Protein and Glioma （蛋白质与胶质瘤）
检索式：Protein* AND Glioma*
The role of fibrinogen-like protein 2 on immunosuppression and malignant progression in glioma
Latha, K., Yan, J., Yang, Y., Gressot, L.V., Kong, L.-Y., Manyam, G., Ezhilarasan, R., Wang, Q., Sulman, E.P., Davis, R.E., Huang, S., Fuller, G.N., Rao, A., Heimberger, A.B., Li, S., Rao, G.
Journal of the National Cancer Institute, 2019 ;111(3):292-300.
摘要: Background: Virtually all low-grade gliomas (LGGs) will progress to high-grade gliomas (HGGs), including glioblastoma, the most common malignant primary brain tumor in adults. A key regulator of immunosuppression, fibrinogen-like protein 2 (FGL2), may play an important role in the malignant transformation of LGG to HGG. We sought to determine the mechanism of FGL2 on tumor progression and to show that inhibiting FGL2 expression had a therapeutic effect. Methods: We analyzed human gliomas that had progressed from low-to high-grade for FGL2 expression. We modeled FGL2 overexpression in an immunocompetent genetically engineered mouse model to determine its effect on tumor progression. Tumors and their associated microenvironments were analyzed for their immune cell infiltration. Mice were treated with an FGL2 antibody to determine a therapeutic effect. Statistical tests were two-sided. Results: We identified increased expression of FGL2 in surgically resected tumors that progressed from low to high grade (n = 10). The Cancer Genome Atlas data showed that LGG cases with overexpression of FGL2 (n = 195) had statistically significantly shorter survival (median = 62.9 months) compared with cases with low expression (n = 325, median = 94.4 months, P < .001). In a murine glioma model, HGGs induced with FGL2 exhibited a mesenchymal phenotype and increased CD4+ forkhead box P3 (FoxP3)+ Treg cells, implicating immunosuppression as a mechanism for tumor progression. Macrophages in these tumors were skewed toward the immunosuppressive M2 phenotype. Depletion of Treg cells with anti-FGL2 statistically significantly prolonged survival in mice compared with controls (n = 11 per group, median survival = 90 days vs 62 days, P = .004), shifted the phenotype from mesenchymal HGG to proneural LGG, and decreased M2 macrophage skewing. Conclusions: FGL2 facilitates glioma progression from low to high grade. Suppressing FGL2 expression holds therapeutic promise for halting malignant transformation in glioma.
题名：FGL2 promotes tumor progression in the CNS by suppressing CD103+ dendritic cell differentiation.
作者：Yan, J;Zhao, Q;Gabrusiewicz, K;Kong, LY;Xia, X;Wang, J;Ott, M;Xu, J;Davis, RE;Huo, L;Rao, G;Sun, SC;Watowich, SS;Heimberger, AB;Li, S
摘要： Few studies implicate immunoregulatory gene expression in tumor cells in arbitrating brain tumor progression. Here we show that fibrinogen-like protein 2 (FGL2) is highly expressed in glioma stem cells and primary glioblastoma (GBM) cells. FGL2 knockout in tumor cells did not affect tumor-cell proliferation in vitro or tumor progression in immunodeficient mice but completely impaired GBM progression in immune-competent mice. This impairment was reversed in mice with a defect in dendritic cells (DCs) or CD103+ DC differentiation in the brain and in tumor-draining lymph nodes. The presence of FGL2 in tumor cells inhibited granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced CD103+ DC differentiation by suppressing NF-κB, STAT1/5, and p38 activation. These findings are relevant to GBM patients because a low level of FGL2 expression with concurrent high GM-CSF expression is associated with higher CD8B expression and longer survival. These data provide a rationale for therapeutic inhibition of FGL2 in brain tumors.
主题词：Antigens, CD/genetics*/抗原, CD/遗传学*
主题词：Gene Expression Regulation, Neoplastic*/基因表达调控, 肿瘤*
主题词：Integrin alpha Chains/genetics*/整合素α链/遗传学*
题名：Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma.
作者：Xu, L;Chen, Y;Mayakonda, A;Koh, L;Chong, YK;Buckley, DL;Sandanaraj, E;Lim, SW;Lin, RY;Ke, XY;Huang, ML;Chen, J;Sun, W;Wang, LZ;Goh, BC;Dinh, HQ;Kappei, D;Winter, GE;Ding, LW;Ang, BT;Berman, BP;Bradner, JE;Tang, C;Koeffler, HP
出处：Proc Natl Acad Sci U S A.2018,115(22):E5086-E5095
摘要： Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.
主题词：E2F1 Transcription Factor*/antagonists & inhibitors/E2F1转录因子*/拮抗剂与抑制剂
主题词：E2F1 Transcription Factor*/metabolism/E2F1转录因子*/代谢
主题词：Protein-Serine-Threonine Kinases*/antagonists & inhibitors/蛋白质丝氨酸苏氨酸激酶*/拮抗剂与抑制剂
主题词：RNA-Binding Proteins*/antagonists & inhibitors/RNA结合蛋白质类*/拮抗剂与抑制剂
题名：Deciphering the complex role of thrombospondin-1 in glioblastoma development.
作者：Daubon, T;Léon, C;Clarke, K;Andrique, L;Salabert, L;Darbo, E;Pineau, R;Guérit, S;Maitre, M;Dedieu, S;Jeanne, A;Bailly, S;Feige, JJ;Miletic, H;Rossi, M;Bello, L;Falciani, F;Bjerkvig, R;Bikfalvi, A
摘要： We undertook a systematic study focused on the matricellular protein Thrombospondin-1 (THBS1) to uncover molecular mechanisms underlying the role of THBS1 in glioblastoma (GBM) development. THBS1 was found to be increased with glioma grades. Mechanistically, we show that the TGFβ canonical pathway transcriptionally regulates THBS1, through SMAD3 binding to the THBS1 gene promoter. THBS1 silencing inhibits tumour cell invasion and growth, alone and in combination with anti-angiogenic therapy. Specific inhibition of the THBS1/CD47 interaction using an antagonist peptide decreases cell invasion. This is confirmed by CD47 knock-down experiments. RNA sequencing of patient-derived xenograft tissue from laser capture micro-dissected peripheral and central tumour areas demonstrates that THBS1 is one of the gene with the highest connectivity at the tumour borders. All in all, these data show that TGFβ1 induces THBS1 expression via Smad3 which contributes to the invasive behaviour during GBM expansion. Furthermore, tumour cell-bound CD47 is implicated in this process.
主题词：Gene Expression Regulation, Neoplastic*/基因表达调控, 肿瘤*
主题词：Transforming Growth Factor beta1/genetics*/β1转化生长因子/遗传学*
题名：FHL2 interacts with EGFR to promote glioblastoma growth.
