However, many GBM tumors develop resistance to TMZ, which is a major obstacle to effective therapy. Recently, dysregulated lipid metabolism has emerged as an important factor contributing to TMZ resistance in GBM. The dysregulation of lipid metabolism is a hallmark of cancer and alterations in lipid metabolism have been linked to multiple aspects of tumor biology, including proliferation, migration, and resistance to therapy. In this review, we aimed to summarize current knowledge on lipid metabolism in TMZ-resistant GBM, including key metabolites and proteins involved in lipid synthesis, uptake, and utilization, and recent advances in the application of metabolomics to study lipid metabolism in GBM. We also discussed the potential of lipid metabolism as a target for novel therapeutic interventions. Finally, we highlighted the challenges and opportunities associated with developing these interventions for clinical use, and the need for further research to fully understand the role of lipid metabolism in TMZ resistance in GBM. Our review suggests that targeting dysregulated lipid metabolism may be a promising approach to overcome TMZ resistance and improve outcomes in patients with GBM.

A 50-year-old male presented to the emergency room after experiencing sudden right upper limb facial numbness and dysphasia, followed by full recovery. A brain CT scan showed hyperdense lesions within the left hemispheric sulcus, which raised suspicion of spontaneous subarachnoid hemorrhage. A T1-weighted MRI showed multiple tiny leptomeningeal enhancements in the same area, and a digital subtraction angiography showed no signs of vascular abnormality. Cerebrospinal fluid cytology revealed atypical melanin-containing cells with minimal pleomorphism. One month later, the patient developed sixth nerve palsy, which was determined to be due to intracranial hypertension. Multiple giant nevi on the legs, trunk, and scalp were also observed. A skin biopsy showed well-defined and symmetrical proliferation of melanocytic nevus cell nests in the dermis. An open biopsy was performed due to the suspicious leptomeningeal lesions, which surprisingly revealed diffuse and thick black-colored tissue infiltration of the leptomeninges. Pathology confirmed the diagnosis of meningeal melanocytosis. A ventriculoperitoneal shunt was then placed, and the patient’s neurological symptoms gradually improved. Based on the presence of multiple giant nevi on the patient’s skin and the finding of diffuse meningeal melanocytosis during the open biopsy, the patient was diagnosed with neurocutaneous melanosis. The patient received 6 cycles triweekly of Ipilimumab and Nivolumab 8 months after initial diagnosis. Unfortunately, the disease progressed and the patient passed away 14 months after initial diagnosis.

Abstract Background Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown. Methods RNA-Seq and mass spectrometry were used to analyze gene expression and metabolites amounts in paired GBM specimens (primary vs. recurrent) and in paired GBM cells (sensitive vs. resistant). ω-3/6 fatty acid and arachidonic acid (AA) metabolism in GBM patients were analyzed by targeted metabolome. Mitochondrial functions were determined by Seahorse XF Mito Stress Test, RNA-Seq, metabolome and substrate utilization for producing ATP. Therapeutic options targeting prostaglandin (PG) E2 in TMZ-resistant GBM were validated in vitro and in vivo. Results Among the metabolic pathways, Sp1 increased the prostaglandin-endoperoxide synthase 2 expression and PGE2 production in TMZ-resistant GBM. Mitochondrial genes and metabolites were obviously increased by PGE2, and these characteristics were required for developing resistance in GBM cells. For inducing TMZ resistance, PGE2 activated mitochondrial functions, including fatty acid β-oxidation (FAO) and tricarboxylic acid (TCA) cycle progression, through PGE2 receptors, E-type prostanoid (EP)1 and EP3. Additionally, EP1 antagonist ONO-8713 inhibited the survival of TMZ-resistant GBM synergistically with TMZ. Conclusion Sp1-regulated PGE2 production activates FAO and TCA cycle in mitochondria, through EP1 and EP3 receptors, resulting in TMZ resistance in GBM. These results will provide us a new strategy to attenuate drug resistance or to re-sensitize recurred GBM.

