Ovarian cancer spheroids constitute a metastatic niche for transcoelomic spread that also engenders drug resistance. Spheroid-forming cells express active STAT3 signaling and display stem cell-like ...properties that may contribute to ovarian tumor progression. In this study, we show that STAT3 is hyperactivated in ovarian cancer spheroids and that STAT3 disruption in this setting is sufficient to relieve chemoresistance. In an NSG murine model of human ovarian cancer, STAT3 signaling regulated spheroid formation and self-renewal properties, whereas STAT3 attenuation reduced tumorigenicity. Mechanistic investigations revealed that Wnt signaling was required for STAT3-mediated spheroid formation. Notably, the Wnt antagonist DKK1 was the most strikingly upregulated gene in response to STAT3 attenuation in ovarian cancer cells. STAT3 signaling maintained stemness and interconnected Wnt/β-catenin signaling via the miR-92a/DKK1-regulatory pathways. Targeting STAT3 in combination with paclitaxel synergistically reduced peritoneal seeding and prolonged survival in a murine model of intraperitoneal ovarian cancer. Overall, our findings define a STAT3-miR-92a-DKK1 pathway in the generation of cancer stem-like cells in ovarian tumors, with potential therapeutic applications in blocking their progression.
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Metastasis is the major cause of death from lung cancer. Quercetin, a widely distributed bioflavonoid, is well known to induce growth inhibition in a variety of human cancer cells, but how it affects ...lung cancer cell invasion and metastasis is unclear. Herein, we found that quercetin inhibited the migration/invasion of non-small cell lung cancer (NSCLC) cell lines and bone metastasis in an orthotopic A549 xenograft model by suppressing the Snail-mediated epithelial-to-mesenchymal transition (EMT). Moreover, survival times of animals were also prolonged after quercetin treatment. Mechanistic investigations found that quercetin suppressed Snail-dependent Akt activation by upregulating maspin and Snail-independent a disintegrin and metalloproteinase (ADAM) 9 expression pathways to modulate the invasive ability of NSCLC cells. In clinical samples, we observed that patients with Snailhigh/p-Akthigh tumors had the shortest survival times. In addition, a lower survival rate was also found in ADAM9high patients than in ADAM9low patients. Overall, our results provide new insights into the role of quercetin-induced molecular regulation in suppressing NSCLC metastasis and suggest that quercetin has potential therapeutic applications for metastatic NSCLC.
•Quercetin inhibits the migration/invasion of NSCLC cells through suppressing the EMT.•Quercetin attenuates bone metastasis and prolongs lifespan in an in vivo model.•Quercetin suppresses snail-dependent Akt activation by upregulating maspin.•Quercetin suppresses snail-independent ADAM9 expression.•Snail or ADAM9 expression is inversely correlated with survival of patients.
Background
Nasopharyngeal carcinoma (NPC) is a common type of head and neck cancer in Asia. Adverse effects occur in over 90% of NPC patients treated with radiotherapy or chemoradiation. Angiotensin ...II receptor blockers (ARBs) are commonly used to treat hypertension without serious adverse effects. However, the anticancer activity of ARBs in NPC remains unclear.
Methods
We investigated the survival impacts of ARBs among NPC patients in a retrospective study. The anticancer effects and related signaling pathways of the ARBs valsartan and losartan were also evaluated in vitro and in vivo.
Result
A total of 927 patients with NPC who had hypertension were enrolled in the study, 272 (29.3%) of whom received ARBs. Kaplan‐Meier analysis revealed that patients who used ARBs had higher rates of 5‐year overall survival (OS; 87.8% vs 75.1%; P = .002) and disease‐specific survival (DSS; 95.4% vs 77.7%; P < .001) than those who did not receive this treatment. Additionally, ARBs inhibited cell proliferation and induced apoptosis by increasing levels of cleaved caspase‐3, cleaved caspase‐9, and cytochrome C; the cell population in the sub‐G1 phase; and caspase‐3 activity in NPC‐TW01 cells. ARBs inhibited tumor growth and angiogenesis via apoptosis in an NPC xenografts model. Interestingly, ARBs inhibited phosphorylation of PI3K/AKT signaling in vitro and in vivo, which is markedly attributed to their antitumor effects in NPC.