作者：Sun, L;Yu, S;Xu, H;Zheng, Y;Lin, J;Wu, M;Wang, J;Wang, A;Lan, Q;Furnari, F;Cavenee, W;Purow, B;Li, M
摘要： Four-and-a-half LIM protein2 (FHL2) is a member of the LIM-only protein family, which plays a critical role in tumorigenesis. We previously reported that FHL2 is upregulated and plays an oncogenic role in glioblastoma (GBM), the most common and aggressive brain tumor. GBM is also marked by amplification of the epidermal growth factor receptor (EGFR) gene and its mutations, of which EGFRvIII is the most common and functionally significant. Here we report that FHL2 physically interacts with the wild-type EGFR and its mutated EGFRvIII form in GBM cells. Expression of FHL2 caused increased EGFR and EGFRvIII protein levels and this was due to an increase in protein stability rather than an increase in EGFR mRNA expression. In contrast, FHL2 knockdown using RNA interference reduced EGFR and EGFRvIII protein expression and the phosphorylation levels of EGFR and AKT. Consistent with these features, EGFR expression was significantly lower in mouse FHL2-null astrocytes, where reintroduction of FHL2 was able to restore EGFR levels. Using established GBM cell lines and patient-derived neurosphere lines, FHL2 silencing markedly induced cell apoptosis in EGFRvIII-positive cells. Targeting FHL2 significantly prevented EGFRvIII-positive GBM tumor growth in vivo. FHL2 expression also positively correlated with EGFR expression in GBM samples from patients. Taken together, our results demonstrate that FHL2 interacts with EGFR and EGFRvIII to increase their levels and this promotes glioma growth, representing a novel mechanism that may be therapeutically targetable.
题名：Gli1-induced deubiquitinase USP48 aids glioblastoma tumorigenesis by stabilizing Gli1.
作者：Zhou, A;Lin, K;Zhang, S;Ma, L;Xue, J;Morris, SA;Aldape, KD;Huang, S
摘要： Aberrant activation of the Hedgehog (Hh) signaling pathway drives the tumorigenesis of multiple cancers. In this study, we screened a panel of deubiquitinases that may regulate the Hh pathway. We find that deubiquitinase USP48 activates Gli-dependent transcription by stabilizing Gli1 protein. Mechanistically, USP48 interacts with Gli1 and cleaves its ubiquitin off directly. In glioblastoma cells, knockdown of USP48 inhibits cell proliferation and the expression of Gli1's downstream targets, which leads to repressed glioblastoma tumorigenesis. Importantly, USP48's effect on cell proliferation and tumorigenesis depends to some extent on Gli1. In addition, we find that the Sonic Hedgehog (SHH) pathway induces USP48 expression through Gli1-mediated transcriptional activation, which forms thus a positive feedback loop to regulate Hh signaling. In human glioblastoma specimens, the expression levels of USP48 and Gli1 proteins are clinically relevant, and high expression of USP48 correlates with glioma malignancy. In summary, our study reveals that the USP48-Gli1 regulatory axis is critical for glioma cell proliferation and glioblastoma tumorigenesis.
主题词：Zinc Finger Protein GLI1/metabolism*/锌指蛋白α/代谢*
LIM and SH3 protein 1 induces glioma growth and invasion through PI3K/AKT signaling and epithelial-mesenchymal transition
LIM和SH3蛋白1通过PI3K / AKT信号传导和上皮-间充质转变诱导神经胶质瘤生长和侵袭
Zhong, C., Li, X., Tao, B., Peng, L., Peng, T., Yang, X., Xia, X., Chen, L.
Biomedicine and Pharmacotherapy, 2019 ;116:109013
摘要: Purpose: This study investigated the underlying mechanism of LIM and SH3 protein 1 (LASP1)-induced malignant glioma growth and invasion. Materials and methods: We compared the expression of LASP1 in malignant glioma tumor tissues and low-grade glioma tissues by immunohistochemistry. We also compared LASP1 overexpression and LASP1 knockout glioma cell proliferation and invasion in vitro and in vivo. We detected activation of the PI3K/AKT signaling pathway and epithelial-mesenchymal transition (EMT) process in tumor cells by western blotting or immunofluorescence. Glioma-bearing mice were used to investigate the anticancer effects of PI3K/AKT inhibitors in combination with temozolomide. Results: We observed the enhanced expression of LASP1 in malignant glioma tumor tissues compared to low-grade glioma tissues, and LASP1 overexpression in glioma cells revealed an elevated capability of proliferation and invasion in vitro and in vivo. LASP1 overexpression also facilitated PI3K/AKT signaling and the EMT process through the downstream transcription factor Snail, which resulted in the intensive invasion of cancer cells. We combined PI3K/AKT inhibitors and temozolomide to block the LASP1/PI3K/AKT/Snail signaling pathway, which dramatically enhanced tumor suppression and provides an innovative approach for clinical glioma treatment. Conclusion: LASP1 is upregulated in malignant glioma and facilitates glioma cell proliferation and invasion by activation the PI3K/AKT/Snail signaling pathway. Blockade of the PI3K/AKT signal efficiently enhanced the anticancer effects of chemotherapeutic agents, which provides an innovative target in glioma treatment.
关键词：EMT ; Glioma ; LASP1 ; PI3K/AKT
题名：Increased expression of NAF1 contributes to malignant phenotypes of glioma cells through promoting protein synthesis and associates with poor patient survival
作者：Wei, J., Yang, Q., Shi, J., Shi, B., Ji, M., Hou, P.
出处：Oncogenesis, 2019 ;8(4):25
摘要: The H/ACA ribonucleoprotein (RNP) complex noncore subunit NAF1 is an indispensable factor during H/ACA RNP maturation, and one of the widely known functions of H/ACA RNP is modulating ribosome biosynthesis. However, the specific biological role and exact mechanism of NAF1 in human cancers including glioma remain largely unclear. In this study, we found that NAF1 was highly expressed in gliomas relative to normal brain tissues, and demonstrated that increased expression of NAF1 was strongly correlated with poor patient survival. Further studies revealed that NAF1 was transcriptionally regulated by c-Myc, NRF2, and telomerase reverse transcriptase (TERT), which are the key molecules associated with malignant progression of gliomas. Moreover, we demonstrated that NAF1 was a functional oncogene in glioma cells through promoting cell growth in vitro and in vivo, survival, migration, and invasion. Mechanistically, NAF1 acted as a rate-limiting controller of cell growth and invasiveness through enhancing 40S subunit assembly and protein synthesis including c-Myc, NRF2, TERT, POLR1A, and POLR2A. These molecules in turn enhanced the transcription and translation of NAF1, thereby forming positive feedback loops between them to promote malignant phenotypes of glioma cells. In addition, our data also showed that NAF1 depletion could trigger ribosome stress, not only impairing ribosomal biosynthesis but also reactivating p53 signaling via blocking MDM2. Taken together, we demonstrated that NAF1 promotes the tumorigenesis and progression of glioma through modulating ribosome assembly and protein synthesis, and predicted that NAF1 may be a potential therapeutic target and valuable prognostic biomarker in gliomas.
