RESUMO
BACKGROUND: Improved treatment of glioblastoma (GBM) needs to address tumor invasion, a hallmark of the disease that remains poorly understood. In this study, we profiled GBM invasion through integrative analysis of histological and single-cell RNA sequencing (scRNA-seq) data from 10 patients. METHODS: Human histology samples, patient-derived xenograft mouse histology samples, and scRNA-seq data were collected from 10 GBM patients. Tumor invasion was characterized and quantified at the phenotypic level using hematoxylin and eosin and Ki-67 histology stains. Crystallin alpha B (CRYAB) and CD44 were identified as regulators of tumor invasion from scRNA-seq transcriptomic data and validated in vitro, in vivo, and in a mouse GBM resection model. RESULTS: At the cellular level, we found that invasive GBM are less dense and proliferative than their non-invasive counterparts. At the molecular level, we identified unique transcriptomic features that significantly contribute to GBM invasion. Specifically, we found that CRYAB significantly contributes to postoperative recurrence and is highly co-expressed with CD44 in invasive GBM samples. CONCLUSIONS: Collectively, our analysis identifies differentially expressed features between invasive and nodular GBM, and describes a novel relationship between CRYAB and CD44 that contributes to tumor invasiveness, establishing a cellular and molecular landscape of GBM invasion.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Animais , Camundongos , Glioblastoma/genética , Glioblastoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Perfilação da Expressão Gênica , Invasividade Neoplásica , Linhagem Celular Tumoral , Modelos Animais de DoençasRESUMO
Glioblastoma (GBM) is the most aggressive tumor of the central nervous system and remains universally lethal due to lack of effective treatment options and their inefficient delivery to the brain. Here the development of multifunctional polymeric nanoparticles (NPs) for effective treatment of GBM is reported. The NPs are synthesized using a novel glutathione (GSH)-reactive poly (2,2â³-thiodiethylene 3,3â³-dithiodipropionate) (PTD) polymer and engineered for brain penetration through neutrophil elastase-triggered shrinkability, iRGD-mediated targeted delivery, and lexiscan-induced autocatalysis. It is found that the resulting lexiscan-loaded, iRGD-conjugated, shrinkable PTD NPs, or LiPTD NPs, efficiently penetrate brain tumors with high specificity after intravenous administration. Furthermore, it is demonstrated that LiPTD NPs are capable of efficient encapsulation and delivery of chemotherapy doxorubicin and sonosensitizer chlorin e6 to achieve combined chemotherapy and sonodynamic therapy (SDT). It is demonstrated that the capability of GSH depletion of LiPTD NPs further augments the tumor cell killing effect triggered by SDT. As a result, treatment with LiPTD NPs effectively inhibits tumor growth and prolongs the survival of tumor-bearing mice. This study may suggest a potential new approach for effective GBM treatment.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Nanopartículas , Animais , Encéfalo , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina , Glioblastoma/tratamento farmacológico , Glutationa , Elastase de Leucócito , Camundongos , Polímeros , Espécies Reativas de OxigênioRESUMO
Glioblastoma (GBM) is a deadly disease without effective treatment. Because glioblastoma stem cells (GSCs) contribute to tumor resistance and recurrence, improved treatment of GBM can be achieved by eliminating GSCs through inducing their differentiation. Prior efforts have been focused on studying GSC differentiation towards the astroglial lineage. However, regulation of GSC differentiation towards the neuronal and oligodendroglial lineages is largely unknown. To identify genes that control GSC differentiation to all three lineages, we performed an image-based genome-wide RNAi screen, in combination with single-cell RNA sequencing, and identified ZNF117 as a major regulator of GSC differentiation. Using patient-derived GSC cultures, we show that ZNF117 controls GSC differentiation towards the oligodendroglial lineage via the Notch pathway. We demonstrate that ZNF117 is a promising target for GSC differentiation therapy through targeted delivery of CRISPR/Cas9 gene-editing nanoparticles. Our study suggests a direction to improve GBM treatment through differentiation of GSCs towards various lineages.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Glioblastoma/patologia , Humanos , Células-Tronco Neoplásicas/metabolismoRESUMO