Conclusion
These data indicate that ARBs not only improve 5‐year OS and DSS among patients with NPC but also exert antiproliferative and antiangiogenesis effects by inducing apoptosis in NPC, supporting that ARBs may be promising agents for treatment of NPC.
Use of angiotensin II receptor blockers (ARBs) is associated with improved survival in patients who have nasopharyngeal carcinoma (NPC). The ARBs valsartan and losartan suppress tumor growth and angiogenesis in NPC xenografts.
Nasopharyngeal carcinoma (NPC), a disease common in the South‐East Asian population, has high lymph node metastatic ability. Melatonin, an endogenously produced substance present in animals, plants, ...fungi, and bacteria, has oncostatic activity via several mechanisms. The molecular mechanisms involved in melatonin‐mediated tumor inhibitory potential are not completely defined. Here, we show that melatonin treatment inhibits TPA‐induced cell motility by regulating the matrix metalloproteinase‐9 (MMP‐9) expression in NPC. We also identified the signaling cascade through which melatonin inhibits MMP‐9 expression; this involves melatonin regulating the binding activity of the transcription factor specificity protein‐1 (SP‐1)‐DNA. Our mechanistic analysis further reveals that the c‐Jun N‐terminal kinase/mitogen‐activated protein kinase pathway is involved in the melatonin‐mediated tumor suppressor activity. Furthermore, the findings indicate a functional link between melatonin‐mediated MMP‐9 regulation and tumor suppressing ability and provide new insights into the role of melatonin‐induced molecular and epigenetic regulation of tumor growth. Thus, we conclude that melatonin suppresses the motility of NPC by regulating TPA‐induced MMP‐9 gene expression via inhibiting SP‐1‐DNA binding ability. The results provide a functional link between melatonin‐mediated SP‐1 regulation and the antimetastatic actions of melatonin on nasopharyngeal carcinoma.
The efficacy and safety of maternal tenofovir disoproxil fumarate (TDF) in reducing mother‐to‐infant hepatitis B virus (HBV) transmissions is not clearly understood. We conducted a prospective, ...multicenter trial and enrolled 118 hepatitis B surface antigen (HBsAg)– and hepatitis B e antigen–positive pregnant women with HBV DNA ≥7.5 log10 IU/mL. The mothers received no medication (control group, n = 56, HBV DNA 8.22 ± 0.39 log10 IU/mL) or TDF 300 mg daily (TDF group, n = 62, HBV DNA 8.18 ± 0.47 log10 IU/mL) from 30‐32 weeks of gestation until 1 month postpartum. Primary outcome was infant HBsAg at 6 months old. At delivery, the TDF group had lower maternal HBV DNA levels (4.29 ± 0.93 versus 8.10 ± 0.56 log10 IU/mL, P < 0.0001). Of the 121/123 newborns, the TDF group had lower rates of HBV DNA positivity at birth (6.15% versus 31.48%, P = 0.0003) and HBsAg positivity at 6 months old (1.54% versus 10.71%, P = 0.0481). Multivariate analysis revealed that the TDF group had lower risk (odds ratio = 0.10, P = 0.0434) and amniocentesis was associated with higher risk (odds ratio 6.82, P = 0.0220) of infant HBsAg positivity. The TDF group had less incidence of maternal alanine aminotransferase (ALT) levels above two times the upper limit of normal for ≥3 months (3.23% versus 14.29%, P = 0.0455), a lesser extent of postpartum elevations of ALT (P = 0.007), and a lower rate of ALT over five times the upper limit of normal (1.64% versus 14.29%, P = 0.0135) at 2 months postpartum. Maternal creatinine and creatinine kinase levels, rates of congenital anomaly, premature birth, and growth parameters in infants were comparable in both groups. At 12 months, one TDF‐group child newly developed HBsAg positivity, presumably due to postnatal infection and inefficient humoral responses to vaccines. Conclusions: Treatment with TDF for highly viremic mothers decreased infant HBV DNA at birth and infant HBsAg positivity at 6 months and ameliorated maternal ALT elevations. (Hepatology 2015;62:375–386
