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1.
Mol Cell Probes ; : 101602, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32447047

RESUMO

Breast cancer is a malignancy and one of the most frequent causes of cancer death among women worldwide. Paclitaxel is a common chemotherapeutic drug and has recently been shown to facilitate tumor cell escape during cytotoxic chemotherapy by inducing inflammatory mediators and pro-survival protein expression. Hyperoside is a flavonoid glycoside compound and exerts anti-inflammation, and anti-tumor growth properties. However, its function in breast cancer chemosensitivity remains poorly elucidated. In this study, hyperoside exhibited little cytotoxicity to normal human breast mammary epithelial cell lines, and also protected against paclitaxel-induced cytotoxicity in MCF-10A. Importantly, treatment with hyperoside engendered not only inhibition of cell viability, but also potentiated cancer cell sensitivity to paclitaxel in TLR4-positive breast cancer MDA-MB-231 cells by suppressing cell viability, and increasing cell apoptosis and caspase-3 activity. Nevertheless, although hyperoside exposure restrained cell viability, its treatment presented little effects to paclitaxel sensitivity in TLR4-null HCC1806 cells. Intriguingly, paclitaxel stimulation activated the TLR4-NF-κB signaling, which was reversed after hyperoside administration. Concomitantly, hyperoside also attenuated paclitaxel-mediated anti-apoptotic Bcl-2 expression, but enhanced the effects of paclitaxel on pro-apoptotic Bax expression, and pro-inflammatory cytokine IL-6 and IL-6 levels in MDA-MB-231 cells. Importantly, restoring the TLR4 pathway overturned hyperoside-evoked chemosensitivity to paclitaxel in MDA-MB-231 cells. Thus, hyperoside may elevate breast cancer cell sensitivity to paclitaxel by blocking TLR4 activation-mediated pro-inflammatory and pro-survival approaches, thereby endorsing its usefulness as a promising therapeutic combination to overcome chemosensitivity in breast cancer.

2.
Cell Death Dis ; 11(4): 230, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286266

RESUMO

Mps one binder 2 (MOB2) regulates the NDR kinase family, however, whether and how it is implicated in cancer remain unknown. Here we show that MOB2 functions as a tumor suppressor in glioblastoma (GBM). Analysis of MOB2 expression in glioma patient specimens and bioinformatic analyses of public datasets revealed that MOB2 was downregulated at both mRNA and protein levels in GBM. Ectopic MOB2 expression suppressed, while depletion of MOB2 enhanced, the malignant phenotypes of GBM cells, such as clonogenic growth, anoikis resistance, and formation of focal adhesions, migration, and invasion. Moreover, depletion of MOB2 increased, while overexpression of MOB2 decreased, GBM cell metastasis in a chick chorioallantoic membrane model. Overexpression of MOB2-mediated antitumor effects were further confirmed in mouse xenograft models. Mechanistically, MOB2 negatively regulated the FAK/Akt pathway involving integrin. Notably, MOB2 interacted with and promoted PKA signaling in a cAMP-dependent manner. Furthermore, the cAMP activator Forskolin increased, while the PKA inhibitor H89 decreased, MOB2 expression in GBM cells. Functionally, MOB2 contributed to the cAMP/PKA signaling-regulated inactivation of FAK/Akt pathway and inhibition of GBM cell migration and invasion. Collectively, these findings suggest a role of MOB2 as a tumor suppressor in GBM via regulation of FAK/Akt signaling. Additionally, we uncover MOB2 as a novel regulator in cAMP/PKA signaling. Given that small compounds targeting FAK and cAMP pathway have been tested in clinical trials, we suggest that interference with MOB2 expression and function may support a theoretical and therapeutic basis for applications of these compounds.