The aging of the immune system is not only an inevitable result but also an important cause of physical aging. The aging of the immune system is rooted in the aging of hematopoietic cells (HSCs), which manifests as decreasing functionality of the adaptive immune system and the innate immune system. C57BL/6 mice of different ages were collected in this study to better understand the changes in the structures of the innate and adaptive immune systems in individuals of different ages and the distribution and changes in immune cells with stem cell properties. The immune cells of the innate and adaptive immune systems, including DCs, monocytes, macrophages, CD4+ T lymphocytes, CD8+ T lymphocytes, and B lymphocytes, were assessed, and the proportions of cells with stem cell properties among these immune cell populations were also tested. Overall, immune cells in the peripheral blood, spleen, and bone marrow of mice exhibit certain regular properties with increasing age. The trend of changes in immune cells in different immune organs differs with age. The changes in lymphocytes in the peripheral blood are more sensitive. Their proportions increase slowly with age and then decrease rapidly to a very low level (less than 5%) after a certain point (9 or 13 months old). Nine to 13 months of age is the most critical time point for assessing changes in the immune system of mice and the most critical time point for detecting changes in the proportion of stem cells. After 13 months of age, the balance and stability of stem cells in mice are disrupted, and animals begin to age rapidly. The ratio of Ly6A to E+CD117+ cells in the peripheral blood, particularly lymphocytes involved in adaptive immunity, represents a specific marker for predicting immune senescence and body senescence.
Assuntos
Envelhecimento/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células-Tronco Hematopoéticas/imunologia , Animais , CamundongosRESUMO
Ten-eleven translocation (TET) proteins, the dioxygenase for DNA hydroxymethylation, are important players in nervous system development and diseases. However, their role in myelination and remyelination after injury remains elusive. Here, we identify a genome-wide and locus-specific DNA hydroxymethylation landscape shift during differentiation of oligodendrocyte-progenitor cells (OPC). Ablation of Tet1 results in stage-dependent defects in oligodendrocyte (OL) development and myelination in the mouse brain. The mice lacking Tet1 in the oligodendrocyte lineage develop behavioral deficiency. We also show that TET1 is required for remyelination in adulthood. Transcriptomic, genomic occupancy, and 5-hydroxymethylcytosine (5hmC) profiling reveal a critical TET1-regulated epigenetic program for oligodendrocyte differentiation that includes genes associated with myelination, cell division, and calcium transport. Tet1-deficient OPCs exhibit reduced calcium activity, increasing calcium activity rescues the differentiation defects in vitro. Deletion of a TET1-5hmC target gene, Itpr2, impairs the onset of OPC differentiation. Together, our results suggest that stage-specific TET1-mediated epigenetic programming and intracellular signaling are important for proper myelination and remyelination in mice.
Assuntos
Encéfalo/metabolismo , Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Camundongos Mutantes Neurológicos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Remielinização/fisiologia , 5-Metilcitosina/análogos & derivados , Animais , Ciclo Celular , Diferenciação Celular , Metilação de DNA , Proteínas de Ligação a DNA/genética , Genoma , Camundongos , Camundongos Knockout , Oligodendroglia/metabolismo , Organogênese , Proteínas Proto-Oncogênicas/genéticaRESUMO
BACKGROUND: Glioma is the most common intracranial primary tumour of adult humans, and its pathological mechanism and molecular characteristics are still under investigation. CDK-associated cullin 1 (CACUL1) has been shown to regulate colorectal carcinoma, lung cancer, and gastric cancer development. OBJECTIVE: This study aims to explore the role of CACUL1 in the pathogenesis of human glioma. METHODS: CACUL1 levels in human glioma tissue microarrays were detected by immunohistochemistry analysis. Two glioblastoma cell lines, namely, U87 and U251, were transfected with CACUL1 siRNA, and cell proliferation, cell cycle, cell apoptosis, and regulating molecules, including cyclinE1, cyclinA2, CDK2, p21, Bcl2, and Bax were assessed by CCK8, flow cytometry, and Western blot. RESULTS: CACUL1 expression in glioma tissue was significantly higher than that in normal brain tissue. CACUL1 knockdown impeded cell proliferation, induced cell apoptosis, and caused G1/S transition arrest in glioblastoma cells. The cell cycle-related proteins CDK2, cyclinE1, and cyclinA2 were dramatically decreased in the CACUL1 siRNA group compared to the non-targeting siRNA group in both U87 and U251 cells, while the CDK inhibitory protein p21 was increased in U87 cells. Additionally, the Bcl-2/Bax ratio was significantly decreased. CONCLUSION: CACUL1 can promote cell proliferation and suppress apoptosis of glioma cells and might serve as a potential oncogene for gliomas.