Abstract Background Glioblastoma (GBM) is the most aggressive and lethal brain tumor. Although the histone deacetylase (HDAC)/transcription factor axis promotes growth in GBM, whether HDACs including HDAC6 are involved in modulating long non-coding RNAs (lncRNAs) to affect GBM malignancy remains obscure. Methods Integrative analysis of microarray and RNA-seq was performed to identify lncRNAs governed by HDAC6. Half-life measurement and RNA-protein pull-down assay combined with isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis were conducted to identify RNA modulators. The effect of LINC00461 on GBM malignancy was evaluated using animal models and cell proliferation-related assays. Functional analysis of the LINC00461 downstream networks was performed comprehensively using ingenuity pathway analysis and public databases. Results We identified a lncRNA, LINC00461, which was substantially increased in stem-like/treatment-resistant GBM cells. LINC00461 was inversely correlated with the survival of mice-bearing GBM and it was stabilized by the interaction between HDAC6 and RNA-binding proteins (RBPs) such as carbon catabolite repression—negative on TATA-less (CCR4-NOT) core exoribonuclease subunit 6 and fused in sarcoma. Targeting LINC00461 using azaindolylsulfonamide, an HDAC6 inhibitor, decreased cell-division-related proteins via the lncRNA-microRNA (miRNA)-mRNA networks and caused cell-cycle arrest, thereby suppressing proliferation in parental and drug-resistant GBM cells and prolonging the survival of mice-bearing GBM. Conclusions This study sheds light on the role of LINC00461 in GBM malignancy and provides a novel therapeutic strategy for targeting the HDAC6/RBP/LINC00461 axis and its downstream effectors in patients with GBM.

Abstract DNA repair promotes the progression and recurrence of glioblastoma (GBM). However, there remain no effective therapies for targeting the DNA damage response and repair (DDR) pathway in the clinical setting. Thus, we aimed to conduct a comprehensive analysis of DDR genes in GBM specimens to understand the molecular mechanisms underlying treatment resistance. Herein, transcriptomic analysis of 177 well-defined DDR genes was performed with normal and GBM specimens (n = 137) from The Cancer Genome Atlas and further integrated with the expression profiling of histone deacetylase 6 (HDAC6) inhibition in temozolomide (TMZ)-resistant GBM cells and patient-derived tumor cells. The effects of HDAC6 inhibition on DDR signaling were examined both in vitro and intracranial mouse models. We found that the expression of DDR genes, involved in repair pathways for DNA double-strand breaks, was upregulated in highly malignant primary and recurrent brain tumors, and their expression was related to abnormal clinical features. However, a potent HDAC6 inhibitor, MPT0B291, attenuated the expression of these genes, including RAD51 and CHEK1, and was more effective in blocking homologous recombination repair in GBM cells. Interestingly, it resulted in lower cytotoxicity in primary glial cells than other HDAC6 inhibitors. MPT0B291 reduced the growth of both TMZ-sensitive and TMZ-resistant tumor cells and prolonged survival in mouse models of GBM. We verified that HDAC6 regulated DDR genes by affecting Sp1 expression, which abolished MPT0B291-induced DNA damage. Our findings uncover a regulatory network among HDAC6, Sp1, and DDR genes for drug resistance and survival of GBM cells. Furthermore, MPT0B291 may serve as a potential lead compound for GBM therapy.

Abstract Background Intratumor subsets with tumor-initiating features in glioblastoma are likely to survive treatment. Our goal is to identify the key factor in the process by which cells develop temozolomide (TMZ) resistance. Methods Resistant cell lines derived from U87MG and A172 were established through long-term co-incubation of TMZ. Primary tumors obtained from patients were maintained as patient-derived xenograft for studies of tumor-initating cell (TIC) features. The cell manifestations were assessed in the gene modulated cells for relevance to drug resistance. Results Among the mitochondria-related genes in the gene expression databases, superoxide dismutase 2 (SOD2) was a significant factor in resistance and patient survival. SOD2 in the resistant cells functionally determined the cell fate by limiting TMZ-stimulated superoxide reaction and cleavage of caspase-3. Genetic inhibition of the protein led to retrieval of drug effect in mouse study. SOD2 was also associated with the TIC features, which enriched in the resistant cells. The CD133+ specific subsets in the resistant cells exhibited superior superoxide regulation and the SOD2-related caspase-3 reaction. Experiments applying SOD2 modulation showed a positive correlation between the TIC features and the protein expression. Finally, co-treatment with TMZ and the SOD inhibitor sodium diethyldithiocarbamate trihydrate in xenograft mouse models with the TMZ-resistant primary tumor resulted in lower tumor proliferation, longer survival, and less CD133, Bmi-1, and SOD2 expression. Conclusion SOD2 plays crucial roles in the tumor-initiating features that are related to TMZ resistance. Inhibition of the protein is a potential therapeutic strategy that can be used to enhance the effects of chemotherapy. Graphical abstract

