L48H37 is a synthetic curcumin analog that has anticancer potentials. Here, we further explored the anticancer effect of L48H37 on oral cancer cells and its mechanistic acts. Cell cycle distribution ...was assessed using flow cytometric analysis. Apoptosis was elucidated by staining with PI/Annexin V and activation of the caspase cascade. Cellular signaling was explored using apoptotic protein profiling, Western blotting, and specific inhibitors. Our findings showed that L48H37 significantly reduced the cell viability of SCC-9 and HSC-3 cells, resulting in sub-G1 phase accumulation and increased apoptotic cells. Apoptotic protein profiling revealed that L48H37 increased cleaved caspase-3, and downregulated cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP) in SCC-9 cells, and the downregulated cIAP1 and XIAP in both oral cancer cells were also demonstrated by Western blotting. Meanwhile, L48H37 triggered the activation of caspases and mitogen-activated protein kinases (MAPKs). The involvement of c-Jun N-terminal kinase (JNK) and p38 MAPK (p38) in the L48H37-triggered apoptotic cascade in oral cancer cells was also elucidated by specific inhibitors. Collectively, these findings indicate that L48H37 has potent anticancer activity against oral cancer cells, which may be attributed to JNK/p38-mediated caspase activation and the resulting apoptosis. This suggests a potential benefit for L48H37 for the treatment of oral cancer.
The gene encoding aldehyde dehydrogenase 7 family member A1 (ALDH7A1) has been associated with the development and prognosis in multiple cancers; however, the role of
polymorphisms in oral cancer ...remains unknown. For this purpose, the influences of
rs13182402 and rs12659017 on oral cancer development and prognosis were analyzed. Our resulted showed that
rs13182402 genotype had less pathologic nodal metastasis among betel quid chewer.
rs13182402 also corresponded to higher expressions in upper aerodigestive mucosa, whole blood, the musculoskeletal system and oral cancer tissues than did the
wild type. Furthermore, ALDH7A1 overexpression in oral cancer cells increased
migration, whereas its silencing reduced cell migration. Conversely, ALDH7A1 expression in tumor tissues and in patients with advanced disease was lower than that in normal tissues and in patients with early-stage disease. When the patients were classified into ALDH7A1-high and -low-expression groups, the high-ALDH7A1 group had superior outcomes in progression-free survival than the low-ALDH7A1 group (5-year survival of 58.7% vs. 48.0%,
= 0.048) did. In conclusion, patients with high ALDH7A1 expression might, however, have more favorable prognoses than those with low ALDH7A1 expression have.
► PUE is widely used as anti-inflammatory and anti-hepatotoxic medicines. ► PUE concentration-dependently inhibited migration/invasion capacities of Saos-2. ► PUE inhibits phosphorylation of ERK1/2 ...and Akt. ► PUE inhibits the binding activities of the transcription factors SP-1.
Phyllanthus urinaria is widely used as anti-inflammatory, antiviral, antibacterial, and anti-hepatotoxic medicines in almost every tropical country. However, scientific evidence supporting its use in cancer metastasis is limited, particularly osteosarcoma. We investigated the effect of P. urinaria extract (PUE) on cell viability, invasion, and migration in the human osteosarcoma Saos-2 cell line, and looked at the impact of PUE on several relevant proteases and signaling pathways. This study demonstrates that PUE, at a range of concentrations (from 0 to 100μg/ml), concentration-dependently inhibited the migration/invasion capacities of Saos-2 without cytotoxic effects. Zymographic and western blot analyses revealed that PUE inhibited the urokinase-type plasminogen activator (u-PA) and matrix metalloproteinase-2 (MMP-2) enzyme activity, as well as protein expression. Western blot analysis also showed that PUE inhibits phosphorylation of ERK1/2 and Akt. Testing of mRNA level, quantitative real-time PCR, and promoter assays evaluated the inhibitory effects of PUE on u-PA expression in Saos-2 cells. The chromatin immunoprecipitation (ChIP) assay was reactive to the transcription protein SP-1, which was inhibited by PUE. In conclusion, PUE suppresses human osteosarcoma Saos-2 cell invasion and migration by transcriptionally inhibiting u-PA via ERK and Akt signaling pathways. Therefore, PUE produces anti-metastatic activity in Saos-2 cells.
