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  • 1
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    Cotargeting CHK1 and PI3K Synergistically Suppresses Tumor Growth of Oral Cavity Squamous Cell Carcinoma in Patient-Derived Xenografts
    MDPI AG ; 2020
    In:  Cancers Vol. 12, No. 7 ( 2020-06-29), p. 1726-
    Details
    In: Cancers, MDPI AG, Vol. 12, No. 7 ( 2020-06-29), p. 1726-
    Abstract: Oral cavity squamous cell carcinomas (OSCCs) are aggressive tumors, and their recurrence leads to poor prognosis and reduced survival rates. This study aimed to identify therapeutic targets and to evaluate the efficacy of targeted inhibitors in OSCC patient-derived xenograft (PDX) models. Herein, we reported that OSCC PDXs recapitulated the genomic signatures of their paired primary tumors and the expression of CHEK1, PIK3CA, and PIK3CD was significantly upregulated in OSCC. The antitumor efficacy of CHK1 inhibitors (PF477736, AZD7762, LY2606368) and PI3K inhibitors (BYL719, GDC0941, GSK1059615) was investigated in OSCC cell lines and PDX models. Targeting either CHK1 or PI3K effectively inhibited cell proliferation and colony formation by inducing cell cycle arrest and apoptosis in in vitro cell-based assays. Cisplatin-based chemotherapy combined with CHK1 inhibitor treatment synergistically inhibited cell proliferation by suppressing CHK1 phosphorylation and inducing PARP cleavage. Furthermore, compared with monotherapy, cotreatment with CHK1 and PI3K inhibitors exerted synergistic anticancer effects by suppressing CHK1, AKT, and 4E-BP1 phosphorylation. In summary, our study identified CHK1 and PI3K as promising targets, especially in a dual treatment strategy combining a CHK1 inhibitor with cisplatin or a PI3K inhibitor as a novel therapeutic approach for OSCC patients with aberrant cell cycle regulation and PI3K signaling activation.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers12071726
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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  • 2
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    circRNAome Profiling in Oral Carcinoma Unveils a Novel circFLNB that Mediates Tumour Growth-Regulating Transcriptional Response
    MDPI AG ; 2020
    In:  Cells Vol. 9, No. 8 ( 2020-08-10), p. 1868-
    Details
    In: Cells, MDPI AG, Vol. 9, No. 8 ( 2020-08-10), p. 1868-
    Abstract: Deep sequencing technologies have revealed the once uncharted non-coding transcriptome of circular RNAs (circRNAs). Despite the lack of protein-coding potential, these unorthodox yet highly stable RNA species are known to act as critical gene regulatory hubs, particularly in malignancies. However, their mechanistic implications in tumor outcome and translational potential have not been fully resolved. Using RNA-seq data, we profiled the circRNAomes of tumor specimens derived from oral squamous cell carcinoma (OSCC), which is a prevalently diagnosed cancer with a persistently low survival rate. We further catalogued dysregulated circRNAs in connection with tumorigenic progression. Using comprehensive bioinformatics analyses focused on co-expression maps and miRNA-interaction networks, we delineated the regulatory networks that are centered on circRNAs. Interestingly, we identified a tumor-associated, pro-tumorigenic circRNA, named circFLNB, that was implicated in maintaining several tumor-associated phenotypes in vitro and in vivo. Correspondingly, transcriptome profiling of circFLNB-knockdown cells showed alterations in tumor-related genes. Integrated in silico analyses further deciphered the circFLNB-targeted gene network. Together, our current study demarcates the OSCC-associated circRNAome, and unveils a novel circRNA circuit with functional implication in OSCC progression. These systems-based findings broaden mechanistic understanding of oral malignancies and raise new prospects for translational medicine.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells9081868
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2661518-6
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  • 3
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    Retinal Circular RNA hsa_circ_0087207 Expression Promotes Apoptotic Cell Death in Induced Pluripotent Stem Cell-Derived Leber’s Hereditary Optic Neuropathy-like Models
    MDPI AG ; 2022
    In:  Biomedicines Vol. 10, No. 4 ( 2022-03-28), p. 788-
    Details
    In: Biomedicines, MDPI AG, Vol. 10, No. 4 ( 2022-03-28), p. 788-
