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1.
Cancer Biol Ther ; 21(1): 43-51, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31526079

RESUMO

Resistance to radiation of cancer cells can be either intrinsic or acquired, leading to treatment failure. In response to DNA damage caused by IR, cancer cells are arrested in cell cycle showing limited proliferation and increased apoptosis. However, radiation-resistant cells are able to overcome the cell cycle block and proceed to proliferation, for which the detailed mechanism remains to be elucidated. In the present study, we showed that radioresistant cells exhibited a recoverable G2/M phase during prolonged cell cycle and manifested lower apoptosis rate and more colony formation. RNA-seq analysis revealed that glutamine synthetase (GS, GLUL) gene was highly expressed in radioresistant cancer cells in comparison with the parental cells, which was in accordance with the G2/M arrest after ionizing radiation. Knocking out of GS in radioresistant cells resulted in a delayed G2/M recovery and lowered proliferation rate after ionizing radiation treatment, which was accompanied with increased inhibitory phosphorylation of CDK1 at Y15 and downregulated Cdc25B, a dual specific phosphatase of CDK1. Moreover, there was an enhanced complex formation of CDK1 and Cyclin B1 when the cells were rescued by re-introducing GS. In vivo, knocking down of GS significantly sensitized CNE2-R xenografts to RT in mice. In this study, we demonstrate a novel role of glutamine synthetase independent of metabolic function in promoting recovery from G2/M arrest caused by ionizing radiation, thus, causing cancer cell resistance to radiotherapy.

3.
Front Cell Dev Biol ; 7: 217, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632968

RESUMO

Background: LncRNAs have been shown to play essential roles in cancer therapeutic response. However, the detailed mechanism of lncRNAs in temozolomide (TMZ) resistance in glioblastoma (GBM) remain to be elucidated. Methods: To elucidate the mechanism maintaining TMZ resistance, we constructed two TMZ-resistant GBM cell lines (T98G-R/U118-R). LncRNAs from four public datasets were reanalyzed, and the candidate lncRNA ADAMTS9-AS2 was evaluated in TMZ-treated GBM patients and in vitro cell lines. Results: Reanalysis of lncRNA expression profiles identified ADAMTS9-AS2 as significantly overexpressed in TMZ-resistant GBM cells and as positively associated with the IC50 of TMZ in GBM cells. Overexpression of ADAMTS9-AS2 was also significantly associated with poor TMZ response and shorter progression-free survival (PFS) in TMZ-treated GBM patients. Knockdown of ADAMTS9-AS2 inhibited proliferation and attenuated the IC50 of TMZ, as well as mitigating invasion and migration in TMZ-resistant GBM cells. Subsequent investigations indicated that reduced expression of ADAMTS9-AS2 significantly suppressed expression of the FUS protein, which was predicted as a direct substrate of ADAMTS9-AS2. Expression trends of FUS were directly correlated with those of ADAMTS9-AS2, as shown by increasing concentrations and prolonged treatment with TMZ. RNA pull-down and RIP assays indicated that both endogenous and exogenous ADAMTS9-AS2 directly binds to the RRM and Znf_RanBP2 domains of FUS, consequently increasing FUS protein expression. Knockdown of ADAMTS9-AS2 reduced the half-life of FUS and decreased FUS protein stability via K48 ubiquitin degradation. Moreover, the E3 ubiquitin-protein ligase MDM2 interacts with and down regulates FUS, while the RRM and Znf_RanBP2 domains of FUS facilitate its binding with MDM2. ADAMTS9-AS2 decreased the interaction between MDM2 and FUS, which mediates FUS K48 ubiquitination. Additionally, knockdown of the ADAMTS9-AS2/FUS signaling axis significantly alleviated progression and metastasis in TMZ-resistant cells. Conclusion: ADAMTS9-AS2 possessed a novel function that promotes TMZ resistance via upregulating the FUS/MDM2 axis in GBM cells. The RRM or Znf_RanBP2 domains of FUS facilitate the combination of ADAMTS9-AS2 and FUS, competitively inhibiting MDM2-dependent FUS K48 ubiquitination and resulting in enhanced FUS stability and TMZ resistance. Our results suggest that the ADAMTS9-AS2/FUS/MDM2 axis may represent a suitable prognostic biomarker and a potential target in TMZ-resistant GBM therapy.

