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  • 1
    Online Resource
    Online Resource
    Horizontal transfer of miR‐23a from hypoxic tumor cell colonies can induce angiogenesis
    Wiley ; 2018
    In:  Journal of Cellular Physiology Vol. 233, No. 4 ( 2018-04), p. 3498-3514
    Details
    In: Journal of Cellular Physiology, Wiley, Vol. 233, No. 4 ( 2018-04), p. 3498-3514
    Abstract: Neo vessel formation by angiogenesis is an important event during many pathological conditions including cancer, where it is indispensable for tumor growth and survival. Although, various pro‐angiogenic cytokines and soluble factors, secreted by tumor cells, have been reported to promote angiogenesis, recent studies have shown regulatory role of exosomes, secreted by tumor cells in the process of angiogenesis. These exosomes are capable of carrying nucleic acids, proteins, etc., as their cargo. Under the light of these facts and considering the presence of miRNAs, the non‐coding RNAs capable of regulating target gene expression, as one of the major cargos in the exosomes, we investigated, whether exosomes derived from normoxic and hypoxic tumor cell colonies exhibit difference in levels of miR‐23∼27∼24 cluster members and if so, to check the significance of their horizontal transfer on the process of angiogenesis. Results of our study showed that exosomes secreted by hypoxic tumor cell colonies possess significantly higher levels of miR23a and can induce angiogenesis. Further, we have shown that exosomes secreted by cells that ectopically over express miR23a is capable of inducing angiogenesis in different angiogenic model systems such as CAM, in ovo Xenograft and HUVEC models systems. Further, mechanistic analysis revealed that miR23a driven regulation of angiogenesis is brought about by down regulation of SIRT1 in the recipient cells. Collectively, the results presented here suggest that exosomal transfer of miR23a from tumor cell colonies can induce the process of angiogenesis by targeting SIRT1 in the recipient endothelial cells.
    Type of Medium: Online Resource
    ISSN: 0021-9541 , 1097-4652
    URL: Issue
    URL: Article
    DOI: 10.1002/jcp.v233.4
    DOI: 10.1002/jcp.26202
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1478143-8
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    YB1 modulates the DNA damage response in medulloblastoma
    Springer Science and Business Media LLC ; 2023
    In:  Scientific Reports Vol. 13, No. 1 ( 2023-05-19)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2023-05-19)
    Abstract: Y-box binding protein 1 ( YBX1 or YB1) is a therapeutically relevant oncoprotein capable of RNA and DNA binding and mediating protein–protein interactions that drive proliferation, stemness, and resistance to platinum-based therapies. Given our previously published findings, the potential for YB1-driven cisplatin resistance in medulloblastoma (MB), and the limited studies exploring YB1-DNA repair protein interactions, we chose to investigate the role of YB1 in mediating radiation resistance in MB. MB, the most common pediatric malignant brain tumor, is treated with surgical resection, cranio-spinal radiation, and platinum-based chemotherapy, and could potentially benefit from YB1 inhibition. The role of YB1 in the response of MB to ionizing radiation (IR) has not yet been studied but remains relevant for determining potential anti-tumor synergy of YB1 inhibition with standard radiation therapy. We have previously shown that YB1 drives proliferation of cerebellar granular neural precursor cells (CGNPs) and murine Sonic Hedgehog (SHH) group MB cells. While others have demonstrated a link between YB1 and homologous recombination protein binding, functional and therapeutic implications remain unclear, particularly following IR-induced damage. Here we show that depleting YB1 in both SHH and Group 3 MB results not only in reduced proliferation but also synergizes with radiation due to differential response dynamics. YB1 silencing through shRNA followed by IR drives a predominantly NHEJ-dependent repair mechanism, leading to faster γH2AX resolution, premature cell cycle re-entry, checkpoint bypass, reduced proliferation, and increased senescence. These findings show that depleting YB1 in combination with radiation sensitizes SHH and Group 3 MB cells to radiation.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-023-35220-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2615211-3
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  • 3
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    Online Resource
    Regulation of poly ADP-ribosylation of VEGF by an interplay between PARP-16 and TNKS-2
    Springer Science and Business Media LLC ; 2020
    In:  Molecular and Cellular Biochemistry Vol. 471, No. 1-2 ( 2020-08), p. 15-27