题名：DHHC protein family targets different subsets of glioma stem cells in specific niches
作者：Chen, X., Hu, L., Yang, H., Ma, H., Ye, K., Zhao, C., Zhao, Z., Dai, H., Wang, H., Fang, Z.
出处：Journal of Experimental and Clinical Cancer Research, 2019 ;38(1):25
摘要: Background: Glioblastomas (GBM) comprise different subsets that exhibit marked heterogeneity and plasticity, leading to a lack of success of genomic profiling in guiding the development of precision medicine approaches against these tumors. Accordingly, there is an urgent need to investigate the regulatory mechanisms for different GBM subsets and identify novel biomarkers and therapeutic targets relevant in the context of GBM-specific niches. The DHHC family of proteins is associated tightly with the malignant development and progression of gliomas. However, the role of these proteins in the plasticity of GBM subsets remains unclear. Methods: This study utilized human glioma proneural or mesenchymal stem cells as indicated. The effects of DHHC proteins on different GBM subsets were investigated through in vitro and in vivo assays (i.e., colony formation assay, flow cytometry assay, double immunofluorescence, western blot, and xenograft model). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to detect the protein complexes of ZDHHC18 and ZDHHC23 in various GBM subtypes, and explore the mechanism of DHHC proteins in targeting different subsets of GSCs in specific niches. Results: ZDHHC18 and ZDHHC23 could target the glioma stem cells of different GBM subsets in the context of their specific niches and regulate the cellular plasticity of these subtypes. Moreover, mechanistic investigations revealed that ZDHHC18 and ZDHHC23 competitively interact with a BMI1 E3 ligase, RNF144A, to regulate the polyubiquitination and accumulation of BMI1. These events contributed to the transition of glioma stem cells in GBM and cell survival under the stressful tumor microenvironment. Conclusions: Our work highlights the role of DHHC proteins in the plasticity of GBM subsets and reveals that BMI1 represents a potential therapeutic target for human gliomas.
Multigene Family* 【多基因族*】
Neoplastic Stem Cells/metabolism* 【肿瘤干细胞/代谢*】
Tumor Microenvironment/genetics* 【肿瘤微环境/遗传学*】
题名：Enhanced Expression of TGFBI Promotes the Proliferation and Migration of Glioma Cells.
作者：Guo, SK;Shen, MF;Yao, HW;Liu, YS
出处：Cell Physiol Biochem.2018,49(3):1097-1109
AIMS:Transforming growth factor beta-induced protein (TGFBI) is an extracellular matrix protein induced by TGF-β. Previous studies have reported that the abnormal expression of TGFBI is related to the occurrence and development of some types of cancers, while the role of TGFBI in glioma is uncertain.
METHODS:The association between TGFBI expression and the prognosis of patients with glioma was analyzed based on data obtained from The Cancer Genome Atlas database. TGFBI expression was analyzed in 3 normal human brains and 57 cases of human gliomas by immunohistochemistry followed by an evaluation of the relationships between TGFBI expression and clinic-pathological features. Furthermore, the RNA interference plasmid pSUPER-shTGFBI was constructed and transfected into U87 and U251 cells to explore the effect of short hairpin RNA against TGFBI (shTGFBI) on cell proliferation, migration, invasion and apoptosis. Western blot analysis was performed to examine the expression of proteins related to apoptosis and proteins in the PI3K/Akt signaling pathway.
RESULTS:High TGFBI expression was found to be associated with poor prognosis in patients with glioblastoma multiforme. Immunohistochemistry showed that TGFBI expression was significantly higher in glioma tissue than in normal human brain tissues. The expression level of TGFBI showed no significant correlation with age, sex, lymph-node metastasis, or pathological grade. sh-TGFBI could inhibit proliferation, invasion and migration and induce apoptosis in U87 and U251 cells in vitro. Furthermore, the phosphorylation levels of AKT and mTOR declined significantly in sh-TGFBI transfected U81 and U251 cells when compared with control.
CONCLUSION:TGFBI was up-regulated in glioma cells and played a promoting role in the growth and motility of U87 and U251 cells. These results suggested that TGFBI has the potential to be a diagnostic marker and to serve as a target for the treatment of gliomas.
主题词：Proto-Oncogene Proteins c-bcl-2/metabolism/原癌基因蛋白质c-bcl-2/代谢
主题词：Transforming Growth Factor beta1/metabolism*/β1转化生长因子/代谢*
主题词：bcl-2-Associated X Protein/metabolism/bcl-2相关X蛋白质/代谢
题名：YAP and MRTF-A, transcriptional co-activators of RhoA-mediated gene expression, are critical for glioblastoma tumorigenicity.
作者：Yu, OM;Benitez, JA;Plouffe, SW;Ryback, D;Klein, A;Smith, J;Greenbaum, J;Delatte, B;Rao, A;Guan, KL;Furnari, FB;Chaim, OM;Miyamoto, S;Brown, JH
摘要： The role of YAP (Yes-associated protein 1) and MRTF-A (myocardin-related transcription factor A), two transcriptional co-activators regulated downstream of GPCRs (G protein-coupled receptors) and RhoA, in the growth of glioblastoma cells and in vivo glioblastoma multiforme (GBM) tumor development was explored using human glioblastoma cell lines and tumor-initiating cells derived from patient-derived xenografts (PDX). Knockdown of these co-activators in GSC-23 PDX cells using short hairpin RNA significantly attenuated in vitro self-renewal capability assessed by limiting dilution, oncogene expression, and neurosphere formation. Orthotopic xenografts of the MRTF-A and YAP knockdown PDX cells formed significantly smaller tumors and were of lower morbidity than wild-type cells. In vitro studies used PDX and 1321N1 glioblastoma cells to examine functional responses to sphingosine 1-phosphate (S1P), a GPCR agonist that activates RhoA signaling, demonstrated that YAP signaling was required for cell migration and invasion, whereas MRTF-A was required for cell adhesion; both YAP and MRTF-A were required for proliferation. Gene expression analysis by RNA-sequencing of S1P-treated MRTF-A or YAP knockout cells identified 44 genes that were induced through RhoA and highly dependent on YAP, MRTF-A, or both. Knockdown of F3 (tissue factor (TF)), a target gene regulated selectively through YAP, blocked cell invasion and migration, whereas knockdown of HBEGF (heparin-binding epidermal growth factor-like growth factor), a gene selectively induced through MRTF-A, prevented cell adhesion in response to S1P. Proliferation was sensitive to knockdown of target genes regulated through either or both YAP and MRTF-A. Expression of TF and HBEGF was also selectively decreased in tumors from PDX cells lacking YAP or MRTF-A, indicating that these transcriptional pathways are regulated in preclinical GBM models and suggesting that their activation through GPCRs and RhoA contributes to growth and maintenance of human GBM.