Assuntos
Neoplasias Encefálicas , Proteínas Culina , Glioblastoma , Apoptose , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , HumanosRESUMO
Shikonin has been reported to exhibit a wide variety of medical functions. However, the strong non-selective cytotoxicity of shikonin can restrict its clinical application. The aim of the present study was to investigate the effects of shikonin at non-cytotoxic doses on the pro-inflammation functions of monocytes and macrophages. The present results suggested that the non-cytotoxic doses of shikonin effectively inhibited lipopolysaccharide (LPS)-induced reactive oxygen species production, NF-κB activation and TNF-α expression in RAW 264.7 mouse macrophages via AMP-activated protein kinase (AMPK) signaling pathway. In addition, the non-cytotoxic doses of shikonin downregulated LPS-induced TNF-α expression via AMPK signaling activation in primary murine bone marrow-derived macrophages, and also in monocytes cultured ex vivo from patients with chronic obstructive pulmonary disease (COPD). The present in vivo results indicated that the low-toxic dose of shikonin suppressed LPS-induced endotoxin shock and TNF-α expression in mice. Collectively, the present results may provide clinical and translational relevance for treating COPD and other TNF-α-related inflammatory disorders.
RESUMO
Temozolomide (TMZ) is the first-line chemotherapy drug that has been used to treat glioma for over a decade, but the benefits are limited by half of the treated patients who acquired resistance. Studies have shown that glioma TMZ resistance is a complex process with multiple factors, which has not been fully elucidated. Ferroptosis, which is a new type of cell death discovered in recent years, has been reported to play an important role in tumor drug resistance. The present study reviews the relationship between ferroptosis and glioma TMZ resistance, and highlights the role of ferroptosis in glioma TMZ resistance. Finally, the investigators discussed the future orientation for ferroptosis in glioma TMZ resistance, in order to promote the clinical use of ferroptosis induction in glioma treatment.
RESUMO
The levels of leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1), a type I transmembrane glycoprotein broadly expressed on the majority of hematopoietic cells, such as T/B cells and natural killer cells, vary significantly during cell differentiation and activation. Previous studies focused mainly on the role of LAIR-1 in physiology and some pathological conditions, including autoimmune diseases. It has been shown that LAIR-1 mediates immune suppression, further resulting in uncontrolled inflammation. Furthermore, recent studies showed that LAIR-1 participates in the development of hematopoietic and non-hematopoietic tumors as well as malaria. This review summarizes the current findings on LAIR-1 in various diseases, its potential roles in pathogenesis, and provides new insight into the treatment of patients through suppression of the function of LAIR-1.