3.
J Exp Clin Cancer Res ; 39(1): 44, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111229

RESUMO

BACKGROUND: FK506-binding protein 9 (FKBP9) is amplified in high-grade gliomas (HGGs). However, the roles and mechanism(s) of FKBP9 in glioma are unknown. METHODS: The expression of FKBP9 in clinical glioma tissues was detected by immunohistochemistry (IHC). The correlation between FKBP9 expression levels and the clinical prognosis of glioma patients was examined by bioinformatic analysis. Glioblastoma (GBM) cell lines stably depleted of FKBP9 were established using lentiviruses expressing shRNAs against FKBP9. The effects of FKBP9 on GBM cells were determined by cell-based analyses, including anchorage-independent growth, spheroid formation, transwell invasion assay, confocal microscopy, immunoblot (IB) and coimmunoprecipitation assays. In vivo tumor growth was determined in both chick chorioallantoic membrane (CAM) and mouse xenograft models. RESULTS: High FKBP9 expression correlated with poor prognosis in glioma patients. Knockdown of FKBP9 markedly suppressed the malignant phenotype of GBM cells in vitro and inhibited tumor growth in vivo. Mechanistically, FKBP9 expression induced the activation of p38MAPK signaling via ASK1. Furthermore, ASK1-p38 signaling contributed to the FKBP9-mediated effects on GBM cell clonogenic growth. In addition, depletion of FKBP9 activated the IRE1α-XBP1 pathway, which played a role in the FKBP9-mediated oncogenic effects. Importantly, FKBP9 expression conferred GBM cell resistance to endoplasmic reticulum (ER) stress inducers that caused FKBP9 ubiquitination and degradation. CONCLUSIONS: Our findings suggest an oncogenic role for FKBP9 in GBM and reveal FKBP9 as a novel mediator in the IRE1α-XBP1 pathway.

4.
Cell Immunol ; 348: 104039, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32007223

RESUMO

Cancer immunotherapy, due to its high anti-tumor efficacy, has attracted considerable attention globally from experts in various fields. However, immunotherapy could be severely toxic; not all patients may respond, thus requiring combination therapy. Therefore, a reasonable selection strategy for early treatment is urgently needed. It is vital to capture the dynamic, heterogeneous, and complex tumor behavior considering the absence of ideal companion biomarkers. Since tumor immune response involves tumor cells, several other cell types, and molecules in the tumor microenvironment, detection is very complex and variable. However, molecular imaging technology, namely the non-invasive whole-body molecular imaging by positron emission tomography and single-photon emission computed tomography, has shown considerable promise in tumor detection and cancer immunotherapy response. Identification of potential novel imaging biomarkers will allow a personalized treatment plan for every patient. Future imaging strategies for these molecules used alone or in combination or continuously, might help stratify patients before or during the early stages of immunotherapy, and might address the immunotherapy challenges encountered by the oncologists.

5.
Int J Mol Med ; 45(2): 497-509, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894257

RESUMO

Development of resistance to endocrine therapy, such as tamoxifen, remains a tricky clinical problem during the treatment of breast cancer. Accumulating evidence suggested that dysregulation of long noncoding (lnc_RNAs contributes to the development of tamoxifen resistance. In the current study, via screening, cytoskeleton regulator RNA (CYTOR) was identified as the most significantly elevated lncRNA in the established tamoxifen resistant MCF7 cell lines (MCF7/TAM1 and MCF7/TAM2) compared with the parental MCF7 cells (MCF7­P). The CCK­8 assay indicated that silencing of CYTOR increased the sensitivity of MCF7/TAM1 and MCF7/TAM2 to tamoxifen treatment. Using bioinformatic analysis, it was predicted that microRNA (miR)­125a­5p might bind to CYTOR and the expression of miR­125a­5p was negatively correlated with CYTOR in the tumor tissues of breast cancer. In addition, RT­qPCR and dual luciferase assays validated that CYTOR directly repressed miR­125a­5p expression in breast cancer cells. Through regulation of miR­125a­5p, CYTOR elevated serum response factor (SRF) expression and activated Hippo and mitogen associated protein kinase signaling pathways to promote breast cancer cell survival upon tamoxifen treatment. In the collected tumor tissues of breast cancer in the present study, high expression of CYTOR was detected in tissues from patients with no response to tamoxifen compared with those from patients who were not treated with tamoxifen. A positive correlation between CYTOR and SRF mRNA expression was observed in tissues collected from patients with breast cancer. In conclusion, the results of the present study demonstrated a pivotal role of CYTOR in mediating tamoxifen resistance in breast cancer.