主题词：Adaptor Proteins, Signal Transducing/genetics*/衔接蛋白质类, 信号转导/遗传学*
主题词：Gene Expression Regulation, Neoplastic/genetics*/基因表达调控, 肿瘤/遗传学*
主题词：rhoA GTP-Binding Protein/genetics/ρA GTP结合蛋白质/遗传学
题名：MicroRNA 10a induces glioma tumorigenesis by targeting myotubularin-related protein 3 and regulating the Wnt/β-catenin signaling pathway
MicroRNA 10a通过靶向肌管相关蛋白3并调节Wnt /β-连环蛋白信号传导途径诱导胶质瘤肿瘤发生
作者：Yan, Y., Yan, H., Wang, Q., Zhang, L., Liu, Y., Yu, H.
出处：FEBS Journal, 2019 .
摘要: MicroRNAs are involved in the regulation of tumor formation. A previous study suggested that miR-10a promotes glioma cell migration and invasion. However, the effect of miR-10a on the proliferation of glioma cells remains unknown. In this study, we demonstrated that miR-10a promoted proliferation and reduced apoptosis in glioma cells by directly targeting the 3′-UTR of myotubularin-related protein 3 (MTMR3). miR-10a enhanced, while MTMR3 weakened, the growth of glioma in vivo. Ectopic expression of MTMR3 neutralized the effect of miR-10a on glioma. Furthermore, miR-10a and MTMR3 regulated β-catenin expression and genes downstream of the Wnt/β-catenin signaling pathway, such as Bcl-2, c-myc, p-c-Jun, and cleaved caspase-3, to affect the proliferation ability and apoptosis of glioma cells. In conclusion, our results indicated that miR-10a regulated cell proliferation and apoptosis by directly targeting MTMR3 and could function as a prognostic factor for progression of glioma.
题名：Proteolipid Protein 2 Overexpression Indicates Aggressive Tumor Behavior and Adverse Prognosis in Human Gliomas
作者：Chen, Y.-H., Hueng, D.-Y., Tsai, W.-C.
出处：International journal of molecular sciences, 2018;19(11).
摘要: Proteolipid protein 2 (PLP2), a membrane protein of the endoplasmic reticulum, is related to tumor proliferation and metastasis in some human cancers, but not in gliomas. First, we performed western-blot analysis, real-time quantitative PCR and immunohistochemical stains to detect PLP2 expression in 4 glioma cell lines and human glioma tissues. In addition, we used small interfering RNA (SiPLP2) and short hairpin RNA (shPLP2) to knockdown PLP2 expression in GBM8401 and LN229 glioma cell lines. After then, the alteration of PLP2 suppressed glioma cells behavior were examined by cell proliferation, wound healing, cell invasion, and colonies formation assays. Finally, the possible mechanism of PLP2 was analyzed by detecting the expression of the proteins related to cell-cycle checkpoints, cell-proliferative signaling factors, and cell-matrix interaction. Compared with normal brain cell lysates and mRNA, all glioma cell lines displayed PLP2 protein and mRNA overexpression. Besides, higher PLP2 IHC staining significantly correlated with more advanced tumor grades and poorer prognosis in human gliomas. Both siPLP2 transfected gliomas showed a clear inhibition of glioma cell proliferation, migration, and invasion as well as down-regulating p-p38, p-ERK, MMP-2, and MMP-9 expression. In conclusion, we successfully demonstrated that PLP2 overexpression played an oncogenic role in glioma development and aggressive tumor behavior.
主题词：Brain Neoplasms/genetics* 【脑肿瘤/遗传学*】
Gene Expression Regulation, Neoplastic* 【基因表达调控, 肿瘤*】
MARVEL Domain-Containing Proteins/genetics* 【含MARVEL结构域蛋白质类/遗传学*】
题名：CRMP2 Phosphorylation Drives Glioblastoma Cell Proliferation.
作者：Moutal, A;Villa, LS;Yeon, SK;Householder, KT;Park, KD;Sirianni, RW;Khanna, R
摘要： Glioblastoma (GBM) is an aggressive primary brain tumor. The rapid growth and the privileged provenance of the tumor within the brain contribute to its aggressivity and poor therapeutic targeting. A poor prognostic factor in glioblastoma is the deletion or mutation of the Nf1 gene. This gene codes for the protein neurofibromin, a tumor suppressor gene that is known to interact with the collapsin response mediator protein 2 (CRMP2). CRMP2 expression and elevated expression of nuclear phosphorylated CRMP2 have recently been implicated in cancer progression. The CRMP2-neurofibromin interaction protects CRMP2 from its phosphorylation by cyclin-dependent kinase 5 (Cdk5), an event linked to cancer progression. In three human glioblastoma cell lines (GL15, A172, and U87), we observed an inverse correlation between neurofibromin expression and CRMP2 phosphorylation levels. Glioblastoma cell proliferation was dependent on CRMP2 expression and phosphorylation by Cdk5 and glycogen synthase kinase 3 beta (GSK3β). The CRMP2 phosphorylation inhibitor (S)-lacosamide reduces, in a concentration-dependent manner, glioblastoma cell proliferation and induced apoptosis in all three GBM cell lines tested. Since (S)-lacosamide is bioavailable in the brain, we tested its utility in an in vivo orthotopic model of GBM using GL261-LucNeo glioma cells. (S)-lacosamide decreased tumor size, as measured via in vivo bioluminescence imaging, by ~54% compared to vehicle control. Our results introduce CRMP2 expression and phosphorylation as a novel player in GBM proliferation and survival, which is enhanced by loss of Nf1.
主题词：Intercellular Signaling Peptides and Proteins/metabolism*/胞间信号肽类和蛋白质类/代谢*
主题词：Nerve Tissue Proteins/metabolism*/神经组织蛋白质类/代谢*
题名：C-Terminal Binding Protein is Involved in Promoting to the Carcinogenesis of Human Glioma.