Abstract Background The small population of glioma stem-like cells (GSCs) contributes to tumor initiation, malignancy, and recurrence in glioblastoma. However, the maintenance of GSC properties in the tumor microenvironment remains unclear. In glioma, non-neoplastic cells create an inflammatory environment and subsequently mediate tumor progression and maintenance. Transcriptional factor CCAAT/enhancer-binding protein delta (CEBPD) is suggested to regulate various genes responsive to inflammatory cytokines, thus prompting us to investigate its role in regulating GSCs stemness after inflammatory stimulation. Methods Stemness properties were analyzed by using spheroid formation. Oncomine and TCGA bioinformatic databases were used to analyze gene expression. Western blotting, quantitative real-time polymerase chain reaction, luciferase reporter assay, and chromatin immunoprecipitation assay were used to analyze proteins and gene transcript levels. The glioma tissue microarrays were used for CEBPD and PDGFA expression by immunohistochemistry staining. Results We first found that IL-1β promotes glioma spheroid formation and is associated with elevated CEBPD expression. Using microarray analysis, platelet-derived growth factor subunit A (PDGFA) was confirmed as a CEBPD-regulated gene that mediates IL-1β-enhanced GSCs self-renewal. Further analysis of the genomic database and tissue array revealed that the expression levels between CEBPD and PDGFA were coincident in glioma patient samples. Conclusion This is the first report showing the activation of PDGFA expression by CEBPD through IL-1β treatment and a novel CEBPD function in maintaining the self-renewal feature of GSCs.

Drug resistance is the main obstacle in the improvement of chemotherapeutic efficacy in glioblastoma. Previously, we showed that dehydroepiandrosterone (DHEA), one kind of androgen/neurosteroid, potentiates glioblastoma to acquire resistance through attenuating DNA damage. Androgen receptor (AR) activated by DHEA or other types of androgen was reported to promote drug resistance in prostate cancer. However, in DHEA-enriched microenvironment, the role of AR in acquiring resistance of glioblastoma remains unknown. In this study, we found that AR expression is significantly correlated with poor prognosis, and AR obviously induced the resistance to temozolomide (TMZ) treatment. Herein, we observed that ALZ003, a curcumin analog, induces FBXL2-mediated AR ubiquitination, leading to degradation. Importantly, ALZ003 significantly inhibited the survival of TMZ-sensitive and –resistant glioblastoma in vitro and in vivo. The accumulation of reactive oxygen species (ROS), lipid peroxidation and suppression of glutathione peroxidase (GPX) 4, which are characteristics of ferroptosis, were observed in glioblastoma cell after treatment of ALZ003. Furthermore, overexpression of AR prevented ferroptosis in the presence of GPX4. To evaluate the therapeutic effect in vivo, we transplanted TMZ-sensitive or -resistant U87MG cells into mouse brain followed by intravenous administration with ALZ003. In addition to inhibiting the growth of glioblastoma, ALZ003 significantly extended the survival period of transplanted mice, and significantly decreased AR expression in the tumor area. Taken together, AR potentiates TMZ resistance for glioblastoma, and ALZ003-mediated AR ubiquitination might open a new insight into therapeutic strategy for TMZ resistant glioblastoma. Keywords: AR, ALZ003, GPX4, Glioblastoma

The accumulation of reactive oxygen species (ROS) commonly occurs during normal aging and during some acute/chronic progressive disorders. In order to avoid oxidative damage, scavenging of these radicals is important. Previously, we identified zinc finger protein 179 (Znf179) as a neuroprotector that increases antioxidant enzymes against superoxide radicals. However, the molecular mechanisms involved in the activation and regulation of Znf179 remain unresolved. Here, by performing sequence alignment, bioinformatics analysis, immunoprecipitation using two specific acetyl-lysine antibodies, and treatment with the histone deacetylase (HDAC) inhibitor SAHA, we determined the lysine-specific acetylation of Znf179. Furthermore, we investigated Znf179 interaction with HDACs and revealed that peroxide insult induced a dissociation of Znf179-HDAC1/HDAC6, causing an increase in Znf179 acetylation. Importantly, HDAC inhibition by SAHA further prompted Znf179 hyperacetylation, which promoted Znf179 to form a transcriptional complex with Sp1 and increased antioxidant gene expression against oxidative attack. In summary, the results obtained in this study showed that Znf179 was regulated by HDACs and that Znf179 acetylation was a critical mechanism in the induction of antioxidant defense systems. Additionally, HDAC inhibitors may have therapeutic potential for induction of Znf179 acetylation, strengthening the Znf179 protective functions against neurodegenerative processes. Keywords: Znf179, SAHA, HDACs, Oxidative stress, Antioxidants

USP24 has previously been reported to be involved in cancer progression. Here, the authors demonstrate that USP24 stabilizes p300 and β-TrCP to increase the levels of NF-κB and histone-3 acetylation, and decrease DNMT1 and IκB levels which promotes IL-6 expression in M2 macrophages and lung cancer cells.