4.
Oncol Rep ; 42(5): 1915-1923, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31485632

RESUMO

As a member of the myotubularin family, myotubularin related protein 3 (MTMR3) has been demonstrated to participate in tumor development, including oral and colon cancer. However, little is known about its functional roles in breast cancer. In the present study, the expression of MTMR3 in breast cancer was evaluated by immunohistochemical staining of tumor tissues from 172 patients. Online data was then used for survival analysis from the PROGgeneV2 database. In vitro, MTMR3 expression was silenced in MDA­MB­231 cells via lentiviral shRNA transduction. MTT, colony formation and flow cytometry assays were performed in the control and MTMR3­silenced cells to evaluate the cell growth, proliferation and cell cycle phase distribution, respectively. Western blotting was used to evaluate the protein expression levels of autophagy­related markers. The results demonstrated that the expression of MTMR3 in breast cancer tissues was significantly increased compared with adjacent normal tissues. MTMR3 was highly expressed in triple­negative breast cancer and was associated with disease recurrence. MTMR3 knockdown in MDA­MB­231 cells inhibited cell proliferation and induced cell cycle arrest and autophagy. The present results indicated that MTMR3 may have an important role in promoting the progression of breast cancer, and its inhibition may serve as a promising therapeutic target for breast cancer treatment.

5.
Virology ; 537: 110-120, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31493649

RESUMO

Influenza A virus infection activates various intracellular signaling pathways, which is mediated by the transcription factors. Here, a quantitative phosphoproteomic analysis of A549 cells after infection with influenza A virus (H5N1) was performed and we found that the transcription factor STAT1 was highly activated. Unexpectedly, upon inhibition of p-STAT1, titers of progeny virus and viral protein synthesis were both reduced. The STAT1 inhibitor Fludarabine (FLUD) inhibited an early progeny step in viral infection and reduced the levels of influenza virus genomic RNA (vRNA). Concomitantly, there was reduced expression of inflammatory cytokines in p-STAT1 inhibited cells. In vivo, suppression of p-STAT1 improved the survival of H5N1 virus-infected mice, reduced the pulmonary inflammatory response and viral burden. Thus, our data demonstrated a critical role for p-STAT1 in influenza virus replication and inflammatory responses. We speculate that STAT1 is an example of a putative antiviral signaling component to support effective replication.

6.
Cancer Med ; 8(14): 6344-6357, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31464090

RESUMO

RIG-I is associated with the occurrence and development of many tumors. However, the role of RIG-I in radiotherapy and chemotherapy in NPC has not been reported to date. In our study, RIG-I expression was significantly reduced in chemoradiotherapy-resistant NPC tissues and cells compared with that in therapy-sensitive tissues and cells. RIG-I expression increased in nonresistant NPC cells, including CNE1 and CNE2, in a dose-dependent manner with increasing chemotherapy drug concentration or radiotherapy dose. RIG-I overexpression promoted radiotherapy and chemotherapy sensitivity in NPC cells, leading to cellular apoptosis and increased expression of the proapoptotic factors BAX and caspase-3. Similarly, RIG-I knockdown in NPC cells promoted chemoradiotherapy resistance and reduced apoptosis. Analysis of microarray data indicated that the expression of IFN/JAK2 and endoplasmic reticulum (ER) stress response markers, such as JAK2, STAT1, IRF9, IFNB1, IRF3, p-IRF3, XBP1, ATF6, IFIT2, and ISG15, was inhibited in chemoradiotherapy-resistant cells compared with that in sensitive cells. Conversely, activation of IFN/JAK2 and ER stress response pathways in NPC cells reduced paclitaxel resistance and increased apoptosis. RIG-I promotes IFN/JAK2 and ER stress response-mediated apoptosis to inhibit chemoradiation resistance in nasopharyngeal carcinoma.