作者：Liu, B;Di, G
摘要： C-terminal binding protein (CtBP) is responsible for regulating the pathogenesis of a lot of cancer types. However, whether CtBP1/2 is involved in regulating the growth and development of human glioma is still obscure. In the present study presented here, our results firstly reveal that CtBP1/2 deficiency, induced by siRNA interference, disrupts the functional integrity of the MRN complex that is responsible for DNA repair in human glioma cells. The dysfunction of the MRN complex further contributes to the up-regulation of ATM and Rad3-related kinase (ATR) and Chk1 signaling pathway, which inhibits cell cycle progression mediated by CDK2, preparing for the initiation of DNA repair. Under the condition of hypoxia, hypoxia-inducible factor-1α (HIF-1α) can be directly regulated by CDK2 on protein level, playing coordinately regulatory role in the carcinogenesis of human glioma cells. Overall, our findings reveal that CtBP1/2 is essential to promote to human glioma cell growth through maintaining the DNA stability regulated by the MRN/ATR/Chk1/CDK2/HIF-1α signaling pathway.
题名：The atypical protein kinase RIOK3 contributes to glioma cell proliferation/survival, migration/invasion and the AKT/mTOR signaling pathway.
非典型蛋白激酶RIOK3有助于神经胶质瘤细胞增殖/存活，迁移/侵袭和AKT / mTOR信号传导途径
作者：Zhang, T;Ji, D;Wang, P;Liang, D;Jin, L;Shi, H;Liu, X;Meng, Q;Yu, R;Gao, S
摘要： The RIO (right open reading frame) protein kinases include RIOK1, RIOK2 and RIOK3. Emerging evidence has suggested an important role of RIO kinases in cancer cell proliferation, apoptosis, migration and invasion. However, the expression profile and specific roles of RIOK3 are largely unknown during glioma progression. In the current study, quantitative real-time PCR, Western blot, and immunohistochemical analysis showed that RIOK3 was upregulated in glioma tissues. Available database analysis revealed that higher levels of RIOK3 were associated with poorer survival outcome in glioma patients. Flow cytometry, CCK8 and EdU assays showed that downregulation of RIOK3 arrested cell cycle progression and inhibited glioma cell proliferation. Wound healing, transwell and gelatin zymography assays revealed that silencing RIOK3 decreased glioma cell migration and invasion. Furthermore, the downregulation of RIOK3 significantly decreased the activity of AKT/mTOR signaling and induced apoptosis in glioma cells. Overexpression of RIOK3 showed the opposite effects on glioma cell proliferation, migration, invasion and the AKT/mTOR pathway. These results indicate that high RIOK3 levels in gliomas appear to contribute to the growth and expansion of this cancer, and may thus serve as a novel therapeutic target.
主题词：Proto-Oncogene Proteins c-akt/metabolism*/原癌基因蛋白质c-akt/代谢*
主题词：TOR Serine-Threonine Kinases/metabolism*/TOR丝氨酸-苏氨酸蛋白激酶/代谢*
题名：Promotive effects of capillary morphogenetic protein 2 on glioma cell invasion and the molecular mechanism
作者：Xu, Y., He, Y., Xu, W., Lu, T., Liang, W., Jin, W.
出处：Folia Neuropathologica, 2019 ;57(1):6-15
摘要: We aimed to explore the role of capillary morphogenetic protein 2 (CMG2) in glioma cell invasion and the possible molecular mechanism. Glioma cells U87 and U251 stably overexpressing CMG2 were constructed by lentiviral transfection. The changes of cell invasion and migration were tested by Matrigel-transwell assay and scratch assay, respectively. A mouse model with orthotopically transplanted tumour was established to evaluate the effects of CMG2 overexpression on the in vivo invasion of glioma cells and survival time. The differences of filopodia and lamellar pseudopodia among glioma cells with different CMG2 expressions were observed by immunofluorescence assay. The expressions of YAP and p-YAP in glioma cells overexpressing CMG2 or not were compared by Western blot. Compared with the control group, overexpression of CMG2 enhanced the invasion and migration capacities of glioma cells (p < 0.05). The tumour tissues of mice transplanted with glioma cells overexpressing CMG2 were obviously invaded, and their survival time was significantly shortened (p < 0.05). Immunofluorescence staining showed that glioma cells overexpressing CMG2 formed more lamellipodia and filopodia than those of the control group. As glioma cells overexpressing CMG2 formed more pseudopodia, the expression of YAP, a key effector protein of the Hippo pathway, was up-regulated. CMG2 promoted the invasion of glioma cells, and may induce pseudopodium formation by up-regulating YAP expression.
索引关键字: capillary morphogenetic protein 2; YAP protein, animal experiment; carcinogenesis; cell invasion; cell migration; glioma; glioma cell; protein expression; protein function; pseudopodium; U-251MG cell line;
题名：Epithelial growth factor receptor expression influences 5-ALA induced glioblastoma fluorescence.
作者：Fontana, AO;Piffaretti, D;Marchi, F;Burgio, F;Faia-Torres, AB;Paganetti, P;Pinton, S;Pieles, U;Reinert, M
摘要： The extent of 5-aminolevulinic acid (5-ALA) guided tumor resection has a determining impact in high-grade glioma and glioblastoma surgery. Yet the intensity of the 5-ALA induced fluorescence may vary within the tumor. We aimed to correlate 5-ALA induced fluorescence with the expression of epithelial growth factor receptor (EGFR) and its constitutively active version EGFRvIII in different glioblastoma (GBM) cell lines. To elucidate the role of EGFR in the metabolism of 5-ALA in GBM cell lines with variable EGFR expression status, we analyzed the activation of EGFR by its primary ligand EGF, and its downstream effect on Heme oxygenase-1 (HO-1), a key enzyme regulating the metabolism of Protoporphyrin IX (PpIX), the fluorescent metabolite of 5-ALA. Effects of direct pharmacological inhibition by Tin(IV)-Protoporphyrin (SnPP) or gene knockdown by small interfering RNA (siRNA) on HO-1 enzyme were analyzed in respect to 5-ALA induced fluorescence. Furthermore, inhibition of EGFR by Gefitinib was tested. A significant difference in 5-ALA induced fluorescence was obtained in U87MG (low EGFR expression) and LN229EGFR cells (EGFR overexpression) compared to BS153 (EGFR overexpression/EGFRvIII+). Treatment of U87MG and LN229EGFR cells with EGF significantly reduced cellular fluorescence, by promoting HO-1 transcription and expression in a concentration-dependent manner. This effect could be reversed by EGFR-specific siRNA treatment, which reduced protein expression of about 80% in U87MG. Remarkably, inhibition of HO-1 activity by SnPP or reduction of HO-1 protein levels by siHO-1 treatment restored fluorescence in all cell lines, independently of EGFR quantitative and qualitative expression. Gefitinib treatment was able to restore fluorescence after EGF stimulation in U87MG cells but not in BS153 cells, overexpressing EGFR/EGFRvIII. In GBM cell lines, 5-ALA induced fluorescence is variable and influenced by EGF-induced downstream activation of HO-1. HO-1 protein expression was identified as a negative regulator of 5-ALA induced fluorescence in GBM cells. We further propose that co-expression of EGFRvIII but not quantitative EGFR expression influence HO-1 activity and therefore cellular fluorescence.