Glioblastoma multiforme (GBM) is a highly malignant type of brain tumor found in humans. GBM cells reproduce quickly, and the median survival time for patients after therapy is approximately 1 year with a high relapse rate. Current therapies and diagnostic tools for GBM are limited; therefore, we searched for a more favorable therapeutic target or marker protein for both therapy and diagnosis. We used mass spectrometry (MS) analysis to identify GBM‐associated marker proteins from human plasma and GBM cell cultures. Additional plasma and 52 brain tissues obtained from patients with gliomas were used to validate the association rate of serum amyloid A1 (SAA1) in different grades of gliomas and its distribution in tumors. Microarray database analysis further validated the coefficient of SAA1 levels in gliomas. The cellular mechanisms of SAA1 in GBM proliferation and infiltration were investigated in vitro. We analyzed the correlation between SAA1 and patients' medication requirement to demonstrate the clinical effects of SAA1 in GBM. SAA1 was identified from MS analysis, and its level was revealed to be correlated with the disease grade, clinical severity, and survival rate of patients with gliomas. In vitro cultures, including GBM cells and normal astrocytes, revealed that SAA1 promotes cell migration and invasion through integrin αVβ3 to activate the Erk signaling pathway. Magnetic resonance imaging and tumor region‐specific microarray analysis identified a correlation between SAA1 and GBM cell infiltration in patients. In summary, our results demonstrate that SAA1 in combination with integrin αV and β3 can serve as an indicator of high glioblastoma risk. We also identified the cellular mechanisms of SAA1 contributing to GBM progression, which can serve as the basis for future GBM therapy.

Acquisition of temozolomide (TMZ) resistance is a major factor leading to the failure of glioblastoma (GBM) treatment. The exact mechanism by which GBM evades TMZ toxicity is not always related to the expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), and so remains unclear. In this study, TMZ-resistant variants derived from MGMT-negative GBM clinical samples and cell lines were studied, revealing there to be increased specificity protein 1 (Sp1) expression associated with reduced reactive oxygen species (ROS) accumulation following TMZ treatment. Analysis of gene expression databases along with cell studies identified the ROS scavenger superoxide dismutase 2 (SOD2) as being disease-related. SOD2 expression was also increased, and it was found to be co-expressed with Sp1 in TMZ-resistant cells. Investigation of the SOD2 promoter revealed Sp1 as a critical transcriptional activator that enhances SOD2 gene expression. Co-treatment with an Sp1 inhibitor restored the inhibitory effects of TMZ, and decreased SOD2 levels in TMZ-resistant cells. This treatment strategy restored susceptibility to TMZ in xenograft animals, leading to prolonged survival in an orthotopic model. Thus, our results suggest that Sp1 modulates ROS scavengers as a novel mechanism to increase cancer malignancy and resistance to chemotherapy. Inhibition of this pathway may represent a potential therapeutic target for restoring treatment susceptibility in GBM.

To assemble the functional circuits of the nervous system, the neuronal axonal growth cones must be precisely guided to their proper targets, which can be achieved through cell-surface guidance receptor activation by ligand binding in the periphery. We investigated the function of paxillin, a focal adhesion protein, as an essential growth cone guidance intermediary in the context of spinal lateral motor column (LMC) motor axon trajectory selection in the limb mesenchyme. Using in situ mRNA detection, we first show paxillin expression in LMC neurons of chick and mouse embryos at the time of spinal motor axon extension into the limb. Paxillin loss-offunction and gain-of-function using in ovo electroporation in chick LMC neurons, of either sex, perturbed LMC axon trajectory selection, demonstrating an essential role of paxillin in motor axon guidance. In addition, a neuron-specific paxillin deletion in mice led to LMC axon trajectory selection errors. We also show that knocking down paxillin attenuates the growth preference of LMC neurites against ephrins in vitro, and erythropoietin-producing human hepatocellular (Eph)-mediated retargeting of LMC axons in vivo, suggesting paxillin involvement in Eph-mediated LMC motor axon guidance. Finally, both paxillin knockdown and ectopic expression of a nonphosphorylable paxillin mutant attenuated the retargeting of LMC axons caused by Src overexpression, implicating paxillin as a Src target in Eph signal relay in this context. In summary, our findings demonstrate that paxillin is required for motor axon guidance and suggest its essential role in the ephrin-Eph signaling pathway resulting in motor axon trajectory selection. [ABSTRACT FROM AUTHOR]

