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Liang M.-L.,National Yang Ming University | Liang M.-L.,Taipei Veterans General Hospital | Hsieh T.-H.,Taipei Medical University | Ng K.-H.,National Yang Ming University | And 23 more authors.
Oncotarget | Year: 2016

Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors affecting children, and outcomes have remained dismal, even with access to new multimodal therapies. In this study, we compared the miRNomes and transcriptomes of pediatric low- (pLGGs) and high-grade gliomas (pHGGs) using small RNA sequencing (smRNA-Seq) and gene expression microarray, respectively. Through integrated bioinformatics analyses and experimental validation, we identified miR-137 and miR-6500-3p as significantly downregulated in pHGGs. miR-137 or miR-6500-3p overexpression reduced cell proliferation in two pHGG cell lines, SF188 and UW479. CENPE, KIF14 and NCAPG levels were significantly higher in pHGGs than pLGGs, and were direct targets of miR-137 or miR-6500-3p. Furthermore, knockdown of CENPE, KIF14 or NCAPG combined with temozolomide treatment resulted in a combined suppressive effect on pHGG cell proliferation. In summary, our results identify novel mRNA/miRNA interactions that contribute to pediatric glioma malignancy and represent potential targets for the development of new therapeutic strategies.

Ke C.-C.,Anticancer, Inc. | Ke C.-C.,National Yang Ming University | Liu R.-S.,National Yang Ming University | Liu R.-S.,Taipei Veterans General Hospital | And 8 more authors.
PLoS ONE | Year: 2013

Mesenchymal stromal cells (MSCs) are multipotent adult stem cells which are recruited to the tumor microenvironment (TME) and influence tumor progression through multiple mechanisms. In this study, we examined the effects of MSCs on the tunmorigenic capacity of 4T1 murine mammary cancer cells. It was found that MSC-conditioned medium increased the proliferation, migration, and efficiency of mammosphere formation of 4T1 cells in vitro. When co-injected with MSCs into the mouse mammary fat pad, 4T1 cells showed enhanced tumor growth and generated increased spontaneous lung metastasis. Using in vivo fluorescence color-coded imaging, the interaction between GFP-expressing MSCs and RFP-expressing 4T1 cells was monitored. As few as five 4T1 cells could give rise to tumor formation when co-injected with MSCs into the mouse mammary fat pad, but no tumor was formed when five or ten 4T1 cells were implanted alone. The elevation of tumorigenic potential was further supported by gene expression analysis, which showed that when 4T1 cells were in contact with MSCs, several oncogenes, cancer markers, and tumor promoters were upregulated. Moreover, in vivo longitudinal fluorescence imaging of tumorigenesis revealed that MSCs created a vascularized environment which enhances the ability of 4T1 cells to colonize and proliferate. In conclusion, this study demonstrates that the promotion of mammary cancer progression by MSCs was achieved through the generation of a cancer-enhancing microenvironment to increase tumorigenic potential. These findings also suggest the potential risk of enhancing tumor progression in clinical cell therapy using MSCs. Attention has to be paid to patients with high risk of breast cancer when considering cell therapy with MSCs. © 2013 Ke et al.

Chan P.-C.,National Yang Ming University | Wu C.-Y.,National Yang Ming University | Chang W.-T.,National Yang Ming University | Lin C.-Y.,National Yang Ming University | And 7 more authors.
Nuclear Medicine and Biology | Year: 2013