6.
Biosci Rep ; 39(8)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31371629

RESUMO

LncRNA SRA1 plays important roles in several types of human diseases. The present study aimed to explore the role of SRA1 in cervical squamous cell carcinoma (CSCC). In the present study, we showed that plasma SRA1 was down-regulated in human papillomavirus (HPV)-negative CSCC patients but not in HPV-positive CSCC patients compared with healthy females. Down-regulated SRA1 distinguished HPV-negative CSCC patients from HPV-positive CSCC patients and healthy females. In HPV-negative CSCC patients, miR-9 was up-regulated and inversely correlated with SRA1. In HPV-negative CSCC cells, SRA1 overexpression caused the down-regulated miR-9, while miR-9 overexpression failed to affect SRA1. Moreover, SRA1 overexpression caused decreased, while miR-9 overexpression caused increased proliferation, migration and invasion rates of cancer cells. In addition, miR-9 overexpression attenuated the effects of SRA1 overexpression. Therefore, SRA1 is down-regulated in HPV-negative CSCC and regulates cancer cell behaviors possibly by down-regulating miR-9.

7.
Exp Ther Med ; 18(1): 475-482, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31258684

RESUMO

MicroRNAs (miRNAs) are small non-coding RNAs that serve pivotal roles in human diseases. Several miRNAs, such as miR-485-3p, have been identified as potential biomarkers for predicting overall survival of patients with glioblastoma (GBM). However, the underlying mechanism of miRNAs in promoting GBM progression remains unknown. In the present study, decreased miR-485-3p expression was detected in tumor tissues from patients with GBM. Using western blot analysis, reverse transcription-quantitative PCR and dual luciferase reporter assay, ring finger protein 135 (RNF135) was confirmed as a target gene of miR-485-3p in GBM cells. Through silencing of RNF135, miR-485-3p inactivated the mitogen-activated protein kinase/ERK1/2 pathway in GBM cells. Moreover, functional assays demonstrated that miR-485-3p inhibited GBM cell proliferation and migration whilst overexpression of RNF135 reversed this effect. Additionally, a negative correlation between miR-485-3p and RNF135 mRNA expression was observed in tissues from patients with glioblastoma. In conclusion, the present results demonstrated that miR-485-3p functioned as a tumor suppressor which suggested that miR-485-3p might have a role in GBM progression.

8.
BMC Cancer ; 19(1): 706, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319814

RESUMO

BACKGROUND: Glioblastoma (GBM) is an extremely deadly form of brain cancer with limited treatment options and thus novel therapeutic modalities are necessary. Histone deacetylase inhibitors (HDACi) have demonstrated clinical and preclinical activities against GBM. (Silent mating type information regulation 2 homolog, Sirt1) abbreviated as Sirtuin 1, has been implicated in GBM. We explored the activity of the Sirt1 activator SRT2183 in glioma cell lines in terms of biological response. METHODS: The effects of SRT2183 on glioma cell growth and neurosphere survival were evaluated in vitro using the CCK-8, clonogenic and neurosphere assays, respectively. Glioma cell cycle arrest and apoptosis were determined by flow cytometry. SRT2183-induced autophagy was investigated by detection of GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta, conversion of the nonlipidated form of LC3 (LC3-I) to the phosphatidylethanolamine-conjugated form (LC3-II). Acetylation of STAT3 and NF-κB in SRT2183-treated glioma cells was examined using immunoprecipitation. The expression levels of anti-apoptotic proteins were assayed by immunoblotting. RESULTS: SRT2183 suppressed glioma cell growth and destroyed neurospheres in vitro. Furthermore, SRT2183 induced glioma cell cycle arrest and apoptosis, accompanying by upregulation of the pro-apoptotic Bim and downregulation of Bcl-2 and Bcl-xL. Notably, ER stress was triggered in glioma cells upon exposure to SRT2183 while the pre-exposure to 4-PBA, an ER stress inhibitor, significantly antagonized SRT2183-mediated growth inhibition in glioma cells. In addition, SRT2183 induced autophagy in glioma cells and pharmacological modulation of autophagy appeared not to affect SRT2183-inhibited cell growth. Of interest, the acetylation and phosphorylation of p65 NF-κB and STAT3 in glioma cells were differentially affected by SRT2183. CONCLUSIONS: Our data suggest the ER stress pathway is involved in SRT2183-mediated growth inhibition in glioma. Further investigation in vivo is needed to consolidate the data.