Oral cancer is a major head and neck cancer that is reported to be causally associated with genetic factors and environmental carcinogens. Endothelial nitric oxide synthase (eNOS) was reported to ...modulate carcinogenesis and progression through nitric oxide (NO) production. Genetic polymorphisms in the eNOS gene can regulate its transcription and further mediate NO production. The purpose of this study was to explore the influences of eNOS gene polymorphisms combined with environmental carcinogens on the predisposition for oral cancer. Two single-nucleotide polymorphisms (SNPs) of the eNOS gene, −786 T > C (rs2070744) and 894G > T (rs1799983), were genotyped in 1200 controls and 1044 patients with oral cancer using a TaqMan-based real-time polymerase chain reaction (PCR). We found that patients who carried the −786 T > C TC genotype were at higher risk for developing an advanced clinical stage (stage III/IV) compared to those with the −786 T > C TT genotype; however, there was no significant association of the two individual SNPs with oral cancer between patients and the control group. According to behavioral exposure to environmental carcinogens, the presence of these two eNOS SNPs combined with tobacco use and/or betel quid chewing profoundly enhanced the risk of oral cancer. Moreover, carriers with the betel quid-chewing habit who had haplotypes of the two eNOS SNPs more easily developed oral cancer. These results indicated an involvement of −786 T > C polymorphisms in the progression of oral cancer and support the interaction between eNOS gene polymorphisms and environmental carcinogens as a predisposing factor of oral carcinogenesis.
•The eNOS −786 T/C genotype associates the risk of developing advanced oral cancer.•A combined effect of eNOS SNPs with carcinogens contributes to oral carcinogenesis.•A combined effect of eNOS haplotype with carcinogens promotes oral carcinogenesis.•The eNOS expression correlates with prognosis of head and neck cancer patients.
In Taiwan, oral cancer is the fourth leading cancer in males and is associated with exposure to environmental carcinogens. WW domain-containing oxidoreductase (WWOX), a tumor suppressor gene, is ...associated with the development of various cancers. We hypothesized that genetic variants of WWOX influence the susceptibility to oral cancer. Five polymorphisms of WWOX gene from 761 male patients with oral cancer and 1199 male cancer-free individuals were genotyped. We observed that individuals carrying the polymorphic allele of WWOX rs11545028 are more susceptible to oral cancer. Furthermore, patients with advanced-stage oral cancer were associated with a higher frequency of WWOX rs11545028 polymorphisms with the variant genotype TT than did patients with the wild-type gene. An additional integrated in silico analysis confirmed that rs11545028 affects WWOX expression, which significantly correlates with tumor expression and subsequently with tumor development and aggressiveness. In conclusion, genetic variants of WWOX contribute to the occurrence of oral cancer, and the findings regarding these biomarkers provided a prediction model for risk assessment.
Oral cancer is the most common malignancy with poor prognosis and is the fourth most common cancer in men in Taiwan. The tissue inhibitor of metalloproteinase-3 (TIMP3) acts as a tumor suppressor ...gene by inhibiting the growth, angiogenesis, migration, and invasion of cancer cells. However, few studies have examined the association of plasma TIMP3 levels with oral squamous cell carcinoma (OSCC), and the role of plasma TIMP3 levels in OSCC progression is still unclear. We measured the plasma TIMP3 levels of 450 OSCC patients and 64 healthy controls by using a commercial enzyme-linked immunosorbent assay. We also analyzed TIMP3 mRNA levels of 328 OSCC patients and 32 normal tissues from The Cancer Genome Atlas (TCGA) dataset. Our results revealed that plasma TIMP3 levels were significantly lower in patients with OSCC than in healthy controls (p < 0.001). Moreover, plasma TIMP3 levels in patients with OSCC were significantly associated with the tumor stage and tumor status but not with the lymph node status, metastasis, and cell differentiation. To verify our findings, we also examined TCGA bioinformatics database and discovered similar results for the association with the pathological stage of OSCC. In conclusion, our results suggest that plasma TIMP3 is a potential biomarker for predicting the tumor stage and T status in patients with OSCC.