    Abstract: Backgrounds: Leber’s hereditary optic neuropathy (LHON) is known as an inherited retinal disorder characterized by the bilateral central vision loss and degeneration of retinal ganglion cells (RGCs). Unaffected LHON carriers are generally asymptomatic, suggesting that certain factors may contribute to the disease manifestations between carriers and patients who carry the same mutated genotypes. Methods: We first aimed to establish the iPSC-differentiated RGCs from the normal healthy subject, the carrier, and the LHON patient and then compared the differential expression profile of circular RNAs (CircRNAs) among RGCs from these donors in vitro. We further overexpressed or knocked down the most upregulated circRNA to examine whether this circRNA contributes to the distinct phenotypic manifestations between the carrier- and patient-derived RGCs. Results: iPSCs were generated from the peripheral blood cells from the healthy subject, the carrier, and the LHON patient and successfully differentiated into RGCs. These RGCs carried equivalent intracellular reactive oxygen species, but only LHON-patient iPSC-derived RGCs exhibited remarkable apoptosis. Next-generation sequencing and quantitative real-time PCR revealed the circRNA hsa_circ_0087207 as the most upregulated circRNA in LHON-patient iPSC-derived RGCs. Overexpression of hsa_circ_0087207 increased the apoptosis in carrier iPSC-derived RGCs, while knockdown of hsa_circ_0087207 attenuated the apoptosis in LHON-patient iPSC-derived RGCs. Predicted by bioinformatics approaches, hsa_circ_0087207 acts as the sponge of miR-665 to induce the expression of a variety of apoptosis-related genes in LHON patient iPSC-derived RGCs. Conclusions: Our data indicated that hsa_circ_0087207 upregulation distinguishes the disease phenotype manifestations between iPSC-derived RGCs generated from the LHON patient and carrier. Targeting the hsa_circ_0087207/miR-665 axis might hold therapeutic promises for the treatment of LHON.
    Type of Medium: Online Resource
    ISSN: 2227-9059
    URL: Article
    DOI: 10.3390/biomedicines10040788
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2720867-9
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  • 4
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    Risk of Mortality in Association with Pregnancy in Women Following Motor Vehicle Crashes: A Systematic Review and Meta-Analysis
    MDPI AG ; 2022
    In:  International Journal of Environmental Research and Public Health Vol. 19, No. 2 ( 2022-01-14), p. 911-
    Details
    In: International Journal of Environmental Research and Public Health, MDPI AG, Vol. 19, No. 2 ( 2022-01-14), p. 911-
    Abstract: The aim of the study was to provide a systematic review and meta-analysis of studies examining the association between mortality risk and motor vehicle crashes (MVCs) in pregnant women compared with nonpregnant women. We used relevant MeSH terms to identify epidemiological studies of mortality risk in relation to MVCs from PubMed, Embase, and MEDLINE databases. The Newcastle–Ottawa Scale (NOS) was used for quality assessment. For comparison of mortality from MVCs between pregnant and nonpregnant women, the pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using a random effects model. The eight studies selected met all inclusion criteria. These studies included 14,120 injured victims who were pregnant at the time of the incident and 207,935 victims who were not pregnant. Compared with nonpregnant women, pregnant women had a moderate but insignificant decrease in mortality risk (pooled OR = 0.68, 95% CI = 0.38–1.22, I2 = 88.71%). Subgroup analysis revealed that the pooled OR significantly increased at 1.64 (95% CI = 1.16–2.33, I2 〈 0.01%) for two studies with a similar difference in the mean injury severity score (ISS) between pregnant and nonpregnant women. Future studies should further explore the risk factors associated with MVCs in pregnant women to reduce maternal mortality.
    Type of Medium: Online Resource
    ISSN: 1660-4601
    URL: Article
    DOI: 10.3390/ijerph19020911
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2175195-X
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  • 5
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    Plasma Level of Circular RNA hsa_circ_0000190 Correlates with Tumor Progression and Poor Treatment Response in Advanced Lung Cancers
    MDPI AG ; 2020
    In:  Cancers Vol. 12, No. 7 ( 2020-06-30), p. 1740-
    Details
    In: Cancers, MDPI AG, Vol. 12, No. 7 ( 2020-06-30), p. 1740-
    Abstract: Lung cancer (LC) causes the majority of cancer-related deaths. Circular RNAs (circRNAs) were reported to play roles in cancers by targeting pro- and anti-oncogenic miRNAs. However, the mechanisms of circRNAs in LC progression and their prognostic value of treatment response remain unclear. By using next generation sequencing (NGS) of LC cell lines’ transcriptomes, we identified highly overexpressed hsa_circ_0000190 and hsa_circ_000164 as potential biomarkers. By using the highly sensitive RT-ddPCR method, these circRNAs were shown to be secreted by cell lines and were detected in human blood. Clinical validation by RT-ddPCR was carried out on 272 (231 LC patients and 41 controls) blood samples. Higher hsa_circ_0000190 levels were associated with larger tumor size (p 〈 0.0001), worse histological type of adenocarcinoma (p = 0.0028), later stage (p 〈 0.0001), more distant metastatic organs (p = 0.0039), extrathoracic metastasis (p = 0.0004), and poor survival (p = 0.047) and prognosis. Using liquid biopsy-based RT-ddPCR, we discovered the correlation between increased hsa_circ_0000190 plasma level (p 〈 0.0001) and higher programmed death-ligand 1 (PD-L1) level in tumor (p = 0.0283). Notably, long-term follow-up of the immunotherapy treated cases showed that upregulated plasma hsa_circ_0000190 level correlated with poor response to systemic therapy and immunotherapy (p = 0.0002, 0.0058, respectively). Secretory circRNAs are detectable in blood by LB-based RT-ddPCR and may serve as blood-based biomarkers to monitor disease progression and treatment efficacy.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers12071740