Assuntos
Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glioblastoma/patologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Sirtuína 1/metabolismo , Acetilação , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , NF-kappa B/antagonistas & inibidores , Fosforilação , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
9.
Cancer Med ; 8(11): 5373-5385, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31350872

RESUMO

Human papillomavirus (HPV) infection which continues to be the most common sexually transmitted disease, has been identified as a major risk factor for cervical cancer. Therefore, it is very important to understand and grasp the distribution of HPV in Chinese population, and make the foundation for the development of cervical cancer vaccine in China. An extensive search strategy was conducted in multiple literature databases. All retrieved studies were screened by October 31, 2018. The prevalence of HPV infection was analyzed using random effects model. A total of 68 studies satisfied the inclusion criteria for our study. The national overall prevalence of HPV infection was 15.54% (95% CI: 13.83%-17.24%). we also performed subgroup analysis by age, geographic location, level of economic development, HPV assay method, and type of HPV infection. The top 5 common HPV types detected in general population, were HPV 16 (3.52%, 95% CI: 3.18%-3.86%), 52 (2.20%, 95% CI: 1.93%-2.46%), 58 (2.10%, 95% CI: 1.88%-2.32%), 18 (1.20%, 95% CI: 1.05%-1.35%), and 33 (1.02%, 95% CI: 0.89%-1.14%). Except for the higher prevalence of HPV infection in 2009 and 2010, the prevalence of HPV infection in other years changed little, ranged from 13.2% to 17.4%. HPV type in Chinese women was quite distinctive. HPV infection played a critical role in the occurrence of cervical cancer, understanding the distribution of HPV type and performing the HPV type testing had important clinical value for colposcopy referral and increasing the detection rate. Therefore, our findings could provide evidence for cervical cancer screening and vaccine, in order to reduce the burden of cervical cancer.

10.
Cancer Med ; 8(10): 4732-4742, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31219228

RESUMO

BACKGROUND: The quantity of metastases lesions is an important reference when it comes to making a more informed treatment decision for patients with colorectal cancer liver metastases. However, the molecular alterations in patients with different numbers of lesions have not been systematically studied. METHODS: We investigated somatic alterations and microsatellite instability (MSI) of liver metastases from patients with single, multiple or diffuse metastasis lesions. A new algorithm "Pathway Damage Score" was developed to comprehensively assess the functional impact of somatic alterations at the pathway level. Pathogenic pathways of different metastasis were identified and their prognosis effects were evaluated. Furthermore, the subnetworks and affected phenotypes of the altered genes in each pathogenic pathway were analyzed. RESULTS: Somatic alterations and altered genes occurred sporadically as well as in MSI state in different metastasis types, although MSS patients had more metastatic lesions than that of the MSI patients. Every metastasis group has their own pathogenic pathways and damaged "Cargo recognition for clathrin-mediated endocytosis" is significantly associated with poor prognosis (P < 0.001). Further pathway subnetwork analysis showed that except conventional drivers, other genes could also contribute to metastasis formation. CONCLUSIONS: Progression of liver metastasis could be driven by the coefficient of all altered genes belonging to the pathways. Thus, compared to somatic alterations and genes, pathway level analysis is more reasonable for functional interpretations of molecular alterations in clinical samples.

11.
J Cell Physiol ; 234(11): 19553-19564, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31066040

RESUMO

This study is carried out to elucidate the role of long noncoding RNAs (lncRNAs) MT1JP in proliferation, invasion, migration, and apoptosis of glioma cells through the regulation of PTEN/Akt signaling pathway. The expression of MT1JP in 80 normal brain tissues and 138 glioma tissues, as well as glioma cell lines, was detected by quantitative reverse-transcription polymerase chain reaction. Besides, glioma cells with overexpression and low expression of MT1JP were constructed to confirm the role of MT1JP in proliferation, invasion, migration, and apoptosis of glioma cells and the growth of glioma cells in vivo through the regulation of PTEN/Akt signaling pathway. MT1JP expression was downregulated in glioma tissues and cells. The low expression of MT1JP was considered as an independent risk factor for predicting overall survival in gliomas. After transfection of MT1JP overexpression plasmid, glioma cells showed decreased proliferation, migration and invasion ability, increased apoptosis rate, and decreased the tumorigenic ability of nude mice. The trends were opposite in glioma cells transfected with MT1JP poor expression plasmid. Collectively, our study suggests that lncRNA MT1JP is responsible for inhibiting proliferation, invasion, and migration while promoting apoptosis of glioma cells through the activation of PTEN/Akt signaling pathway.