    Details
    In: Molecular and Cellular Biochemistry, Springer Science and Business Media LLC, Vol. 471, No. 1-2 ( 2020-08), p. 15-27
    Type of Medium: Online Resource
    ISSN: 0300-8177 , 1573-4919
    URL: Article
    DOI: 10.1007/s11010-020-03746-2
    RVK:
    WD 5725
    RVK:
    WD 5275
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2003615-2
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  • 4
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    CSIG-34. LIN28B-LET-7-PBK PATHWAY IS AN IMPORTANT REGULATOR OF GROUP 3 MEDULLOBLASTOMA PROLIFERATION
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii46-vii46
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii46-vii46
    Abstract: Children with Group 3 medulloblastoma (MB) have a very poor long-term outcome and many do not survive beyond 5 years. Several drivers for Group 3 MB have been identified but none have resulted in targeted therapy to date. LIN28B is a stem cell factor upregulated in Group 3 MB and is associated with worse survival. Here we investigate the role of the LIN28B pathway in Group 3 MB development. Pharmacologic inhibition of the LIN28B pathway is feasible and may provide a unique opportunity to target this tumor. Using LIN28B knockdown and overexpression in Group 3 MB cells we test LIN28B’s effect on proliferation, self-renewal and metastasis. We investigate the effect of LIN28B knockdown on survival as well as proliferation and apoptosis markers using orthotopic xenografts in vivo. We also investigate the role of let-7 and its downstream target PBK on Group 3 MB proliferation. Finally, we use a LIN28 inhibitor 1632 and a PBK inhibitor HITOPK032 to treat Group 3 MB cell lines and then assess their impact on proliferation and apoptosis. We find that down-regulation of LIN28B or PBK using shRNA results in significant reduction in cell proliferation. In contrast overexpression of LIN28B increases Group 3 cell proliferation and tumor sphere formation. LIN28B knockdown also significantly (p & lt; 0.01) increases survival in mice with orthotopic Group 3 tumors. The LIN28 inhibitor 1632 also leads to significant reduction in MB growth through decreased cell cycle entry and increased apoptosis. In addition, HITOPK032 also demonstrates significant reduction in Group 3 MB cell proliferation at low micromolar concentration. We also demonstrate that HITOPK032 in combination with CDK 4/6 inhibition can additively inhibit proliferation of Group 3 MB cells. Our study establishes a critical role for the LIN28B-let-7-PBK pathway in Group3 MB and provides encouraging preliminary preclinical results for drugs that target this pathway.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.183
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 5
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    Online Resource
    CSIG-32. microRNA 211, A POTENTIAL THERAPEUTIC AGENT FOR GROUP 3 MEDULLOBLASTOMA IN CHILDREN
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi40-vi40
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi40-vi40
    Abstract: Medulloblastoma (MB) is a central nervous system (CNS) tumor that predominantly affects children and requires aggressive therapy. Affected individuals often suffer from treatment-related side-effects and treatment-resistant recurrences associated with high morbidity and mortality rates. There are four major molecular MB subgroups: wingless-type (Wnt)-activated, sonic hedgehog (Shh)-activated, group III (G3), and group IV (G4) MBs. While the molecular pathology of Wnt- and Shh-activated MBs is well defined, rather less is known about G3 and G4 MB's genetic basis, so their molecular diagnosis and consequent management have remained challenging. MBs develop through various genetic, epigenetic, and non-coding (nc)RNA-related mechanisms, with the role of ncRNAs, particularly microRNAs, in MB tumor growth is poorly defined. We addressed this knowledge gap with an exemplar of microRNA-211 (miR-211) implicated in G3 MB tumor growth. Compared to other MB subgroups, miR-211 is significantly downregulated in G3 MB cell lines, underscoring its important role as a therapeutic agent and a biomarker. miR-211 overexpression in G3 MB cells significantly reduced cell proliferation, invasion, 3D colony formation, and induced apoptosis. Oxygen consumption rates are higher in engineered cells, and we postulate that miR-211 is involved in G3 MB mitochondrial energy metabolism. miR-211 expressed G3 MB cells injected into mouse cerebella produce smaller tumors than those derived from parental cells. We applied single-cell RNA sequencing and immune histochemical assays to characterize tumors to identify the molecular mechanism of miR-211- driven tumor reduction in G3 MBs, and our preliminary results support that miR-211 is an attractive therapeutic agent to treat this aggressive MB subtype.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.158
