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  • American Association for Cancer Research (AACR)  (4)
  • 1
    Online Resource
    Online Resource
    Abstract 5726: A novel tumor-promoting role for miR-4516 in glioblastoma
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5726-5726
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5726-5726
    Abstract: Background: Glioblastomas are the most aggressive high-grade brain tumors, which are often life-threatening due to their location and rapid growth. Although survival rates differ depending on a variety of genetic and environmental factors, the average survival rate for a glioblastoma (GBM) patient is less than 15 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. Here we demonstrate a novel role for miR-4516 in promoting growth and migration of GBM and establish the molecular mechanisms mediating these functions. Methods: Formalin-fixed, paraffin-embedded tissue blocks (n=268) were collected for all patients and total RNA was isolated. miRNAs were analyzed simultaneously using the nCounter human miRNA v2 assay (NanoString Technologies; Seattle,WA). Functional characterization studies were conducted in vitro and in vivo. The effect of miR-4516 on GBM cell growth and motility were evaluated by cell proliferation assay, migration and invasion assay, and Annexin-V assay. Realtime PCR, immunoblotting, and 3’ untranslated region luciferase assays were used to analyze miR-4516 targets and signaling pathways. Intracranial injection will be performed to investigate the role of miR-4516 in tumor growth in vivo. Results: Univariate analysis showed that miR-4516 expression in GBM patients was inversely correlated with overall survival (FDR=0.002, p=1.02E-05). Knockdown of miR-4516 blocked tumor growth and induced cell apoptosis. Tumor cell growth, migration and invasion were induced in both transient miR-4516 overexpressed GBM cells (LN229, LN18, and U87) and stable miR-4516 overexpressed GBM cells (U87-EGFRvIII). These miR-4516 tumor-promoting effects were mediated in part via direct targeting PTPN14 and CDKN1A. Investigation of the other miR-4516 targets and in vivo functional study are in process. Conclusion: Taken together, these results suggest that miR-4516 acts as a prognostic biomarker for GBM patients. Funding Information: 1R01CA169368 (PI: Houghton; Co-I:Chakravarti); 1R01CA11522358 Multiple-PI R01: Chakravarti (PI); Xia (PI); 1R01CA1145128 Baroukhim (PI); Chakravarti (Co-PI) 7/2015-6/2020; R01CA108633 (PI:Chakravarti); 1RC2CA148190 (Scientific PI: Chakravarti) Citation Format: Tiantian Cui, Ashley Gray, Ziyan Liu, Marjolein Geurts, Pierre Robe, Joseph McElroy, Erica Hlavin Bell, Arnab Chakravarti. A novel tumor-promoting role for miR-4516 in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5726. doi:10.1158/1538-7445.AM2017-5726
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-5726
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Abstract 1228: Spatial transcriptomics: Data processing revisited to address noise interference
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1228-1228
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1228-1228
    Abstract: Background: Spatially resolved transcriptomics is a novel and already highly recognized method that allows RNA sequencing results to be annotated with local tissue phenotypes. The NanoString GeoMx Digital Spatial Profiling (DSP) Platform allows users to collect RNA expression data from manually selected Regions of Interest (ROIs) on FFPE tissue sections. Here, we extensively evaluated data from the DSP platform with its associated pipeline and identify significant background noise interference issues which compromise data interpretation. Alternative and more suitable workflows are presented for correct data analysis. Methods: In this study, 12 paired tumor samples were collected from six glioma patients who underwent two separate resections. For all patients, the first resection was a low grade astrocytoma (WHO grade II or III) and the second resection was a high grade astrocytoma (WHO grade IV). The DSP platform was used to collect expression data of 1,800 genes from 72 ROIs (i.e. 6 per sample). Biological replicates were made of eight tumors from four patients. Gene expression data was normalized with both standard NanoString methods and several alternative methods (e.g. DeSeq2, gamma fit correction and quantile normalization). Weighted Gene Co-expression Network analysis (WGCNA) was used for biological validation. In addition to our own study, six publicly available NanoString DSP datasets were evaluated. Results: Data distributions of all glioma samples, when exposed to standard data processing, were burdened with significant background noise interference. Notably, differences in noise interference were largest between biologically distinct tumor subgroups (i.e. between first and second glioma resections), which was confirmed in replicate experiments. The noise interference patterns were also present in all six publicly available NanoString DSP datasets which will invariably lead to incorrect interpretation of the underlying biology. To correct for noise interference, we tested several normalization methods. The relatively crude quantile normalization method provided the least biased result and showed the highest concordance with bulk RNA sequencing data. To evaluate the biological validity of our alternative approach, we used T cell counts from our