12.
Technol Cancer Res Treat ; 18: 1533033818821421, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30760122

RESUMO

Currently, despite the advances in individualized treatment, breast cancer still remains the deadliest form of cancer in women. Diagnostic, prognostic, and therapy-predictive methods are mainly based on the evaluation of tumor tissue samples and are aimed to improve the overall therapeutic level. Therefore, the exploration of a series of circulating biomarkers, which serve as the information source of tumors and could be obtained by peripheral blood samples, represents a high field of interest. Apart from classical biomarkers, exosomes, which are nanovesicles, are emerging as an accessible and efficient source of cell information. The purpose of this review is to summarize the peculiarities of the presently available breast cancer exosomal biomarkers; the review also provides the prediction of a multitude of potential target genes of exosomal microRNAs using 4 databases.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Exossomos/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Humanos , Prognóstico
13.
Technol Cancer Res Treat ; 18: 1533033818821401, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30803356

RESUMO

MicroRNA-374a has been abnormally expressed in several cancer types; however, its role in glioma remains unclear. Therefore, we aimed to investigate whether microR-374a participated in the progression of glioma. Expression of microR-374a in glioma cell lines and normal cell line was measured by quantitative real-time polymerase chain reaction. Luciferase reporter assay and Western blot were used to detect the targets of microR-374a. In vitro functional experiments were conducted to investigate the biological role of microR-374a. Low expression of microR-374a was found in glioma cell lines. Prokineticin 2 was identified as a direct target of microR-374a in glioma. Investigations on the mechanisms related to glioma progression showed that microR-374a inhibited glioma cell proliferation, cell cycle progression, and cell invasion through targeting Prokineticin 2. Taken together, these results revealed that microR-374a functions as tumor suppressor by targeting Prokineticin 2, suggesting it might be a novel therapeutic target for glioma.


Assuntos
Movimento Celular , Proliferação de Células , Hormônios Gastrointestinais/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , MicroRNAs/genética , Neuropeptídeos/metabolismo , Apoptose , Hormônios Gastrointestinais/genética , Glioma/genética , Glioma/metabolismo , Humanos , Neuropeptídeos/genética , Transdução de Sinais , Células Tumorais Cultivadas
14.
J Cell Physiol ; 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30697721

RESUMO

Promoting the antitumor effects of cell-based immunotherapy for clinical application remains a difficult challenge. Nocardia rubra cell-wall skeleton (N-CWS) is an immunotherapeutic agent for cancers that have been proven to possess the ability to activate immune response without showing toxicity. However, its effects on immune cells that are derived from tumor patients and cultured in vitro remain unclear. As expected, N-CWS can enhance the proliferation and viability of cytokine-induced killer (CIK) cells, dendritic cells (DCs), and natural killer (NK) cells. The maturation of DCs and specific cytotoxicity against NK cells and CIK cells were consistently promoted. The TUNEL-staining and the Annexin V/propidium iodide assay revealed that after treatment with N-CWS, the stimulated CIK/NK cells could induce DNA breaks in tumor cells. Furthermore, quantitative real-time polymerase chain reaction and western blot analysis showed upregulation of proapoptotic biomarkers (caspase-3 and caspase-9) and a downregulation of the antiapoptotic biomarker Bcl-2 in the tumor cells of the N-CWS-treated group, indicating that N-CWS could induce hepatocellular carcinoma cell apoptosis via CIK/NK cells. Finally, CIK/NK cells could notably suppress the invasion and migration of tumor cells in the presence of N-CWS. Our study provides evidence that N-CWS could significantly increase the growth of CIK cells, DCs, and NK cells, particularly due to its robust antitumor activities by inducing apoptosis, and attenuate the invasion and migration of tumor cells.