7.
Cell Rep ; 28(5): 1136-1143.e4, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31365859

RESUMO

Radiation resistance is a critical problem in radiotherapy for cancer. Radiation kills tumor cells mainly through causing DNA damage. Thus, efficiency of DNA damage repair is one of the most important factors that limits radiotherapy efficacy. Glutamine physiologically functions to generate protein and nucleotides. Here, we study the impact of glutamine metabolism on cancer therapeutic responses, in particular under irradiation-induced stress. We show that radiation-resistant cells possessed low glycolysis, mitochondrial respiration, and TCA cycle but high glutamine anabolism. Transcriptome analyses revealed that glutamine synthetase (GS), an enzyme catalyzing glutamate and ammonia to glutamine, was responsible for the metabolic alteration. ChIP and luciferase reporter assays revealed that GS could be transcriptionally regulated by STAT5. Knockdown of GS delayed DNA repair, weakened nucleotide metabolism, and enhanced radiosensitivity both in vitro and in vivo. Our data show that GS links glutamine metabolism to radiotherapy response through fueling nucleotide synthesis and accelerating DNA repair.

8.
Front Oncol ; 9: 552, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293979

RESUMO

Background: Conventional methods for predicting treatment response to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) are limited. Methods: This study retrospectively recruited 134 LARC patients who underwent standard nCRT followed by total mesorectal excision surgery in our institution. Based on pre-operative axial T2-weighted images, machine learning radiomics was performed. A receiver operating characteristic (ROC) curve was performed to test the efficiencies of the predictive model. Results: Among the 134 patients, 32 (23.9%) achieved pathological complete response (pCR), 69 (51.5%) achieved a good response, and 91 (67.9%) achieved down-staging. For prediction of pCR, good-response, and down-staging, the predictive model demonstrated high classification efficiencies, with an AUC value of 0.91 (95% CI: 0.83-0.98), 0.90 (95% CI: 0.83-0.97), and 0.93 (95% CI: 0.87-0.98), respectively. Conclusion: Our machine learning radiomics model showed promise for predicting response to nCRT in patients with LARC. Our predictive model based on the commonly used T2-weighted images on pelvic Magnetic Resonance Imaging (MRI) scans has the potential to be adapted in clinical practice. Novelty and Impact Statements: Methods for predicting the response of the locally advanced rectal cancer (LARC, T3-4, or N+) to neoadjuvant chemoradiotherapy (nCRT) is lacking. In the present study, we developed a new machine learning radiomics method based on T2-weighted images. As a non-invasive tool, this method facilitates prediction performance effectively. It achieves a satisfactory overall diagnostic accuracy for predicting of pCR, good response, and down-staging show an AUC of 0.908, 0.902, and 0.930 in LARC patients, respectively.

9.
J Cell Mol Med ; 23(9): 6060-6071, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31211507

RESUMO

The integrated stress response (ISR) is critical for cancer cell survival during stress stimuli and has been implicated in the resistance to cancer therapeutics, in which the mechanism, however, is poorly understood. Here, we showed that paclitaxel, the major chemotherapy drug for breast cancer, induced ISR and phosphorylated ser51 residue of EIF2S1 by EIF2AK3 and EIF2AK4. When exposed to paclitaxel, cancer cells activated the EIF2AK3/EIF2AK4-pEIF2S1-ATF4 axis and maintained redox homoeostasis by inducing expression of the major antioxidant enzymes HMOX1, SHMT2 and SLC7A11. Paclitaxel-mediated cell death was significantly increased following loss of ISR or ATF4 expression. This sensitizing effect could be partially rescued by Trolox, a ROS scavenger. We demonstrated that the alternative initiation factor EIF2A was essential for cancer cell survival after paclitaxel-mediated ISR both in vitro and in vivo. Moreover, patients with breast cancer exhibited higher ISR after chemotherapy, and the elevated mRNA levels of HMOX1, SHMT2 and EIF2A were correlated with poor prognosis. Collectively, our findings reveal a novel mechanism for paclitaxel resistance and suggest that targeting EIF2A combined with ISR agonist may be a potential treatment regimen to overcome drug resistance for breast cancer.