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 6
    Online Resource
    Online Resource
    ER stress mediated regulation of miR23a confer Hela cells better adaptability to utilize glycolytic pathway
    Wiley ; 2018
    In:  Journal of Cellular Biochemistry Vol. 119, No. 6 ( 2018-06), p. 4907-4917
    Details
    In: Journal of Cellular Biochemistry, Wiley, Vol. 119, No. 6 ( 2018-06), p. 4907-4917
    Abstract: Cancer cells exhibit increased dependency on aerobic glycolysis, a phenomenon referred as the “Warburg effect” and therefore, blocking glycolysis by using non‐metabolizable analogues of glucose, like 2‐Deoxy glucose (2‐DG), has been proposed to be of huge therapeutic importance. One of the major drawbacks of using 2‐DG as a chemotherapeutic agent is that it can induce ER stress. ER stress is a hall mark in many solid tumors and the unfolded protein response (UPR) associated with it initiates many survival mechanisms in cancer cells. In the present study, we report a novel survival mechanism associated with ER stress, by which the cancer cells become more adapted to aerobic glycolysis. When ER stress was induced in Hela cells by treating them with 2‐DG or Thapsigargin (TG) the expression and activity of LDH was significantly up regulated, conferring the cells a greater glycolytic potential. A simultaneous decrease was observed in the expression of miR‐23a, which was predicted in silico to have target site on the 3′UTR of LDH A and B mRNAs. miRNA over expression studies and mRNA degradation assays suggest that miR‐23a could target LDH A and LDH B mRNAs. Further on the basis of our results and previous scientific reports, we propose that “c‐Myc,” which is over expressed during ER stress, repress the expression of miR‐23a, which in turn regulates the expression of its target genes viz., LDH A and LDH B, thereby making the cells more competent to survive in tumor microenvironment, which requires efficient use of aerobic glycolysis.
    Type of Medium: Online Resource
    ISSN: 0730-2312 , 1097-4644
    URL: Issue
    URL: Article
    DOI: 10.1002/jcb.v119.6
    DOI: 10.1002/jcb.26718
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1479976-5
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  • 7
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    Online Resource
    2-Deoxy Glucose Modulates Expression and Biological Activity of VEGF in a SIRT-1 Dependent Mechanism : R EGULATION OF VEGF BY 2-DG
    Wiley ; 2017
    In:  Journal of Cellular Biochemistry Vol. 118, No. 2 ( 2017-02), p. 252-262
    Details
    In: Journal of Cellular Biochemistry, Wiley, Vol. 118, No. 2 ( 2017-02), p. 252-262
    Type of Medium: Online Resource
    ISSN: 0730-2312
    URL: Issue
    URL: Article
    DOI: 10.1002/jcb.v118.2
    DOI: 10.1002/jcb.25629
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 1479976-5
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  • 8
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    TMIC-81. INCREASED LEVEL OF IGFBP2 PROMOTES TUMOR METASTASIS IN SHH MEDULLOBLASTOMA
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii289-vii289
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii289-vii289
    Abstract: Medulloblastoma (MB) is the most common pediatric brain malignancy. MB comprises 5 major subgroups known as WNT, SHH p53wt, SHH p53mut, Group 3 and Group 4. Among the four MB subgroups SHH group is the most dominant molecular subgroup in infants and adults. These tumors are proposed to arise from cerebellar granule neuron precursors (CGNPs), whose developmental expansion requires SHH signaling from the neighboring Purkinje neurons. Previous reports suggest that SHH group features a unique tumor microenvironment compared with other MB groups. To better understand how SHH MB cells interact with Tumor Microenvironment, we performed cytokine array analysis of culture media from SHH group Patient Tumor cells, spontaneous SHH MB mouse tumor cells and SHH MB cell lines. Further, confirmed these results using ELISA, Western blot, and immunofluorescence from human SHH MB cell lines, Smo/A1 mouse tumor primary cells and PZp53Med cell lines. In continuation to the observation of IGFBP2 expression in various cell types in single cell analysis, we analyzed the presence of IGFBP2 in astrocytes using Smo/A1 mouse tumor Immunohistochemistry. Our data showed increased levels of IGFBP2 produced by SHH MB cell lines compared to others. We analyzed the role of IGFBP2 in SHH MB tumor growth and metastasis. IGFBP2 knock-down stable cell lines showed phenotypic changes including reduced cell proliferation, cell migration and EMT. Further western blot analysis of IGFBP2 KD cells showed reduced expression of EMT markers also reduced the activation of STAT3. Our preliminary in vitro data suggest IGFBP2 exerts it metastasis-promoting role in SHH MB by regulating the expression of EMT marker proteins and matrix remodeling proteins. Further functional studies suggest that in SHH MB, IGFBP2 may regulate a STAT3-mediated EMT program to metastasize. These findings provide a strong rationale for further pursuing how IGFBP2 promotes medulloblastoma tumor cell growth and migration in vivo.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.1124