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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  • 6
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    Efficacy of Postoperative Unilateral Neck Irradiation in Patients with Buccal Mucosa Squamous Carcinoma with Extranodal Extension: A Propensity Score Analysis
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 23 ( 2021-11-29), p. 5997-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 23 ( 2021-11-29), p. 5997-
    Abstract: Unilateral radiotherapy (RT) as a postoperative treatment for multiple ipsilateral lymph node (LN) metastases remains controversial. We investigated the efficacy of postoperative unilateral RT for buccal mucosa squamous cell carcinoma (BMSCC) with extranodal extensions (ENEs). We retrospectively reviewed the clinical records of 186 patients with ENE+ BMSCC who received postoperative RT during 1997–2016. Propensity score matching was used to establish comparable cohorts. The endpoints were contralateral nodal control (CLNC), overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), local control (LC), and regional control (RC). After matching, 123 patients were selected for analysis; 45 (36.6%) and 78 (63.4%) patients underwent unilateral and bilateral RT, respectively. The median follow-up was 36.27 months. The survival outcomes in the unilateral and bilateral RT groups were similar: 3-year CLNC (85.6% vs. 89.1%, p = 0.748), OS (53.2% vs. 57.4%, p = 0.229), DFS (46.5% vs. 48.6%, p = 0.515), DMFS (70.7% vs. 72.0%, p = 0.499), LC (78.0% vs. 75.6%, p = 0.692), and RC (79.9% vs. 76.2%, p = 0.465). On multivariable Cox regression analysis, unilateral and bilateral RT showed comparable outcomes; the number of ENEs ≥ 4 was the only significant prognostic factor for all clinical outcomes. Using decision tree analysis, we classified our patients to have a low, intermediate, or high risk of contralateral failure based on three factors: number of ENEs, margin status, and tumor stage. In conclusion, postoperative unilateral RT did not worsen outcomes in patients with ENE+ BMSCC in this cohort. The decision tree model may assist physicians in optimizing and tailoring radiation fields.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13235997
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 7
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    Hsp40 Protein DNAJB6 Interacts with Viral NS3 and Inhibits the Replication of the Japanese Encephalitis Virus
    MDPI AG ; 2019
    In:  International Journal of Molecular Sciences Vol. 20, No. 22 ( 2019-11-14), p. 5719-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 20, No. 22 ( 2019-11-14), p. 5719-
    Abstract: The Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus prevalent in east and southeast Asia, the Western Pacific, and northern Australia. Since viruses are obligatory intracellular pathogens, the dynamic processes of viral entry, replication, and assembly are dependent on numerous host-pathogen interactions. Efforts to identify JEV-interacting host factors are ongoing because their identification and characterization remain incomplete. Three enzymatic activities of flavivirus non-structural protein 3 (NS3), including serine protease, RNA helicase, and triphosphatase, play major roles in the flaviviruses lifecycle. To identify cellular factors that interact with NS3, we screened a human brain cDNA library using a yeast two-hybrid assay, and identified eight proteins that putatively interact with NS3: COPS5, FBLN5, PPP2CB, CRBN, DNAJB6, UBE2N, ZNF350, and GPR137B. We demonstrated that the DnaJ heat shock protein family (Hsp40) member B6 (DNAJB6) colocalizes and interacts with NS3, and has a negative regulatory function in JEV replication. We also show that loss of DNAJB6 function results in significantly increased viral replication, but does not affect viral binding or internalization. Moreover, the time-course of DNAJB6 disruption during JEV infection varies in a viral load-dependent manner, suggesting that JEV targets this host chaperone protein for viral benefit. Deciphering the modes of NS3-interacting host proteins functions in virion production will shed light on JEV pathogenic mechanisms and may also reveal new avenues for antiviral therapeutics.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms20225719
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 8
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    Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90
    MDPI AG ; 2018