10.
Cell Death Dis ; 10(6): 405, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138777

RESUMO

Hepatitis B virus-encoded X protein (HBx) acts as a tumor promoter during hepatocellular carcinoma (HCC) development, probably by regulating the expression of host proteins through protein-protein interaction. A proteomics approach was used to identify HBx-interacting proteins involved in HBx-induced hepatocarcinogenesis. We validated the proteomics findings by co-immunoprecipitation and confocal microscopy. We performed cell proliferation, migration assays and cell cycle analyses in HCC cells. Finally, we confirmed the clinical significance of our findings in samples from patients. We found that cortactin (CTTN) is a novel HBx-interacting protein, and HBx regulates the expression of CTTN in the HCC cell lines MHCC-LM3 and HepG2. Mechanistically, by upregulating the expression of cAMP response element-binding protein (CREB1) and its downstream targets, such as cyclin D1 and MMP-9, the effects of the HBx-CTTN interaction on the enhancement of cellular proliferation and migration were maintained by inhibiting cell cycle arrest. In addition, we demonstrated that the levels of CTTN and CREB1 were closely correlated in clinical samples from HBV-infected patients with HCC. Overall, our data suggests that HBx contributes to cell migration and proliferation of HCC cells by interacting with CTTN and regulating the expression of CTTN and CREB1. Therefore, the HBx/CTTN/CREB1 axis is a potential novel therapeutic target in HCC.

11.
Front Oncol ; 9: 369, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31143705

RESUMO

Intrahepatic cholangiocarcinoma (ICC) ranks as the second most malignant type of primary liver cancer with a high degree of incidence and a very poor prognosis. Fat mass and obesity-associated protein (FTO) functions as an eraser of the RNA m6A modification, but its roles in ICC tumorigenesis and development remain unknown. We showed here that the protein level of FTO was downregulated in clinical ICC samples and cell lines and that FTO expression was inversely correlated with the expression of CA19-9 and micro-vessel density (MVD). A Kaplan-Meier survival analysis showed that a low expression of FTO predicted poor prognosis in ICC. in vitro, decreased endogenous expression of FTO obviously reduced apoptosis of ICC cells. Moreover, FTO suppressed the anchorage-independent growth and mobility of ICC cells. Through mining the database, FTO was found to regulate the integrin signaling pathway, inflammation signaling pathway, epidermal growth factor receptor (EGFR) signaling pathway, angiogenesis, and the pyrimidine metabolism pathway. RNA decay assay showed that oncogene TEAD2 mRNA stability was impaired by FTO. In addition, the overexpression of FTO suppressed tumor growth in vivo. In conclusion, our study demonstrated the critical roles of FTO in ICC.

12.
Redox Biol ; 24: 101189, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30986607

RESUMO

Radiotherapy (RT) is the major modality for control of glioblastoma multiforme (GBM), the most aggressive brain tumor in adults with poor prognosis and low patient survival rate. To improve the RT efficacy on GBM, the mechanism causing tumor adaptive radioresistance which leads to the failure of tumor control and lethal progression needs to be further elucidated. Here, we conducted a comparative analysis of RT-treated recurrent tumors versus primary counterparts in GBM patients, RT-treated orthotopic GBM tumors xenografts versus untreated tumors and radioresistant GBM cells versus wild type cells. The results reveal that activation of STAT3, a well-defined redox-sensitive transcriptional factor, is causally linked with GBM adaptive radioresistance. Database analysis also agrees with the worse prognosis in GBM patients due to the STAT3 expression-associated low RT responsiveness. However, although the radioresistant GBM cells can be resensitized by inhibition of STAT3, a fraction of radioresistant cells can still survive the RT combined with STAT3 inhibition or CRISPR/Cas9-mediated STAT3 knockout. A complementally enhanced activation of ERK1/2 by STAT3 inhibition is identified responsible for the survival of the remaining resistant tumor cells. Dual inhibition of ERK1/2 and STAT3 remarkably eliminates resistant GBM cells and inhibits tumor regrowth. These findings demonstrate a previously unknown feature ofSTAT3-mediated ERK1/2 regulation and an effective combination of two targets in resensitizing GBM to RT.

13.
J Exp Clin Cancer Res ; 38(1): 171, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31014370

RESUMO

Cancer-associated fibroblasts (CAFs) plays an essential role in cancer cell growth, metabolism and immunoreaction. Autophagy is an intracellular self-degradative process that balances cell energy source and regulates tissue homeostasis. Targeting autophagy has gained interest with multiple preclinical and clinical trials, such as the pharmacological inhibitor chloroquine or the inducer rapamycin, especially in exploiting its ability to modulate the secretory capability of CAFs to enhance drug delivery or inhibit it to prevent its influence on cancer cell chemoresistance. In this review, we summarize the reports on autophagy in cancer-associated fibroblasts by detailing the mechanism and role of autophagy in CAFs, including the hypoxic-autophagy positive feedback cycle, the metabolic cross-talk between CAFs and tumors induced by autophagy, CAFs secreted cytokines promote cancer survival by secretory autophagy, CAFs autophagy-induced EMT, stemness, senescence and treatment sensitivity, as well as the research of antitumor chemicals, miRNAs and lncRNAs. Additionally, we discuss the evidence of molecules in CAFs that are relevant to autophagy and the contribution to sensitive treatments as a potential target for cancer treatment.