15.
Oncol Res ; 27(4): 475-486, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-29793559

RESUMO

Glioma is the most common malignant tumor of the central nervous system, and it is characterized by high relapse and fatality rates and poor prognosis. Bufalin is one of the main ingredients of Chan-su, a traditional Chinese medicine (TCM) extracted from toad venom. Previous studies revealed that bufalin exerted inhibitory effects on a variety of tumor cells. To demonstrate the inhibitory effect of bufalin on glioma cells and glioma stem-like cells (GSCs) and discuss the underlying mechanism, the proliferation of glioma cells was detected by MTT and colony formation assays following treatment with bufalin. In addition, we investigated whether bufalin inhibits or kills GSCs using flow cytometry, Western blotting, and reverse transcription polymerase chain reaction analysis (RT-PCR). Finally, we investigated whether bufalin could improve the therapeutic effect of temozolomide (TMZ) and discussed the underlying mechanism. Taken together, our data demonstrated that bufalin inhibits glioma cell growth and proliferation, inhibits GSC proliferation, and kills GSCs. Bufalin was found to induce the apoptosis of GSCs by upregulating the expression of the apoptotic proteins cleaved caspase 3 and poly(ADP-ribose) polymerase (PARP) and by downregulating the expression of human telomerase reverse transcriptase, which is a marker of telomerase activity. Bufalin also improved the inhibitory effect of TMZ on GSCs by activating the mitochondrial apoptotic pathway. These results suggest that bufalin damages GSCs, induces apoptosis, and enhances the sensitivity of GSCs to TMZ.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bufanolídeos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Temozolomida/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos
16.
Bosn J Basic Med Sci ; 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31999936

RESUMO

Glioblastoma multiforme (GBM) is a highly invasive cancer with a high recurrence rate. The prognosis of GBM patients remains poor, even after standard surgical resection combined with chemoradiotherapy. Thus, there is an urgent need for new therapeutic targets in GBM. In recent years, microRNAs have received considerable attention due to their important role in tumor development and progression. In this study, we investigated the role of miR-129-5p and miR-129-5p/ZFP36L1 axis in GBM tumorigenesis. Analysis of GSE103228 microarray data from the GEO database showed that miR-129-5p was significantly downregulated in GBM vs. normal brain tissues. Quantitative reverse transcription PCR analysis of miR-129-5p expression in seven GBM cell lines (LN229, A172, U87, T98G, U251, H4, and LN118) vs. normal human astrocytes (NHA) showed miR-129-5p was significantly downregulated in GBM cells. Overexpression of miR-129-5p in LN229 and A172 cells significantly suppressed cell proliferation, migration, invasion, and colony-forming ability. Target Scan analysis identified ZFP36L1 as the target of miR-129-5p. UALCAN dataset analysis found that ZFP36L1 was significantly upregulated in GBM vs. normal brain tissues, and high ZFP36L1 expression was positively associated with the poor survival of GBM patients. Western blot analysis demonstrated that ZFP36L1 was significantly upregulated in seven GBM cell lines vs. NHA. Overexpression of miR-129-5p in LN229 and A172 cells significantly inhibited ZFP36L1 mRNA and protein expression, while overexpression of ZFP36L1 in LN229 and A172 cells reversed miR-129-5p-mediated inhibition on GBM tumorigenesis. Our results revealed an important role of miR-129-5p in the negative regulation of ZFP36L1 expression in GBM, suggesting new candidates for targeted therapy in GBM patients.