tissue regions as an independent parameter, that were quantified using immune fluorescence. Unsupervised WGCNA identified gene clusters enriched for lymphocyte genes that highly correlated with T cell quantities in ROIs, confirming that alternative normalization can extract a biological signal from the DSP platform. Conclusion: The DSP Platform platform suffers from significant noise interference when using standard analysis tools that obscure its results. Here, we revised the workflow and provide an alternative normalization that adequately addresses noise interference and enables correct interpretation of gene expression data. Citation Format: Levi van Hijfte, Marjolein Geurts, Wies R. Vallentgoed, Paul H. Eilers, Peter A. Sillevis Smitt, Reno Debets, Pim J. French. Spatial transcriptomics: Data processing revisited to address noise interference [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1228.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1228
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    Online Resource
    Online Resource
    Abstract 3423: Elucidation of the role of miR-575 on tumorigenesis in glioblastoma
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3423-3423
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3423-3423
    Abstract: Glioblastoma (GBM) patients currently face poor survival outcomes with an average survival rate less than 15 months, with only 3-5% of patients survive more than 36 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. MiRNAs are small regulatory molecules that play a crucial role in carcinogenesis via repression of oncogenes and tumor-suppressor genes either transcriptionally or post-transcriptionally. Our clinical data (n=268) shows that miR-575 is one of the top miRNAs associated with GBM overall survival (FDR: 0.0036, p-value: 5.77E-05) by univariate analysis (NanoString Technologies; Seattle, WA). This study was designed to investigate the expression and function of miR-575 in GBM. Basal expression of miR-575 was first detected in GBM cell lines prior to functional experimentation. Cell proliferation, colony formation, migration and invasion assays were performed to understand the role of miR-575 in GBM. We found that overexpression of miR-575 significantly increased cell proliferation and cell motility in LN229 and U251 cell lines. Additionally, BLID, a tumor-suppressor gene, was negatively regulated by miR-575 at the transcriptional level by qRT-PCR, which will be further investigated at the post-transcriptional level by western blot. Up-regulation of miR-575 in GBM cell lines suggests that it could be acting as an oncogene by degrading the mRNA of BLID. Luciferase assays also showed negative regulation of BLID expression by miR-575, supporting our hypothesis and findings in other cancers. In conclusion, miR-575 might act as an oncogene in GBM, and BLID may be a putative target gene of miR-575. This mechanism could potentially be useful as a novel prognostic biomarker for GBM patients after further in vitro and in vivo validation. Funding: 1R01CA169368 (PI: Houghton; Co-I:Chakravarti); 1R01CA11522358 Multiple-PI R01: Chakravarti (PI); Xia (PI); 1R01CA1145128 Baroukhim (PI); Chakravarti (Co-PI) 7/2015-6/2020; R01CA108633 (PI:Chakravarti); 1RC2CA148190 (Scientific PI: Chakravarti). Citation Format: Ashley N. Gray, Tiantian Cui, Marjolein Geurts, Pierre Robe, Joseph McElroy, Erica Hlavin Bell, Arnab Chakravarti. Elucidation of the role of miR-575 on tumorigenesis in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3423. doi:10.1158/1538-7445.AM2017-3423
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-3423
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    A Novel miR-146a-POU3F2/SMARCA5 Pathway Regulates Stemness and Therapeutic Response in Glioblastoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Molecular Cancer Research Vol. 19, No. 1 ( 2021-01-01), p. 48-60
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 1 ( 2021-01-01), p. 48-60
    Abstract: Rapid tumor growth, widespread brain-invasion, and therapeutic resistance critically contribute to glioblastoma (GBM) recurrence and dismal patient outcomes. Although GBM stem cells (GSC) are shown to play key roles in these processes, the molecular pathways governing the GSC phenotype (GBM-stemness) remain poorly defined. Here, we show that epigenetic silencing of miR-146a significantly correlated with worse patient outcome and importantly, miR-146a level was significantly lower in recurrent tumors compared with primary ones. Further, miR-146a overexpression significantly inhibited the proliferation and invasion of GBM patient-derived primary cells and increased their response to temozolomide (TMZ), both in vitro and in vivo. Mechanistically, miR-146a directly silenced POU3F2 and SMARCA5, two transcription factors that mutually regulated each other, significantly compromising GBM-stemness and increasing TMZ response. Collectively, our data show that miR-146a–POU3F2/SMARCA5 pathway plays a critical role in suppressing GBM-stemness and increasing TMZ-response, suggesting that POU3F2 and SMARCA5 may serve as novel therapeutic targets in GBM. Implications: miR-146a predicts favorable prognosis and the miR-146a–POU3F2/SMARCA5 pathway is important for the suppression of stemness in GBM.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-20-0353
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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