Monoamine oxidase B (MAOB), a neurotransmitter‐degrading enzyme, was reported to reveal conflicting roles in various cancers. However, the functional role of MAOB and impacts of its genetic variants ...on prostate cancer (PCa) is unknown. Herein, we genotyped four loci of MAOB single‐nucleotide polymorphisms (SNPs), including rs1799836 (A/G), rs3027452 (G/A), rs6651806 (A/C) and rs6324 (G/A) in 702 PCa Taiwanese patients. We discovered that PCa patients carrying the MAOB rs6324 A‐allele exhibited an increased risk of having a high initial prostate‐specific antigen (iPSA) level (>10 ng/mL). Additionally, patients with the rs3027452 A‐allele had a higher risk of developing distal metastasis, particularly in the subpopulation with high iPSA levels. In a subpopulation without postoperative biochemical recurrence, patients carrying the rs1799836 G‐allele had a higher risk of developing lymph node metastasis and recurrence compared to those carrying the A‐allele. Furthermore, genotype screening in PCa cell lines revealed that cells carrying the rs1799836 G‐allele expressed lower MAOB levels than those carrying the A‐allele. Functionally, overexpression and knockdown of MAOB in PCa cells respectively suppressed and enhanced cell motility and proliferation. In clinical observations, correlations of lower MAOB expression levels with higher Gleason scores, advanced clinical T stages, tumour metastasis, and poorer prognosis in PCa patients were noted. Our findings suggest that MAOB may act as a suppressor of PCa progression, and the rs3027452 and rs1799836 genetic variants of MAOB are linked to PCa metastasis within the Taiwanese population.
Background
The abnormal modification of chondroitin sulfate is one of the leading causes of disease, including cancer progression. During chondroitin sulfate biosynthesis, the CHST11 enzyme plays a ...vital role in its modification, but its role in cancer is not fully understood. Therefore, understanding the relationship between CHST11 and pulmonary‐related diseases through clinically relevant information may be useful for diagnosis or treatment.
Methods
A variety of pulmonary fibrosis clinical gene expression omnibus (GEO) datasets were used to assess the association between CHST11‐related manifestations and fibrosis. Multiple lung cancer‐related databases, including The Cancer Genome Atlas, GEO datasets, UCSC Xena, GEPIA2, Cbioportal and ingenuity pathway analysis were used to evaluate the clinical correlation between CHST11 and lung cancer and potential molecular mechanisms. For drug repurposing prediction, the molecules that correlated with CHST11 were subjected to the LINCS L1000 algorithm. A variety of in vitro assays were performed to evaluate the in‐silico models, including RNA and protein expression, proliferation, migration and invasion.
Results
Clinical analyses indicate that the levels of CHST11 are significantly elevated in cases of pulmonary‐related diseases, including fibrosis and lung cancer. According to multiple lung cancer cohorts, CHST11 is the only member of the carbohydrate sulfotransferase family associated with overall survival for lung adenocarcinomas, and it is highly related to smoking‐induced lung cancer patients. Based on the results of in vitro experiments, CHST11 expression contributes to tumor malignancy and promotes multiple fibrotic activators. Correlation‐based ingenuity pathway analysis indicated that CHST11‐related molecules contributed to pulmonary fibrosis or lung adenocarcinomas via similar upstream stimulators. Based on known molecular regulatory relationships, CHST11 has been associated with the regulation of TGF‐β and INFγ as important molecules contributing to fibrosis and cancer progression. Interestingly, WordCloud analysis revealed that CHST11‐related molecules are involved in regulation primarily by integrin signaling, and these relationships were consistently reflected in the analysis of cell lines and the clinical correlation. A CHST11 signature‐based drug repurposing analysis demonstrated that the CHST11/integrin axis could be targeted by AG‐1478 (Tyrphostin AG 1478), brefeldin A, geldanamycin and importazole.