    In:  Marine Drugs Vol. 16, No. 6 ( 2018-06-10), p. 204-
    Details
    In: Marine Drugs, MDPI AG, Vol. 16, No. 6 ( 2018-06-10), p. 204-
    Abstract: Heteronemin, a marine sesterterpenoid-type natural product, possesses diverse bioactivities, especially antitumor effect. Accumulating evidence shows that heteronemin may act as a potent anticancer agent in clinical therapy. To fully understand the antitumor mechanism of heteronemin, we further explored the precise molecular targets in prostate cancer cells. Initially, heteronemin exhibited potent cytotoxic effect against LNcap and PC3 prostate cancer cells with IC50 1.4 and 2.7 μM after 24 h, respectively. In the xenograft animal model, the tumor size was significantly suppressed to about 51.9% in the heteronemin-treated group in comparison with the control group with no significant difference in the mice body weights. In addition, the results of a cell-free system assay indicated that heteronemin could act as topoisomerase II (topo II) catalytic inhibitor through the elimination of essential enzymatic activity of topoisomerase IIα expression. We found that the use of heteronemin-triggered apoptosis by 20.1–68.3%, caused disruption of mitochondrial membrane potential (MMP) by 66.9–99.1% and promoted calcium release by 1.8-, 2.0-, and 2.1-fold compared with the control group in a dose-dependent manner, as demonstrated by annexin-V/PI, rhodamine 123 and Fluo-3 staining assays, respectively. Moreover, our findings indicated that the pretreatment of LNcap cells with an inhibitor of protein tyrosine phosphatase (PTPi) diminished growth inhibition, oxidative and Endoplasmic Reticulum (ER) stress, as well as activation of Chop/Hsp70 induced by heteronemin, suggesting PTP activation plays a crucial rule in the cytotoxic activity of heteronemin. Using molecular docking analysis, heteronemin exhibited more binding affinity to the N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. Finally, heteronemin promoted autophagy and apoptosis through the inhibition of Hsp 90 and topo II as well as PTP activation in prostate cancer cells. Taken together, these multiple targets present heteronemin as an interesting candidate for its future development as an antiprostatic agent.
    Type of Medium: Online Resource
    ISSN: 1660-3397
    URL: Article
    DOI: 10.3390/md16060204
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2175190-0
    SSG: 15,3
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  • 9
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    MicroRNA-23a-3p Down-Regulation in Active Pulmonary Tuberculosis Patients with High Bacterial Burden Inhibits Mononuclear Cell Function and Phagocytosis through TLR4/TNF-α/TGF-β1/IL-10 Signaling via Targeting IRF1/SP1
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 22 ( 2020-11-14), p. 8587-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 22 ( 2020-11-14), p. 8587-
    Abstract: The aim of this study is to explore the role of microRNAs (miR)-21/23a/146a/150/155 targeting the toll-like receptor pathway in active tuberculosis (TB) disease and latent TB infection (LTBI). Gene expression levels of the five miRs and predicted target genes were assessed in peripheral blood mononuclear cells from 46 patients with active pulmonary TB, 15 subjects with LTBI, and 17 non-infected healthy subjects (NIHS). THP-1 cell lines were transfected with miR-23a-3p mimics under stimuli with Mycobacterium TB-specific antigens. Both miR-155-5p and miR-150-5p gene expressions were decreased in the active TB group versus the NIHS group. Both miR-23a-3p and miR-146a-5p gene expressions were decreased in active TB patients with high bacterial burden versus those with low bacterial burden or control group (LTBI + NIHS). TLR2, TLR4, and interleukin (IL)10 gene expressions were all increased in active TB versus NIHS group. MiR-23a-3p mimic transfection reversed ESAT6-induced reduction of reactive oxygen species generation, and augmented ESAT6-induced late apoptosis and phagocytosis, in association with down-regulations of the predicted target genes, including tumor necrosis factor (TNF)-α, TLR4, TLR2, IL6, IL10, Notch1, IL6R, BCL2, TGF-β1, SP1, and IRF1. In conclusion, the down-regulation of miR-23a-3p in active TB patients with high bacterial burden inhibited mononuclear cell function and phagocytosis through TLR4/TNF-α/TGF-β1/IL-10 signaling via targeting IRF1/SP1.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21228587
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 10
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    Inhibition of Arachidonate 12/15-Lipoxygenase Improves α-Galactosidase Efficacy in iPSC-Derived Cardiomyocytes from Fabry Patients
    MDPI AG ; 2018
    In:  International Journal of Molecular Sciences Vol. 19, No. 5 ( 2018-05-16), p. 1480-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 19, No. 5 ( 2018-05-16), p. 1480-
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms19051480
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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