Assuntos
Autofagia/genética , Transformação Celular Neoplásica/genética , Neoplasias/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , MicroRNAs/genética , Neoplasias/patologia , RNA Longo não Codificante/genética
14.
Biochem Biophys Res Commun ; 513(1): 28-34, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-30935690

RESUMO

Dysfunction of Girdin plays a crucial role in the development of a variety of tumors. Phosphorylated regulation of Girdin has been studied extensively. However, how Girdin is dephosphorylated remains unclear. In this study, we report a mechanism of Girdin dephosphorylation and the importance of this mechanism in the migration of breast cancer cells. We show that the protein phosphatase 2A (PP2A) complex can bind to Girdin via the modulating B subunit. Overexpression or knockdown of PP2A inhibits or increases the phosphorylation of Girdin at serine 1416, respectively. PP2Ac-induced Girdin dephosphorylation is involved in the inhibition of breast cancer cell migration. Furthermore, in human breast cancer samples, PP2Ac expression is negatively correlated with the phosphorylation of Girdin, and low expression of PP2Ac is correlated with tumor stage, grade and lymph node metastasis of breast cancer. These data indicate that PP2A regulates Girdin dephosphorylation and highlight the critical role of this pathway in breast cancer metastasis.

15.
Am J Sports Med ; 47(4): 942-953, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30870031

RESUMO

BACKGROUND: Low-intensity pulsed ultrasound (LIPUS), as a safe biophysiotherapy, can enhance bone-tendon (B-T) healing in vivo and induce osteogenic or chondrogenic differentiation of mesenchymal stromal cells in vitro. This study aimed to determine whether LIPUS can improve the efficacy of transplanted mesenchymal stromal cells on B-T healing. HYPOTHESIS: LIPUS can induce lineage-specific differentiation of transplanted adipose-derived stromal cells (ASCs) at the B-T healing site, thus resulting in superior healing quality when compared with LIPUS or ASCs alone. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 112 mature rabbits with partial patellectomy in the hindlimb were randomly assigned into mock sonication without ASCs (control), ultrasonication without ASCs (LIPUS), mock sonication with ASCs (ASCs), and ultrasonication with ASCs (LIPUS + ASCs). The treatment time of the mock sonication or ultrasonication was 20 minutes per day. Autologous ASCs were transplanted to the healing site by fibrin glue during the operation, and LIPUS was delivered daily starting at postoperative day 3 until euthanasia. The patella-patellar tendon junctions were postoperatively harvested at 8 and 16 weeks for radiological, histological, and mechanical evaluations. Additionally, 9 animals were used for ASC tracking with mCherry protein. RESULTS: Radiologically, there was more new bone formation and remodeling in the LIPUS + ASCs group as compared with the other groups. Synchrotron radiation micro-computed tomography showed that the LIPUS + ASCs group significantly increased bone volume fraction, trabecular thickness, and trabecular number at the healing site as compared with the other groups at postoperative 8 weeks ( P < .05 for all). Histologically, immunohistochemical staining confirmed that the transplanted mCherry-ASCs can differentiate into osteoblasts and fibrochondrocytic-like cells. Meanwhile, as compared with the other groups, the LIPUS + ASCs group showed more formation and maturity of the fibrocartilage layer and new bone at postoperative weeks 8 and 16 ( P < .05 for all). Biomechanically, the LIPUS + ASCs group showed significantly higher failure load and stiffness versus the other groups at postoperative weeks 8 and 16 ( P < .05 for all). CONCLUSION: Autologous ASC transplantation stimulated with LIPUS can result in superior B-T healing quality when compared with LIPUS or ASCs alone. CLINICAL RELEVANCE: This study demonstrates the effectiveness of using ASC transplantation stimulated with LIPUS for B-T healing and provides a foundation for future clinical studies.