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 9
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    Online Resource
    The long noncoding RNA lnc-HLX-2-7 is oncogenic in Group 3 medulloblastomas
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. 4 ( 2021-04-12), p. 572-585
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. 4 ( 2021-04-12), p. 572-585
    Abstract: Medulloblastoma (MB) is an aggressive brain tumor that predominantly affects children. Recent high-throughput sequencing studies suggest that the noncoding RNA genome, in particular long noncoding RNAs (lncRNAs), contributes to MB subgrouping. Here we report the identification of a novel lncRNA, lnc-HLX-2-7, as a potential molecular marker and therapeutic target in Group 3 MBs. Methods Publicly available RNA sequencing (RNA-seq) data from 175 MB patients were interrogated to identify lncRNAs that differentiate between MB subgroups. After characterizing a subset of differentially expressed lncRNAs in vitro and in vivo, lnc-HLX-2-7 was deleted by CRISPR/Cas9 in the MB cell line. Intracranial injected tumors were further characterized by bulk and single-cell RNA-seq. Results Lnc-HLX-2-7 is highly upregulated in Group 3 MB cell lines, patient-derived xenografts, and primary MBs compared with other MB subgroups as assessed by quantitative real-time, RNA-seq, and RNA fluorescence in situ hybridization. Depletion of lnc-HLX-2-7 significantly reduced cell proliferation and 3D colony formation and induced apoptosis. Lnc-HLX-2-7–deleted cells injected into mouse cerebellums produced smaller tumors than those derived from parental cells. Pathway analysis revealed that lnc-HLX-2-7 modulated oxidative phosphorylation, mitochondrial dysfunction, and sirtuin signaling pathways. The MYC oncogene regulated lnc-HLX-2-7, and the small-molecule bromodomain and extraterminal domain family‒bromodomain 4 inhibitor Jun Qi 1 (JQ1) reduced lnc-HLX-2-7 expression. Conclusions Lnc-HLX-2-7 is oncogenic in MB and represents a promising novel molecular marker and a potential therapeutic target in Group 3 MBs.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa235
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 10
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    Online Resource
    BIOL-08. IGFBP2 PROMOTES TUMOR METASTASIS IN SHH MEDULLOBLASTOMA
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_1 ( 2021-06-01), p. i4-i4
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_1 ( 2021-06-01), p. i4-i4
    Abstract: Medulloblastoma (MB) is the most common pediatric brain malignancy. MB comprises 5 major subgroups known as WNT, SHH p53wt, SHH p53mut, Group 3 and Group 4. Among the four MB subgroups SHH group is the most dominant molecular subgroup in infants and adults. These tumors are proposed to arise from cerebellar granule neuron precursors (CGNPs), whose developmental expansion requires SHH signaling from the neighboring Purkinje neurons. Previous reports suggest that SHH group features a unique tumor microenvironment compared with other MB groups. Recently, we performed cytokine array analysis of culture media from different MB cell lines. Interestingly, our data showed increased levels of IGFBP2 produced by SHH MB cell lines compared to others. We confirmed these results using ELISA and Western blotting from 3 human SHH MB cell lines, and Smo/A1 mouse tumor cells. IGFBP2 is a member of IGFBP super family of proteins; it plays important roles in tumor cell proliferation, metastasis and drug resistance. We analyzed the role of IGFBP2 in SHH group medulloblastoma tumor growth and metastasis. IGFBP2 knock-down stable cell lines showed phenotypic changes including reduced cell proliferation, cell migration and colony size. Our preliminary in vitro data suggest IGFBP2 exerts it metastasis-promoting role in SHH MB by regulating the expression of EMT marker proteins such as N cadherin, slug etc. and matrix remodeling proteins like MMPs and TIMPs. We are currently performing functional studies in organotypic tumor slice cultures to validate these findings and establish IGFBP2 as a novel regulator of aggressive tumor growth and spread in SHH MB.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab090.015
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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