Objective: Previous studies have shown that the accumulation level of FMAU in tumor is proportional to its proliferation rate. This study demonstrated that 2'-deoxy-2'-[18F]fluoro-β-d-arabinofuranosyluracil ([18F]FMAU) is a promising PET probe for noninvasively monitoring the therapeutic efficacy of 6% PEGylated liposomal vinorelbine (lipo-VNB) in a subcutaneous murine NG4TL4 sarcoma mouse model. Methods: Female syngenic FVB/N mice were inoculated with NG4TL4 cells in the right flank. After tumor size reached 150±50mm3 (day 0), lipo-VNB (5mg/kg) was intravenously administered on days 0, 3 and 6. To monitor the therapeutic efficacy of lipo-VNB, [18F]FMAU PET was employed to evaluate the proliferation rate of tumor, and it was compared with that observed from [18F]FDG/[18F]fluoroacetate PET. The expression of proliferating cell nuclear antigen (PCNA) in tumor during treatment was determined by semiquantitative analysis of immunohistochemical staining. Results: A significant inhibition (p<0.001) in tumor growth was observed on day 3 after a single dose treatment. The tumor-to-muscle ratio (T/M) derived from [18F]FMAU-PET images of lipo-VNB-treated group declined from 2.33±0.16 to 1.26±0.03 after three doses of treatment, while that of the control remained steady. The retarded proliferation rate of lipo-VNB-treated sarcoma was confirmed by PCNA immunohistochemistry staining. However, both [18F]FDG and [18F]fluoroacetate microPET imaging did not show significant difference in T/M between the therapeutic and the control groups throughout the entire experimental period. Conclusion: Lipo-VNB can effectively impede the growth of NG4TL4 sarcoma. [18F]FMAU PET is an appropriate modality for early monitoring of the tumor response during the treatment course of lipo-VNB. © 2013 Elsevier Inc.

Hsieh T.-H.,National Yang Ming University | Chien C.-L.,Cheng Hsin General Hospital | Chien C.-L.,Taipei Veterans General Hospital | Lee Y.-H.,National Yang Ming University | And 21 more authors.
Carcinogenesis | Year: 2014

Embryonal tumors of the central nervous system represent a highly malignant tumor group of medulloblastoma (MB), atypical teratoid/rhabdoid tumor (AT/RT) and primitive neuroectodermal tumor that frequently afflict children. AT/RT is often misdiagnosed as MB/primitive neuroectodermal tumor but with higher recurrence and lower survival rates. Pathogenesis of AT/RT is largely unknown. In this study, we report both the miRNome and transcriptome traits in AT/RT and MB by using small RNA sequencing and gene expression microarray analyses. Our findings demonstrate that the miR-221/222-encoded micro RNAs are abundantly expressed in AT/RT but not in MB, which contribute substantially to the malignancy of embryonal tumors. miR-221/222 targeted SUN2, a newly discovered tumor suppressor, directly to increase cell proliferation and tumor malignancy in vitro and in vivo. Immunohistochemistry against SUN2 in a tissue microarray of 33 AT/RT and 154 MB tumor specimens also detected less SUN2 protein in AT/RT. Collectively, this study uncovers a novel tumor suppressor, SUN2, plays a critical role in miR-221/222-mediated AT/RT malignancy as well as supports miR-221/222 and SUN2 represent new promising targets for more active therapies in AT/RT. In addition, our miRNome and transcriptome data also provide a roadmap for further embryonal tumor research. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Wu C.-Y.,National Yang Ming University | Chan P.-C.,National Yang Ming University | Chou L.-S.,National Yang Ming University | Chang C.-W.,Taipei Veterans General Hospital | And 8 more authors.
Molecular Imaging and Biology | Year: 2014

Purpose: This study aims to demonstrate that pulsed high-intensity focused ultrasound (pulsed-HIFU) may enhance the fructose-conjugated 4-borono-L-phenylalanine (BPA-Fr) accumulation in tumor lesion using 18F-FBPA-Fr microPET scans. Procedures: To the mice bearing orthotopic SASC03 human tongue squamous carcinoma xenograft, a 2-min pulsed-HIFU was applied to tumor. Immediately after pulsed-HIFU treatment, 18F-FBPA-Fr was intravenously injected, and biological characterizations including microPET imaging and biodistribution were conducted. Results: Both biodistribution studies and microPET imaging performed after intravenous injection of 18F-FBPA-Fr revealed higher tumor uptake in HIFU-treated mice than that of the control. CD31 and Ki-67 histochemical staining of tumor sections and H&E staining of nearby normal tissues revealed no significant difference between the pulsed-HIFU-treated mice and the control. Conclusion: This study demonstrated that pulsed-HIFU was beneficial to the accumulation of boron drug in the head and neck tumor lesion and may enhance the therapeutic efficacy of clinical BNCT. © 2013 World Molecular Imaging Society.

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