The precise assembly of a functional nervous system relies on the guided migration of axonal growth cones, which is made possible by signals transmittedtothecytoskeletonbycellsurface-expressedguidancereceptors.Weinvestigatedthefunctionofephexin1,aRhoguaninenucleotide exchange factor, as an essential growth-cone guidance intermediary in the context of spinal lateral motor column (LMC) motor axon trajectory selection in the limb mesenchyme. Using in situmRNAdetection, we first show that ephexin1 is expressed inLMCneurons of chick and mouse embryos at the time of spinal motor axon extension into the limb. Ephexin1 loss of function and gain of function using in ovo electroporation in chickLMCneurons, of either sex, perturbedLMCaxontrajectory selection, demonstratinganessential role of ephexin1 inmotoraxonguidance. Inaddition,ephexin1loss inmiceof eithersexled toLMCaxontrajectory selection errors.Wealsoshowthatephexin1knockdownattenuates the growth preference of LMC neurites against ephrins in vitro and Eph receptor-mediated retargeting of LMC axons in vivo, suggesting that ephexin1 is required in Eph-mediated LMC motor axon guidance. Finally, both ephexin1 knockdown and ectopic expression of nonphosphorylatable ephexin1 mutant attenuated the retargeting of LMC axons caused by Src overexpression, implicating ephexin1 as an Src target in Eph signal relay in this context. In summary, our findings demonstrate that ephexin1 is essential for motor axon guidance and suggest an important role in relaying ephrin:Eph signals that mediate motor axon trajectory selection. [ABSTRACT FROM AUTHOR]

Background: Glioma stem-like cells (GSCs) are proposed to be responsible for high resistance in glioblastoma multiforme (GBM) treatment. In order to find new strategies aimed at reducing GSC stemness and improving GBM patient survival, we investigated the effects and mechanism of a histone deacetylases (HDACs) inhibitor, suberoylanilide hydroxamic acid (SAHA), since HDAC activity has been linked to cancer stem-like cell (CSC) abundance and properties. Methods: Human GBM cell lines were plated in serum-free suspension cultures allowed for sphere forming and CSC enrichment. Subsequently, upon SAHA treatment, the stemness markers, cell proliferation, and viability of GSCs as well as cellular apoptosis and senescence were examined in order to clarify whether inhibition of GSCs occurs. Results: We demonstrated that SAHA attenuated cell proliferation and diminished the expression stemness-related markers (CD133 and Bmi1) in GSCs. Furthermore, at high concentrations (more than 5 μM), SAHA triggered apoptosis of GSCs accompanied by increases in both activation of caspase 8- and caspase 9-mediated pathways. Interestingly, we found that a lower dose of SAHA (1 μM and 2.5 μM) inhibited GSCs via cell cycle arrest and induced premature senescence through p53 up-regulation and p38 activation. Conclusion: SAHA induces apoptosis and functions as a potent modulator of senescence via the p38-p53 pathway in GSCs. Our results provide a perspective on targeting GSCs via SAHA treatment, and suggest that SAHA could be used as a potent agent to overcome drug resistance in GBM patients. [ABSTRACT FROM AUTHOR]

Most studies on heat shock protein 90 (Hsp90) have focused on the involvement of Hsp90 in the interphase, whereas the role of this protein in the nucleus during mitosis remains largely unclear. In this study, we found that the level of the acetylated form of Hsp90 decreased dramatically during mitosis, which indicates more chaperone activity during mitosis. We thus probed proteins that interacted with Hsp90 by liquid chromatography/mass spectrometry (LC/MS) and found that nucleolin was one of those interacting proteins during mitosis. The nucleolin level decreased upon geldanamycin treatment, and Hsp90 maintained the cyclin-dependent kinase 1 (CDK1) activity to phosphorylate nucleolin at Thr-641/707. Mutation of Thr641/707 resulted in the destabilization of nucleolin in mitosis. We globally screened the level of mitotic mRNAs and found that 229 mRNAs decreased during mitosis in the presence of geldanamycin. Furthermore, a bioinformatics tool and an RNA immunoprecipitation assay found that 16 mRNAs, including cadherin and Bcl-xl, were stabilized through the recruitment of nucleolin to the 3'-untranslated regions (3'-UTRs) of those genes. Overall, strong correlations exist between the up-regulation of Hsp90, nucleolin, and the mRNAs related to tumorigenesis of the lung. Our findings thus indicate that nucleolin stabilized by Hsp90 contributes to the lung tumorigenesis by increasing the level of many tumor-related mRNAs during mitosis. [ABSTRACT FROM AUTHOR]