Assuntos
Doenças Autoimunes/genética , Malária/genética , Neoplasias/genética , Receptores Imunológicos/fisiologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linfócitos B/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Humanos , Células Matadoras Naturais/fisiologia , Malária/imunologia , Malária/patologia , Neoplasias/imunologia , Neoplasias/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
Increasing evidence indicates that the inflammatory tumor microenvironment can lead to cancer cell metastasis. Shikonin, which is extracted from the Chinese herb Zicao (the dried root of Lithospermum erythrorhizon), possesses various pharmacological effects, but its effect on tumor metastasis in the inflammatory microenvironment remains unknown. In the present study, we aimed to investigate the potential effect of shikonin on tumor metastasis in an inflammatory microenvironment as well as the underlying molecular mechanisms. It was found that, in the inflammatory microenvironment simulated by THP1 cell conditioned medium (THP1CM) in vitro, shikonin significantly inhibited the epithelialmesenchymal transition (EMT), migration and invasion of human lung adenocarcinoma cell lines A549 and H1299. In addition, we found that interleukin6 (IL6), which is expressed in THP1CM, promoted the EMT of lung adenocarcinoma cells, and shikonin markedly inhibited IL6induced EMT and cell motility. Moreover, shikonin inhibited IL6induced phosphorylation of signal transducer and activator of transcription 3 (STAT3), prevented phosphorylated STAT3 (pSTAT3) translocation into the nucleus, and suppressed pSTAT3 transactivation activity. Additionally, it was found that shikonin inhibited lung metastasis, EMT and expression of pSTAT3 of A549 cells in vivo. Furthermore, IL6 levels in human lung adenocarcinoma tissues were significantly associated with tumornodemetastasis stage and lymph node metastasis, and its expression was correlated with tumorassociated macrophage (TAM) infiltration. Together, these results suggest that shikonin suppresses the migration and invasion of human lung adenocarcinoma cells in an inflammatory microenvironment involving the IL6/STAT3 signaling pathway.
Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Metástase Linfática/tratamento farmacológico , Naftoquinonas/farmacologia , Células A549 , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/secundário , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Medicamentos de Ervas Chinesas/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/imunologia , Feminino , Humanos , Interleucina-6/análise , Interleucina-6/metabolismo , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Metástase Linfática/imunologia , Masculino , Pessoa de Meia-Idade , Naftoquinonas/uso terapêutico , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/prevenção & controle , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Leukocyte immunoglobulin (Ig)-like receptor subfamily B member 1 (LILRB1) involves in the occurrence and development of various tumors through transmitting immune inhibitory signals. However, the regulatory mechanism of LILRB1 underlying the disease progression of adenocarcinoma remains vague. This study is aimed to disclose the expression pattern of LILRB1 on adenocarcinoma and its indicative roles on the diagnosis and prognosis of adenocarcinoma patients. METHODS: LILRB1 level in microarray was measured using immunohistochemistry (IHC) staining. Expression analysis of LILRB1 gene were based on the Gene Expression Profiling Interactive Analysis 2.0 (GEPIA2) and Oncomine databases. Survival and correlation analyses were analyzed using The Cancer Genome Atlas (TCGA) database (Breastinvasivecarcinoma, TCGA-BRCA). RESULTS: The IHC results showed that the number of LILRB1-positive cells were robustly elevated in some common subtypes of adenocarcinoma including thyroid gland papillary carcinoma, gastric mixed adenocarcinoma, colon and rectal mucinous adenocarcinoma, pancreatic ductal adenocarcinoma and invasive ductal breast carcinoma compared to their corresponding para-carcinoma. Although the enhancement of LILRB1 expression was only observed in pancreaticadenocarcinoma (PAAD) by using GEPIA2, its expression presented a significant increase in the above subtypes of adenocarcinoma by analyzing using Oncomine database. Besides, there had a significant positive association between LILRB1 expression status and pathological stages, and a negative association between LILRB1 status and Overall Survival (OS) probability in the above certain subtypes of adenocarcinoma. CONCLUSION: LILRB1 is abnormally upregulated in certain subtypes of adenocarcinoma. Patients with low LILRB1 possibly portend a good prognosis in adenocarcinoma. These findings imply that LILRB1 may act as a diagnostic and prognostic target in some subtypes of adenocarcinoma.
Assuntos
Adenocarcinoma , Antígenos CD , Receptor B1 de Leucócitos Semelhante a Imunoglobulina , Adenocarcinoma/diagnóstico , Humanos , Imunoglobulinas , Leucócitos , PrognósticoRESUMO
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid progenitor and precursor cells at different stages of differentiation, which play an important role in tumor immunosuppression. Glioma is the most common and deadliest primary malignant tumor of the brain, and ample evidence supports key contributions of MDSCs to the immunosuppressive tumor microenvironment, which is a key factor stimulating glioma progression. In this review, we summarize the source and characterization of MDSCs, discuss their immunosuppressive functions, and current approaches that target MDSCs for tumor control. Overall, the review provides insights into the roles of MDSC immunosuppression in the glioma microenvironment and suggests that MDSC control is a powerful cellular therapeutic target for currently incurable glioma tumors.