16.
Nat Commun ; 10(1): 1211, 2019 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-30858377

RESUMO

The original version of this Article contained an error in the spelling of the author Brett L. Ecker, which was incorrectly given as Brett Ecker. This has now been corrected in both the PDF and HTML versions of the Article.

17.
Reprod Biol Endocrinol ; 17(1): 15, 2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30674332

RESUMO

OBJECTIVE: To assess the predictive value of each individual morphological parameter: blastocoele expansion degree, inner cell mass (ICM), and trophectoderm (TE) grades on the clinical pregnancy outcome in frozen-warmed embryo transfer (FET) cycles. METHODS: This is a retrospective cohort study, including 1154 FET cycles receiving vitrified-warmed one or two blastocysts transfer from August 2011 through to May 2018. The correlation between blastocyst morphology parameters and clinical outcome after FET was assessed. RESULTS: In the subgroup analysis based on clinical pregnancy, the patients who achieved clinical pregnancy had a significantly higher degree of blastocyst expansion (3.69 ± 0.68 vs. 3.53 ± 0.78, P = 0.000) and had a thicker endometrium (9.65 ± 1.63 vs. 9.28 ± 1.64) compared with those with non-clinical pregnancy. The logistic regression analysis showed that among the three blastocyst morphology parameters, only the blastocoele expansion degree was significantly correlated with the clinical pregnancy outcome and had ability to predict the outcome after FET cycles with one or two vitrified-warmed blastocysts transferred. Both ICM and TE stages were not associated with pregnancy outcomes. CONCLUSIONS: The blastocoele expansion degree may be essential for successful pregnancy and should be given priority when selecting frozen blastocyst for transfer.


Assuntos
Blastocisto/fisiologia , Criopreservação/métodos , Transferência Embrionária/métodos , Vitrificação , Adulto , Blastocisto/citologia , Técnicas de Cultura Embrionária , Implantação do Embrião , Feminino , Congelamento , Humanos , Nascimento Vivo , Modelos Logísticos , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Estudos Retrospectivos
18.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1201-1213, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30659926

RESUMO

Viral noncoding RNAs (Epstein-Barr virus-encoded RNAs, EBERs) are believed to play a critical role in the progression of lymphoma and nasopharyngeal carcinoma (NPC). However, the accurate mechanisms accounting for their oncogenic function have not been elucidated, especially in terms of interaction between tumor cells and mesenchymal cells. Here, we report that, in addition to NPC cells, EBERs are also found in endothelial cells in Epstein-Barr virus (EBV)-infected NPC parenchymal tissues, which implicates NPC-derived extracellular vesicles (EVs) in transmitting EBERs to endothelial cells. In support of this hypothesis, we first ascertained if EBERs could be transferred to endothelial cells via EVs isolated from NPC culture supernatant. Then, we clarified that EVs-derived EBERs could promote angiogenesis through stimulation of VCAM-1 expression. Finally, we explored the involvement of EBER recognition by TLR3 and RIG-I in NPC angiogenesis. Our observations collectively illustrate the significance and mechanism of EVs-derived EBERs in angiogenesis and underlie the interaction mechanisms between EBV-infected NPC cells and the tumor microenvironment.