Abstract
Tissue inhibitor of metalloproteinase (TIMP)-3, a member of the TIMP family, is the only substance that can bind with the ECM and its main role is regulating the cell cycle and cancer cell ...progression. However, little is known about whether abnormal expression and promoter methylation of TIMP-3 facilitates oral cancer metastasis. In this study, DNA methylation levels of the TIMP-3 CpG islands were assessed using bisulfite DNA sequencing and methylation-specific PCR. The results shown that expression of TIMP-3 is decreased in most oral cancer tissues compared with adjacent normal tissues (p<0.001). DNA methylation analysis showed a hypermethylation of TIMP-3 gene in oral cancer cell lines and in oral cancer tumors. Furthermore, suppression of TIMP-3 transcription by DNA methylation involves inhibition of transcription factor SP1 binding to the TIMP-3 promoter. Functional analyses revealed that the stable overexpression of TIMP-3 reduced the migration ability in oral cancer cells (p<0.001). Moreover, the expression levels of the epithelial markers E-cadherin were increased, while the expression levels of the mesenchymal markers vimentin and fibronectin were decreased in cells overexpressing TIMP-3. In conclusion, these results suggest that suppression of TIMP-3 by DNA methylation contributes to oral cancer metastasis.
Citation Format: Shun-Fa Yang, Chun-Wen Su, Chiao-Wen Lin. Methylation-mediated silencing of TIMP-3 facilitates oral cancer metastasis by modulating binding of SP1 transcription factor. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-151. doi:10.1158/1538-7445.AM2015-LB-151
This article is devoted to the study of variable 2-microlocal Besov-type and Triebel- Lizorkin-type spaces. These variable function spaces are defined via a Fourier-analytical approach. The authors ...then characterize these spaces by means of Q-transforms, Peetre maximal functions, smooth atoms, ball means of differences and approximations by analytic functions. As applications, some re- lated Sobolev-type embeddings and trace theorems of these spaces are Mso established. Moreover, some obtained results, such as characterizations via approximations by analytic functions, are new even for the classical variable Besov and Triebel-Lizorkin spaces.
A multicomponent metallic glass (MG) with highly efficient and anomalous durability for catalyzing water splitting is reported. The outstanding performance of the MG catalyst contributed by ...self‐optimized active sites originates from the intrinsic chemical heterogeneity and selective dealloying on the disordered surface; thus, a new mechanism for improving the durability of catalysts is uncovered.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19)
.... The development of a vaccine is likely to take at least 12-18 months, and the typical timeline for approval of a new antiviral therapeutic agent can exceed 10 years. Thus, repurposing of known drugs could substantially accelerate the deployment of new therapies for COVID-19. Here we profiled a library of drugs encompassing approximately 12,000 clinical-stage or Food and Drug Administration (FDA)-approved small molecules to identify candidate therapeutic drugs for COVID-19. We report the identification of 100 molecules that inhibit viral replication of SARS-CoV-2, including 21 drugs that exhibit dose-response relationships. Of these, thirteen were found to harbour effective concentrations commensurate with probable achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod
and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825 and ONO 5334. Notably, MDL-28170, ONO 5334 and apilimod were found to antagonize viral replication in human pneumocyte-like cells derived from induced pluripotent stem cells, and apilimod also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, their known pharmacological and human safety profiles will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.
PDF