Assuntos
Glioma/imunologia , Glioma/terapia , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Microambiente Tumoral/imunologia , Animais , Transporte Biológico , Diferenciação Celular , Progressão da Doença , Humanos , Terapia de ImunossupressãoRESUMO
Strategies for selectively imaging and delivering drugs to tumours typically leverage differentially upregulated surface molecules on cancer cells. Here, we show that intravenously injected carbon quantum dots, functionalized with multiple paired α-carboxyl and amino groups that bind to the large neutral amino acid transporter 1 (which is expressed in most tumours), selectively accumulate in human tumour xenografts in mice and in an orthotopic mouse model of human glioma. The functionalized quantum dots, which structurally mimic large amino acids and can be loaded with aromatic drugs through π-π stacking interactions, enabled-in the absence of detectable toxicity-near-infrared fluorescence and photoacoustic imaging of the tumours and a reduction in tumour burden after the targeted delivery of chemotherapeutics to the tumours. The versatility of functionalization and high tumour selectivity of the quantum dots make them broadly suitable for tumour-specific imaging and drug delivery.
Assuntos
Aminoácidos/química , Carbono/química , Sistemas de Liberação de Medicamentos/métodos , Pontos Quânticos/química , Nanomedicina Teranóstica/métodos , Animais , Engenharia Biomédica , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos NusRESUMO
Cancer is a key cause of death worldwide. Despite the development of radiotherapy, chemotherapy and even immunotherapy, surgery remains the standard treatment for cancer patients. Recently, many studies have shown that propofol, a commonly used anesthetic drug, can affect the prognosis of cancer. In this review, we provide an overview of the molecular mechanisms of propofol in the development of cancer. Propofol not only affects epigenetic pathways, such as those involving miRNA, lncRNA and histone acetylation, but also modulates genetic signaling pathways, including the hypoxia, NF-κB, MAPK, SLUG and Nrf2 pathways. In addition, propofol influences the immune function of patients and impacts the degree of immunosuppression. Furthermore, we briefly summarize the clinical trials on the effect of propofol in cancer development. Ultimately, further studies distinguishing the types of tumors in clinical trials are needed to clarify the correlation between propofol and cancer.
Assuntos
Hipnóticos e Sedativos/uso terapêutico , Neoplasias/tratamento farmacológico , Propofol/uso terapêutico , Humanos , Hipnóticos e Sedativos/farmacologia , Propofol/farmacologiaRESUMO
Ferroptosis is a newly discovered type of cell death decided by iron-dependent lipid peroxidation, but its role in glioblastoma cell death remains unclear. Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), has been associated with antitumorigenic effects in many cancers. In this study, we first found that ibuprofen inhibited the viabilities of glioblastoma cells in vitro and in vivo, accompanied by abnormal increase in intracellular lipid peroxidation. Further study showed that the cell growth inhibition caused by ibuprofen could be rescued by the ferroptosis inhibitors deferoxamine (DFO), ferrostatin-1 and Liproxstatin-1. Nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) are key regulators of ferroptosis. Our data showed that Nrf2, GPX4 and SLC7A11 were downregulated in glioblastoma cells under ibuprofen treatment. Interestingly, we found that decreased mRNA expression of GPX4 and SLC7A11 was accompanied with reduced Nrf2, which is a redox sensitive transcription factor that controls the expression of intracellular redox-balancing proteins such as GPX4 and SLC7A11. All the data suggested that Nrf2 could regulate the expression of GPX4 and SLC7A11 in glioma cells. Taken together, our findings reveal that ibuprofen could induce ferroptosis of glioblastoma cells via downregulation of Nrf2 signaling pathway and is a potential drug for glioma treatment.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Ibuprofeno/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/patologia , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
In patients with cancer, drug tolerance often occurs during the use of chemotherapy drugs, seriously affecting patient prognosis and survival. Therefore, scientists began to study the factors that affect chemotherapy drug sensitivity, and the high correlation between Schlafen-11 (SLFN11) and sensitivity to chemical drugs (mainly DNA-damaging agents, DDAs) has received increasing attention since it was discovered through bioinformatics analyses. Regarding the mechanism, SLFN11 may sensitise cells to chemotherapy drugs by preventing DNA damage repair. In recent years, SLFN11 has gradually become a hot research topic, and the results are enriching our understanding of this molecule. Indeed, the biological functions of SLFN11 under normal physiological conditions and in cancer, changes in its expression levels and mechanisms promoting apoptosis within the context of chemotherapeutic interventions have gradually been uncovered. Studies to date provide knowledge and the experimental and theoretical bases underlying SLFN11 and its effects on sensitivity to chemotherapy drugs. This review summarises the existing research on SLFN11 with the aim of achieving a more comprehensive understanding and furthering the development of strategies to target SLFN11 in the treatment of cancer.
Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteínas Nucleares/metabolismo , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais , Sobrevivência Celular , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , HumanosRESUMO
Shikonin, a traditional Chinese medicine, has been identified as being capable of inducing apoptosis in various tumors, including glioma, and is thus considered to be a promising therapeutic agent for tumor therapy. However, little is known about the molecular mechanism of shikonin in glioma. The present study investigated the influence of shikonin on the proliferation and apoptosis of glioma cells U251 and U87MG and explored the potential molecular mechanisms. It was identified that shikonin was able to induce apoptosis in human glioma cells in a time and dosedependent manner, and a decreased expression level of cluster of differentiation (CD)147 was observed in shikonintreated U251 and U87MG cells. Knockdown of CD147 inhibited U251 and U87MG cell growth, whereas CD147 overexpression enhanced cell growth and decreased shikonininduced apoptosis. Additionally, an increased expression level of CD147 suppressed the elevated production of reactive oxygen species and mitochondrial membrane potential levels induced by shikonin. The data indicated that shikonininduced apoptosis in glioma cells was associated with the downregulation of CD147 and the upregulation of oxidative stress. CD147 may be an optional target of shikonininduced cell apoptosis in glioma cells.
Assuntos
Apoptose/efeitos dos fármacos , Basigina/metabolismo , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Naftoquinonas/farmacologia , Basigina/antagonistas & inibidores , Basigina/genética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Glioma/patologia , Humanos , Medicina Tradicional Chinesa , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Whether persons with schizophrenia have a higher or lower incidence of cancer has been discussed for a long time. Due to the complex mechanisms and characteristics of different types of cancer, it is difficult to evaluate the exact relationship between cancers and schizophrenia without considering the type of tumor. Schizophrenia, a disabling mental illness that is now recognized as a neurodevelopmental disorder, is more correlated with brain tumors, such as glioma, than other types of tumors. Thus, we mainly focused on the relationship between schizophrenia and glioma morbidity. Glioma tumorigenesis and schizophrenia may share similar mechanisms; gene/pathway disruption would affect neurodevelopment and reduce the risk of glioma. The molecular defects of disrupted-in-schizophrenia-1 (DISC1), P53, brain-derived neurotrophic factor (BDNF) and C-X-C chemokine receptors type 4 (CXCR4) involved in schizophrenia pathogenesis might play opposite roles in glioma development. Many microRNAs (miRNAs) such as miR-183, miR-9, miR-137 and miR-126 expression change may be involved in the cross talk between glioma prevalence and schizophrenia. Finally, antipsychotic drugs may have antitumor effects. All these factors show that persons with schizophrenia have a decreased incidence of glioma; therefore, epidemiological investigation and studies comparing genetic and epigenetic aberrations involved in both of these complex diseases should be performed. These studies can provide more insightful knowledge about glioma and schizophrenia pathophysiology and help to determine the target/strategies for the prevention and treatment of the two diseases.