Conclusions
This study provides the first demonstration that CHST11 may be used as a biomarker for pulmonary fibrosis or lung cancer, and the levels of CHST11 were increased by TGF‐β and INFγ. The molecular simulation analyses demonstrate that the CHST11/integrin axis is a potential therapeutic target for treating lung cancer.
In this study, expression of CHST11 was linked to pulmonary related diseases such as fibrosis and lung cancer progression. It may be possible to provide alternative strategies for pulmonary diseases by targeting CHST11‐related events.
To date, all-inorganic lead halide perovskite quantum dots have emerged as promising materials for photonic, optoelectronic devices, and biological applications, especially in solar cells, raising ...numerous concerns about their biosafety. Most of the studies related to the toxicity of perovskite quantum dots (PeQDs) have focused on the potential risks of hybrid perovskites by using zebrafish or human cells. So far, the neurotoxic effects and fundamental mechanisms of PeQDs remain unknown. Herein, a comprehensive methodology is designed to investigate the neurotoxicity of PeQDs by using Caenorhabditis elegans as a model organism. The results show that the accumulation of PeQDs mainly focuses on the alimentary system and head region. Acute exposure to PeQDs results in a decrease in locomotor behaviors and pharyngeal pumping, whereas chronic exposure to PeQDs causes brood decline and shortens lifespan. In addition, some abnormal issues occur in the uterus during reproduction assays, such as vulva protrusion, impaired eggs left in the vulva, and egg hatching inside the mother. Excessive reactive oxygen species formation is also observed. The neurotoxicity of PeQDs is explained by gene expression. This study provides a complete insight into the neurotoxicity of PeQD and encourages the development of novel nontoxic PeQDs.
Renal cell carcinoma (RCC) is the most lethal of all urological malignancies because of its potent metastasis potential. Melatonin exerts multiple tumor‐suppressing activities through ...antiproliferative, proapoptotic, and anti‐angiogenic actions and has been tested in clinical trials. However, the antimetastastic effect of melatonin and its underlying mechanism in RCC are unclear. In this study, we demonstrated that melatonin at the pharmacologic concentration (0.5–2 mm) considerably reduced the migration and invasion of RCC cells (Caki‐1 and Achn). Furthermore, we found that melatonin suppressed metastasis of Caki‐1 cells in spontaneous and experimental metastasis animal models. Mechanistic investigations revealed that melatonin transcriptionally inhibited MMP‐9 by reducing p65‐ and p52‐DNA‐binding activities. Moreover, the Akt‐mediated JNK1/2 and ERK1/2 signaling pathways were involved in melatonin‐regulated MMP‐9 transactivation and cell motility. Clinical samples revealed an inverse correlation between melatonin receptor 1A (MTNR1A) and MMP‐9 expression in normal kidney and RCC tissues. In addition, a higher survival rate was found in MTNR1Ahigh/MMP‐9low patients than in MTNR1Alow/MMP‐9high patients. Overall, our results provide new insights into the role of melatonin‐induced molecular regulation in suppressing RCC metastasis and suggest that melatonin has potential therapeutic applications for metastastic RCC.
The tissue inhibitor of metalloproteinase-3 (TIMP3) is the only member of the TIMP family that binds to the extracellular matrix and suppresses cancer cell growth, angiogenesis, migration, and ...invasion. However, whether the abnormal expression and promoter methylation of TIMP3 facilitates oral cancer metastasis remain unclear. In this study, the DNA methylation levels of TIMP3 CpG islands were assessed through pyrosequencing. Artificial modulation of TIMP3 was performed to explore the role of TIMP3 in tumor metastasis in vitro and in vivo. Our results showed that the suppression of TIMP3 transcription by DNA methylation involves the inhibition of the binding of the transcription factor Sp1 to the TIMP3 promoter as well as the upregulation of DNMT1 and DNMT3B. Functional analyses revealed that TIMP3 overexpression reduced migration and invasion abilities in oral cancer cells and inhibited lymph node metastasis in vivo. Moreover, TIMP3 regulated epithelial-mesenchymal transition by increasing the expression of the epithelial markers and reducing the expression of the mesenchymal markers. In conclusion, our findings suggested that the suppression of TIMP3 by DNA methylation contributes to oral cancer metastasis.
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