17.
Biol Res ; 51(1): 56, 2018 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-30537994

RESUMO

BACKGROUND: Glioma is the most prevalent malignant tumor in human central nervous systems. Recently, the development of resistance to radiotherapy in glioma patients markedly vitiates the therapy outcome. MiR-153-3p has been reported to be closely correlated with tumor progression, but its effect and molecular mechanism underlying radioresistance remains unclear in glioma. METHODS: The expression of miR-153-3p was determined in radioresistant glioma clinical specimens as well as glioma cell lines exposed to irradiation (IR) using quantitative real-time PCR. Cell viability, proliferation and apoptosis were then evaluated by MTT assay, colony formation assay, Flow cytometry analysis and caspase-3 activity assay in glioma cells (U87 and U251). Tumor forming was evaluated by nude mice model in vivo. TUNEL staining was used to detect cell apoptosis in nude mice model. The target genes of miR-153-3p were predicted and validated using integrated bioinformatics analysis and a luciferase reporter assay. RESULTS: Here, we found that miR-153-3p was down-regulated in radioresistant glioma clinical specimens as well as glioma cell lines (U87 and U251) exposed to IR. Enhanced expression of miR-153-3p promoted the radiosensitivity, promoted apoptosis and elevated caspase-3 activity in glioma cells in vitro, as well as the radiosensitivity in U251 cell mouse xenografs in vivo. Mechanically, B cell lymphoma-2 gene (BCL2) was identified as the direct and functional target of miR-153-3p. Moreover, restoration of BCL2 expression reversed miR-153-3p-induced increase of radiosensitivity, apoptosis and caspase-3 activity in U251 cells in vitro. In addition, clinical data indicated that the expression of miR-153-3p was significantly negatively associated with BCL2 in radioresistance of glioma samples. CONCLUSIONS: Our findings suggest that miR-153-3p is a potential target to enhance the effect of radiosensitivity on glioma cells, thus representing a new potential therapeutic target for glioma.


Assuntos
Genes bcl-2/fisiologia , Glioma/genética , MicroRNAs/fisiologia , MicroRNAs/efeitos da radiação , Tolerância a Radiação/genética , Adulto , Análise de Variância , Western Blotting , Caspase 3/análise , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Regulação para Baixo , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Marcação de Genes/métodos , Genes bcl-2/efeitos da radiação , Glioma/radioterapia , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , MicroRNAs/análise , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Tempo
18.
Am J Cancer Res ; 8(8): 1514-1527, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210920

RESUMO

In addition to direct oncolysis, oncolytic viruses trigger immunogenic cell death (ICD) and primes antitumor immunity. We have previously shown that oncolytic Newcastle disease virus (NDV), strain FMW (NDV/FMW), induces apoptosis and/or autophagy in cancer cells. In this study, we investigated whether oncolytic NDV can induce ICD in lung cancer cells and whether apoptosis or autophagy plays a role in NDV-triggered ICD. To this end, we examined cell surface expression of calreticulin (CRT) on NDV-infected lung cancer cells and measured ICD determinants, high mobility group box 1 (HMGB1), heat shock protein 70/90 (HSP70/90) and ATP in supernatants following viral infection. Flow cytometric analysis using anti-CRT antibody and PI staining of NDV-infected lung cancer cells showed an increase in the number of viable (propidium iodide-negative) cells, suggesting the induction of CRT exposure upon NDV infection. In addition, confocal and immunoblot analysis using anti-CRT antibody showed that an enhanced accumulation of CRT on the cell surface of NDV-infected cells, indicating the translocation of CRT to the cell membrane upon NDV infection. We further demonstrated that NDV infection induced the release of secreted HMGB1 and HSP70/90 by examining the concentrated supernatants of NDV-infected cells. Furthermore, pre-treatment with either the pan-caspase inhibitor z-VAD-FMK or the necrosis inhibitor Necrostain-1, had no impact on NDV-induced release of ICD determinants in lung cancer cells. Rather, depletion of autophagy-related genes in lung cancer cells significantly inhibited the induction of ICD determinants by NDV. Of translational importance, in a lung cancer xenograft model, treatment of mice with supernatants from NDV-infected cells significantly inhibited tumour growth. Together, these results indicate that oncolytic NDV is a potent ICD-inducer and that autophagy contributes to NDV-mediated induction of ICD in lung cancer cells.