19.
ACS Appl Mater Interfaces ; 11(3): 2891-2907, 2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30620556

RESUMO

Functional fibrocartilage regeneration is a bottleneck during bone-tendon healing, and the currently available tissue-engineering strategies for fibrocartilage regeneration are insufficient because of a lack of appropriate scaffold that can load large seeding-cells and induce chondrogenesis of stem cells. The acellular fibrocartilage scaffold (AFS) contains active growth factors as well as tissue-specific epitopes for cell-matrix interactions, which make it a potential scaffold for tissue-engineered fibrocartilage. A limitation to this scaffold is that its low porosity inhibits cells loading and infiltration. Here, inspired by book appearance, we sectioned native fibrocartilage tissue (NFT) into book-shape to improve cells loading and infiltration, and then decellularized with four protocols: (1) 2% SDS for 6-h, (2) 2% SDS for 24-h, (3) 4 SDS for 6-h, (4) 4% SDS for 24-h, followed by nuclease digestion. The optimal protocol was screened with respect to microstructures, DNA residence, native ingredients reservation, and chondrogenic inducibility of the AFS. In vitro studies demonstrated that this screened scaffold is noncytotoxicity and low-immunogenicity, allows adipose-derived stromal cells (ASCs) attachment and proliferation, shows superior chondrogenic inducibility, and stimulates collagen or glycosaminoglycans secretion. The underlying mechanism for this chondrogenic inducibility may be related to hedgehog pathway activating. Additionally, a novel pattern for fabricating tissue-engineered fibrocartilage was developed to enlarge seeding-cells loading, namely, cell-sheets sandwiched by book-shaped scaffold. In-vivo studies indicate that this screened scaffold alone could induce endogenous cells to satisfactorily regenerate fibrocartilage at 16-week, as characterized by fibrocartilaginous extracellular matrix (ECM) deposition and good interface integration. Interleaving this book-shaped AFS with autologous ASCs-sheets significantly enhanced its ability to regenerate fibrocartilage. Cell tracking demonstrated that fibrochondrocytes, osteoblasts, and osteocytes in the healing interface at postoperative 8-week partly originated from the sandwiched ASCs-sheets. On that basis, we propose the use of this book-shaped AFS and cell sheet technique for fabricating tissue-engineered fibrocartilage to improve bone-tendon healing.


Assuntos
Condrogênese/efeitos dos fármacos , Fibrocartilagem/transplante , Engenharia Tecidual , Cicatrização/efeitos dos fármacos , Adipócitos/química , Adipócitos/metabolismo , Animais , Regeneração Óssea/efeitos dos fármacos , Colágeno/administração & dosagem , Colágeno/química , Fibrocartilagem/química , Humanos , Osteoblastos/efeitos dos fármacos , Coelhos , Células-Tronco/efeitos dos fármacos , Tendões/efeitos dos fármacos , Tendões/crescimento & desenvolvimento , Tendões/fisiopatologia , Tecidos Suporte/química
20.
Eur Radiol ; 29(1): 429-438, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29948068

RESUMO

OBJECTIVES: To retrospectively review the radiological and clinicopathological features of gliosarcoma (GSM) and differentiate it from glioblastoma multiforme (GBM). METHODS: The clinicopathological data and imaging findings (including VASARI analysis) of 48 surgically and pathologically confirmed GSM patients (group 1) were reviewed in detail, and were compared with that of other glioblastoma (GBM) cases in our hospital (group 2). RESULTS: There were 28 men and 20 women GSM patients with a median age of 52.5 years (range, 24-80 years) in this study. Haemorrhage (n = 21), a salt-and-pepper sign on T2-weighted images (n = 36), unevenly thickened wall (n = 36) even appearing as a paliform pattern (n = 32), an intra-tumoural large feeding artery (n = 32) and an eccentric cystic portion (ECP) (n = 19) were more commonly observed in the GSM group than in GBM patients. Based on our experience, GSM can be divided into four subtypes according to magnetic resonance imaging (MRI) features. When compared to GBM (group 2), there were more patients designated with type III lesions (having very unevenly thickened walls) and IV (solid) lesions among the GSM cases (group 1). On univariate prognostic analysis, adjuvant therapy (radiotherapy, chemotherapy, and radiochemotherapy) and existence of an eccentric cyst region were prognostic factors. However, Cox's regression model showed only adjuvant therapy as a prognostic factor for GSM. CONCLUSIONS: When compared to GBM, certain imaging features are more likely to occur in GSM, which may help raise the possibility of this disease. All GSM patients are recommended to receive adjuvant therapy to achieve a better prognosis with radiotherapy, chemotherapy or radiochemotherapy all as options. KEY POINTS: • Diagnosis of gliosarcoma can be suggested preoperatively by imaging. • Gliosarcoma can be divided into four subtypes based on MRI. • Paliform pattern and ECP tend to present in gliosarcoma more than GBM. • The cystic subtype of gliosarcoma may predict a more dismal prognosis. • All gliosarcoma patients should receive adjuvant therapy to achieve better prognosis.


Assuntos
Neoplasias Encefálicas/diagnóstico , Encéfalo/diagnóstico por imagem , Gliossarcoma/diagnóstico , Imagem por Ressonância Magnética/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto Jovem
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