主题词：Receptor, Epidermal Growth Factor/metabolism*/受体, 表皮生长因子/代谢*
题名：Brain lipid binding protein mediates the proliferation of human glioblastoma cells by regulating ERK1/2 signaling pathway in vitro.
脑脂质结合蛋白通过体外调节ERK1 / 2信号通路介导人胶质母细胞瘤细胞的增殖
作者：Tian, W;Shi, J;Qin, J;Jin, G;Han, X;Li, H
出处：In Vitro Cell Dev Biol Anim.2018,54(2):156-162
摘要： Brain lipid binding protein (BLBP) is highly expressed in the radial glial cells (RGCs) of the central nervous system (CNS), in glioblastomas, and, in vitro, in U251 cells. In this report, we have demonstrated that increased BLBP expression in glioblastoma is associated with poor survival and used a double-vector CRISPR/Cas9 lentiviral system to deplete endogenous BLBP from U251 cells, we found that loss of BLBP induced cell growth inhibition and S-phase arrest. Moreover, an increase in P53 and a decrease in p-ERK1/2 were observed after BLBP depletion, suggesting a potential mechanism by which loss of BLBP results in growth inhibition.
主题词：Fatty Acid-Binding Protein 7/metabolism*/脂肪酸结合蛋白7/代谢*
主题词：Mitogen-Activated Protein Kinase 1/metabolism/丝裂原活化蛋白激酶1/代谢
主题词：Tumor Suppressor Proteins/metabolism*/肿瘤抑制蛋白质类/代谢*
题名：RIP2 promotes glioma cell growth by regulating TRAF3 and activating the NF-κB and p38 signaling pathways.
作者：Cai, X;Yang, Y;Xia, W;Kong, H;Wang, M;Fu, W;Long, M;Hu, Y;Xu, D
摘要： Receptor-interacting protein 2 (RIP2) has recently been reported to be involved in tumor infiltration and cancer metastasis. However, the function of RIP2 in human astrocytoma remains unclear. In the present study, we showed that the expressions of RIP2 and Bcl-xL were positively correlated with the malignant grade in 28?cases of astrocytoma of various grades and 6?cases of normal human tissues. In addition, increased activity of the NF?κB and p38 signaling pathways in astrocytoma tissue was observed. Cytological experiments indicated that RIP2 promoted human glioblastoma cell proliferation by inducing expression of Bcl-xL, and knockdown of endogenous RIP2 promoted cell apoptosis. Mechanistically, knockdown of RIP2 suppressed downstream events including the canonical and alternative NF-κB pathway as well as the mitogen-activated protein kinase (p38) pathway. In addition, the present study also demonstrated that tumor necrosis factor receptor-associated factor 3 (TRAF3), as a novel RIP2 binding partner, was downregulated in glioma tissues and functionally was a negative regulator involved in RIP2-induced glioma cell growth. Taken together, the present study established a negative link between RIP2 and TRAF3 proteins and identifies a new pathway for regulating astrocytoma progression.
主题词：Receptor-Interacting Protein Serine-Threonine Kinase 2/genetics*/受体作用蛋白丝氨酸-苏氨酸激酶2/遗传学*
主题词：TNF Receptor-Associated Factor 3/genetics*/TNF受体相关因子3/遗传学*
题名：Up-regulation of ANKDR49, a poor prognostic factor, regulates cell proliferation of gliomas.
作者：Hao, C;Duan, H;Li, H;Pei, M;Liu, Y;Fan, Y;Zhang, C
摘要： The Ankyrin repeat domain 49 (ANKRD49) is an evolutionarily conserved protein, which is related to mediate protein-protein interaction. However, the function of ANKRD49 in human glioma remains elusive. Mining through The Cancer Genome Atlas (TCGA) database, we found that the expression of ANKRD49 was increased in glioma tissues and that high expression of ANKRD49 was strongly associated with high disease grade and poor overall survival. To investigate the role of ANKRD49 in malignant glioma, lentivirus expressing shRNA targetting ANKRD49 was constructed in U251 and U87 malignant glioma cells. We demonstrated that ANKRD49 knockdown reduced the proliferation rate of U251 and U87 cells. Further mechanism analysis indicated that depletion of ANKRD49 led to the cell-cycle arrest and induced apoptosis in U251 and U87 cells. ANKRD49 knockdown also changed the expression of key effectors that are involved in stress response, cell cycle, and apoptosis, including p-HSP27 (heat shock protein 27), p-Smad2 (SMAD family member 2), p-p53, p-p38, p-MAPK (mitogen-activated protein kinase), p-SAPK/JNK (stress-activated protein kinase/c-jun n-terminal kinase), cleveagated Caspase-7, p-Chk1 (checkpoint kinase 1), and p-eIF2a (eukaryotic translation initiation factor 2a). Taken together, our findings implicate that ANKRD49 promotes the proliferation of human malignant glioma cells. ANKRD49 maybe an attractive target for malignant glioma therapy.
主题词：Biomarkers, Tumor/genetics*/肿瘤标记, 生物学/遗传学*
主题词：Central Nervous System Neoplasms/genetics*/中枢神经系统肿瘤/遗传学*
主题词：Central Nervous System Neoplasms/pathology/中枢神经系统肿瘤/病理学
题名：GBP3 promotes glioma cell proliferation via SQSTM1/p62-ERK1/2 axis.