19.
J Exp Clin Cancer Res ; 37(1): 165, 2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-30041665

RESUMO

BACKGROUND: Aberrant activation of ß-catenin and Yes-associated protein (YAP) signaling pathways has been associated with hepatocellular carcinoma (HCC) progression. The LIM domain protein Ajuba regulates ß-catenin and YAP signaling and is implicated in tumorigenesis. However, roles and mechanism of Ajuba expression in HCC cells remain unclear. The E3 ligase Hakai has been shown to interact with other Ajuba family members and whether Hakai interacts and regulates Ajuba is unknown. METHODS: HCC cell lines stably depleted of Ajuba or Hakai were established using lentiviruses expressing shRNAs against Ajuba or Hakai. The effects of Ajuba on HCC cells were determined by a number of cell-based analyses including anchorage-independent growth, three dimension cultures and trans-well invasion assay. In vivo tumor growth was determined in a xenograft model and Ajuba expression in tumor sections was examined by immunohistochemistry. Co-immunoprecipitation, confocal microscopy and immunoblot assay were used to examine the expression and interaction between Ajuba and Hakai. RESULTS: Depletion of Ajuba in HCC cells significantly enhanced anchorage-independent growth, invasion, the formation of spheroids and tumor growth in a xenograft model, suggesting a tumor suppressor function for Ajuba in HCC. Mechanistically, Ajuba depletion triggered E-cadherin loss and ß-catenin translocation with increased Cyclin D1 levels. In addition, depletion of Ajuba upregulated the levels of YAP and its target gene CYR61. Furthermore, siRNA-mediated knockdown of either ß-catenin or YAP attenuated the pro-tumor effects by Ajuba depletion on HCC cells. Notably, Ajuba stability in HCC cells was regulated by Hakai, an E3 ligase for E-cadherin. Hakai interacted with Ajuba via its HYB domain and induced Ajuba neddylation, which was antagonized by the neddylation inhibitor, MLN4924, but not MG132. We further show that overexpression of Hakai in HCC cells markedly increased anchorage-independent growth, spheroid-formation ability and tumor growth in xenografts whereas Hakai depletion resulted in these opposite effects, indicating an oncogenic role for Hakai in HCC. Hakai also induced ß-catenin translocation with increased levels of Cyclin D1. CONCLUSIONS: Our data suggest a role for Ajuba and Hakai in HCC, and uncover the mechanism underlying the regulation of Ajuba stability.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas com Domínio LIM/genética , Neoplasias Hepáticas/genética , Ubiquitina-Proteína Ligases/metabolismo , beta Catenina/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Humanos , Proteínas com Domínio LIM/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Transfecção
20.
Mol Med Rep ; 18(1): 557-563, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29749500

RESUMO

Vacquinol­1 (Vacq), a quinolone derivative, has recently been reported to display potent antitumor effects in glioblastomas by inducing cellular massive vacuolization and cell death. However, whether Vacq induces cytotoxicities in other types of cancers, and the potential underlying mechanism, remain to be investigated. In the present study, it was revealed that Vacq suppressed cell growth and colony formation in the hepatocellular carcinoma (HCC) cell lines BEL7402 and Huh7. In addition, treatment with Vacq increased the number of early and late apoptotic cells as assessed by flow cytometry with fluorescein isothiocyanate­conjugated Annexin V and propidium iodide double staining. Notably, the effect by Vacq in the tested cells could be inhibited by pretreatment with a broad specificity caspase inhibitor Z­VAD­FMK, suggesting that Vacq may induce apoptosis in HCC cells. Morphologically, exposure to Vacq resulted in nuclear fragmentation and the apoptotic body formation in HCC cells. Furthermore, Vacq treatment increased the cleavage of caspase­3, caspase­9 and poly(adenosine diphosphate­ribose) polymerase­1. Mechanistic analysis revealed that Vacq upregulated the expressions of pro­apoptotic proteins [B­cell lymphoma 2 (bcl­2)­associated X protein (Bax) and Bcl­2­like protein 11] and downregulated the pro­survival protein, Bcl­2, expression in HCC cells. Furthermore, Vacq induced Bax translocation. Of note, Vacq displayed inhibitory effects on patient­derived HCC cells in two­dimensional (2D) and three-dimensional (3D) cultures. Taken together, the data suggested that Vacq induced intrinsic apoptosis and may be utilized as an effective reagent for HCC treatment.


Assuntos
Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Piperidinas/farmacologia , Quinolinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/fisiopatologia , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/fisiopatologia , Piperidinas/uso terapêutico , Quinolinas/uso terapêutico
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