GBP3通过SQSTM1 / p62-ERK1 / 2轴促进神经胶质瘤细胞增殖
作者：Xu, H;Sun, L;Zheng, Y;Yu, S;Ou-Yang, J;Han, H;Dai, X;Yu, X;Li, M;Lan, Q
出处：Biochem Biophys Res Commun.2018,495(1):446-453
摘要： Guanylate binding proteins (GBPs) are interferon-inducible large GTPases and play a crucial role in cell-autonomous immunity. However, the biology function of GBPs in cancer remains elusive. GBP3 is specifically expressed in adult brain. Here we show that GBP3 is highly elevated in human glioma tumors and glioma cell lines. Overexpression of GBP3 dramatically increased glioma cell proliferation whereas silencing GBP3 by RNA interference produced opposite effects. We further showed that GBP3 expression was able to induce sequestosome-1(SQSTM1, also named p62) expression and activate extracellular signal-regulated kinase (ERK1/2). The SQSTM1-ERK1/2 signaling cascade was essential for GBP3-promoted cell growth because depletion of SQSTM1 markedly reduced the phosphorylated ERK1/2 levels and GBP3-mediated cell growth, and inhibition of mitogen-activated protein kinase/ERK kinase abolished GBP3-induced glioma cell proliferation. Consistently, GBP3 overexpression significantly promoted glioma tumor growth in?vivo and its expression was inversely correlated with the survival rate of glioma patients. Taken together, these results for the first time suggest that GBP3 contributes to the proliferation of glioma cells via regulating SQSTM1-ERK1/2 pathway, and GBP3 might represent as a new potential therapeutic target against glioma.
主题词：MAP Kinase Signaling System*/MAP激酶信号系统*
题名：Hypoxia-induced production of peptidylarginine deiminases and citrullinated proteins in malignant glioma cells.
作者：Sase, T;Arito, M;Onodera, H;Omoteyama, K;Kurokawa, MS;Kagami, Y;Ishigami, A;Tanaka, Y;Kato, T
出处：Biochem Biophys Res Commun.2017,482(1):50-56
摘要： BACKGROUND:Recently, it has been reported that hypoxia highly enhances expression of peptidylarginine deiminase (PAD) 4 and production of citrullinated proteins in some tumor cells. However, little is known about malignant gliomas on this issue. Therefore, we here investigated whether expression of PADs was induced by hypoxia and whether PADs citrullinated intracellular proteins if induced using U-251?MG cells of a human malignant glioma cell line. METHODS:Expression of PADs in U-251?MG cells, cultured under hypoxia or normoxia for 24?h, was investigated by quantitative polymerase chain reaction (qPCR). Citrullination of proteins in the cells and the cell lysates incubated for 48?h with or without Ca2+ was detected by western blotting. Citrullinated proteins were identified by mass spectrometry. RESULTS:The mRNA levels of PAD1, 2, 3, and 4 were up-regulated by hypoxia in a hypoxia-inducible factor-1-dependent manner in U-251?MG cells. In spite of the increased expression, intracellular proteins were not citrullinated. However, the induced PADs citrullinated U-251?MG cell-derived proteins when the cells were lysed. Multiple proteins citrullinated by hypoxia-induced PADs were identified. In addition, the extracellular domain of vascular endothelial growth factor receptor 2 was citrullinated by human PAD2 in?vitro. CONCLUSION:Our data may contribute to understanding of pathophysiology of malignant gliomas from the aspects of protein citrullination.
题名：IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65.
IGF2 mRNA结合蛋白3（IMP3）通过增强RELA / p65蛋白的翻译促进神经胶质瘤细胞迁移
作者：Bhargava, S;Visvanathan, A;Patil, V;Kumar, A;Kesari, S;Das, S;Hegde, AS;Arivazhagan, A;Santosh, V;Somasundaram, K
摘要： The diffusely infiltrative nature of glioblastoma (GBM) makes them highly recurrent. IGF2 mRNA-binding protein 3 (IMP3), a GBM upregulated RNA binding protein, promotes glioma cell migration. An integrative bioinformatics analysis identified p65 (RELA), a subunit of NF-κB heterodimer as a target and an important mediator of IMP3 promoted glioma cell migration. IMP3 increased p65 protein levels without any change in p65 transcript levels, but promoted its polysome association. RIP-PCR demonstrated the binding of IMP3 to p65 transcript. UV crosslinking experiments with in vitro transcribed RNA confirmed the specific and direct binding of IMP3 to sites on p65 3'UTR. Further, IMP3 induced luciferase activity from p65 3'UTR reporter carrying wild type sites but not mutated sites. Exogenous overexpression of p65 from a 3'UTR-less construct rescued the reduced migration of glioma cells in IMP3 silenced condition. In addition, IMP3 silencing inhibited glioma stem-like cell maintenance and migration. The exogenous overexpression of 3'UTR-less p65 significantly alleviated the inhibition of neurosphere formation observed in IMP3 silenced glioma stem-like cells. Further, we show that IMP3 is transcriptionally activated by NF-κB pathway indicating the presence of a positive feedback loop between IMP3 and p65. This study establishes p65 as a novel target of IMP3 in increasing glioma cell migration and underscores the significance of IMP3-p65 feedback loop for therapeutic targeting in GBM.
主题词：Gene Expression Regulation, Neoplastic/genetics*/基因表达调控, 肿瘤/遗传学*
主题词：Transcription Factor RelA/metabolism*/转录因子RelA/代谢*
题名：RNF138-mediated ubiquitination of rpS3 is required for resistance of glioblastoma cells to radiation-induced apoptosis.
作者：Kim, W;Youn, H;Lee, S;Kim, E;Kim, D;Sub Lee, J;Lee, JM;Youn, B
出处：Exp Mol Med.2018,50(1):e434
摘要： An interaction between ribosomal protein S3 (rpS3) and nuclear factor kappa B or macrophage migration inhibitory factor in non-small-cell lung cancer is responsible for radioresistance. However, the role of rpS3 in glioblastoma (GBM) has not been investigated to date. Here we found that in irradiated GBM cells, rpS3 translocated into the nucleus and was subsequently ubiquitinated by ring finger protein 138 (RNF138). Ubiquitin-dependent degradation of rpS3 consequently led to radioresistance in GBM cells. To elucidate the apoptotic role of rpS3, we analyzed the interactome of rpS3 in ΔRNF138 GBM cells. Nuclear rpS3 interacted with DNA damage inducible transcript 3 (DDIT3), leading to DDIT3-induced apoptosis in irradiated ΔRNF138 GBM cells. These results were confirmed using in vivo orthotopic xenograft models and GBM patient tissues. This study aims to clarify the role of RNF138 in GBM cells and demonstrate that rpS3 may be a promising substrate of RNF138 for the induction of GBM radioresistance, indicating RNF138 as a potential target for GBM therapy.
题名：KPNB1 inhibition disrupts proteostasis and triggers unfolded protein response-mediated apoptosis in glioblastoma cells.
作者：Zhu, ZC;Liu, JW;Li, K;Zheng, J;Xiong, ZQ
摘要： The nuclear import receptor karyopherin β1 (KPNB1) is involved in the nuclear import of most proteins and in the regulation of multiple mitotic events. Upregulation of KPNB1 has been observed in cancers including glioblastoma. Depletion of KPNB1 induces mitotic arrest and apoptosis in cancer cells, but the underlying mechanism is not clearly elucidated. Here, we found that downregulation and functional inhibition of KPNB1 in glioblastoma cells induced growth arrest and apoptosis without apparent mitotic arrest. KPNB1 inhibition upregulated Puma and Noxa and freed Mcl-1-sequestered Bax and Bak, leading to mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Moreover, combination of Bcl-xL inhibitors and KPNB1 inhibition enhanced apoptosis in glioblastoma cells. KPNB1 inhibition promoted cytosolic retention of its cargo and impaired cellular proteostasis, resulting in elevated polyubiquitination, formation of aggresome-like-induced structure (ALIS), and unfolded protein response (UPR). Ubiquitination elevation and UPR activation in KPNB1-deficient cells were reversed by KPNB1 overexpression or inhibitors of protein synthesis but aggravated by inhibitors of autophagy-lysosome or proteasome, indicating that rebalance of cytosolic/nuclear protein distribution and alleviation of protein overload favor proteostasis and cell survival. Chronic activation of eIF2α/ATF4 cascade of UPR was responsible for the upregulation of Puma and Noxa, apoptosis and ABT-263 sensitivity. Taken together, our findings demonstrate that KPNB1 is required for proteostasis maintenance and its inhibition induces apoptosis in glioblastoma cells through UPR-mediated deregulation of Bcl-2 family members.
主题词：Apoptosis Regulatory Proteins/metabolism/凋亡调节蛋白质类/代谢
主题词：Gene Expression Regulation, Neoplastic/基因表达调控, 肿瘤
主题词：Proto-Oncogene Proteins c-bcl-2/metabolism/原癌基因蛋白质c-bcl-2/代谢
主题词：Unfolded Protein Response*/折叠蛋白反应*
题名：Bone morphogenetic protein signaling mediated by ALK-2 and DLX2 regulates apoptosis in glioma-initiating cells.
作者：Raja, E;Komuro, A;Tanabe, R;Sakai, S;Ino, Y;Saito, N;Todo, T;Morikawa, M;Aburatani, H;Koinuma, D;Iwata, C;Miyazono, K
摘要： Bone morphogenetic protein (BMP) signaling exerts antitumor activities in glioblastoma; however, its precise mechanisms remain to be elucidated. Here, we demonstrated that the BMP type I receptor ALK-2 (encoded by the ACVR1 gene) has crucial roles in apoptosis induction of patient-derived glioma-initiating cells (GICs), TGS-01 and TGS-04. We also characterized a BMP target gene, Distal-less homeobox 2 (DLX2), and found that DLX2 promoted apoptosis and neural differentiation of GICs. The tumor-suppressive effects of ALK-2 and DLX2 were further confirmed in a mouse orthotopic transplantation model. Interestingly, valproic acid (VPA), an anti-epileptic compound, induced BMP2, BMP4, ACVR1 and DLX2 mRNA expression with a concomitant increase in phosphorylation of Smad1/5. Consistently, we showed that treatment with VPA induced apoptosis of GICs, whereas silencing of ALK-2 or DLX2 expression partially suppressed it. Our study thus reveals BMP-mediated inhibitory mechanisms for glioblastoma, which explains, at least in part, the therapeutic effects of VPA.
主题词：Activin Receptors, Type I/metabolism*/激活素受体,Ⅰ型/代谢*
主题词：Bone Morphogenetic Proteins/metabolism*/骨形态发生蛋白质类/代谢*
主题词：Neoplastic Stem Cells/metabolism*/肿瘤干细胞/代谢*
题名：Proliferative and Invasive Effects of Progesterone-Induced Blocking Factor in Human Glioblastoma Cells.
作者：Gutiérrez-Rodríguez, A;Hansberg-Pastor, V;Camacho-Arroyo, I
出处：Biomed Res Int.2017,2017:1295087
摘要： Progesterone-induced blocking factor (PIBF) is a progesterone (P4) regulated protein expressed in different types of high proliferative cells including astrocytomas, the most frequent and aggressive brain tumors. It has been shown that PIBF increases the number of human astrocytoma cells. In this work, we evaluated PIBF regulation by P4 and the effects of PIBF on proliferation, migration, and invasion of U87 and U251 cells, both derived from human glioblastomas. PIBF mRNA expression was upregulated by P4 (10?nM) from 12 to 24?h. Glioblastoma cells expressed two PIBF isoforms, 90 and 57?kDa. The content of the shorter isoform was increased by P4 at 24?h, while progesterone receptor antagonist RU486 (10?μM) blocked this effect. PIBF (100 ng/mL) increased the number of U87 cells on days 4 and 5 of treatment and induced cell proliferation on day 4. Wound-healing assays showed that PIBF increased the migration of U87 (12-48 h) and U251 (24 and 48 h) cells. Transwell invasion assays showed that PIBF augmented the number of invasive cells in both cell lines at 24?h. These data suggest that PIBF promotes proliferation, migration, and invasion of human glioblastoma cells.
主题词：Suppressor Factors, Immunologic/metabolism*/抑制因子, 免疫/代谢*
题名：Cathepsin L is involved in X-ray-induced invasion and migration of human glioma U251 cells.
作者：Xiong, Y;Ji, W;Fei, Y;Zhao, Y;Wang, L;Wang, W;Han, M;Tan, C;Fei, X;Huang, Q;Liang, Z
摘要： An important therapeutic method of glioblastoma, the most common primary brain tumor, is radiotherapy. However, several studies reported recently that radiation could also promote the invasion and migration of malignant tumor. Herein, we have identified that a significant increase of migration and invasiveness of human glioma U251 cells undergoing X-ray was observed compared to controls, accompanied by the increase of cathepsin L (CTSL), which is a lysosomal cysteine protease overexpressed and secreted by tumor cells. To verify if there was a relationship between CTSL and the X-ray-induced glioma invasion, a CTSL specific inhibitor Z-FY-CHO or a short hairpin RNA interference was used to pretreat U251 cells. As a result, the cell invasion and migration was impaired via down-regulation of CTSL. Additionally, a marked reduction of the cell-signaling molecules Rho kinase was also detected compared with controls. We also found that CTSL is involved in EMT progress: both in vitro and in clinical specimens. Overall, our findings show that CTSL is an important protein which mediates cell invasion and migration of human glioma U251 cells induced by X-ray, and the inhibition of CTSL expression might diminish the invasion of U251 cells by reducing the activity of RhoA and CDC42 as well as EMT positive markers.
主题词：Cell Movement/radiation effects*/细胞运动/辐射效应*
主题词：cdc42 GTP-Binding Protein/metabolism/cdc42 GTP结合蛋白质/代谢
主题词：rhoA GTP-Binding Protein/metabolism/ρA GTP结合蛋白质/代谢