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With the rapid emergence of antibiotic-resistant pathogens, nanomaterial-assisted catalytic sterilization has been well developed to combat pathogenic bacteria by elevating the level of reactive oxygen species including hydroxyl radical (·OH). Although promising, the ultra-short lifetime and limited diffusion distance of ·OH severely limit their practical antibacterial usage. Herein, the rational design and preparation of novel virus-like copper silicate hollow spheres (CSHSs) are reported, as well as their applications as robust artificial bacteriophages for localized bacterial capture and enhanced catalytic sterilization in the treatment of oral infectious diseases. During the whole process of capture and killing, CSHSs can efficiently capture bacteria via shortening the distance between bacteria and CSHSs, produce massive ·OH around bacteria, and further iinducing the admirable effect of bacterial inhibition. By using mucosal infection and periodontitis as typical oral infectious diseases, it is easily found that the bacterial populations around lesions in animals after antibacterial treatment fall sharply, as well as the well-developed nanosystem can decrease the inflammatory reaction and promote the hard or soft tissue repair. Together, the high Fenton-like catalytic activity, strong bacterial affinity, excellent antibacterial activity, and overall safety of the nanoplatform promise its great therapeutic potential for further catalytic bacterial disinfection.
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As the main challenge of dental healthcare, oral infectious diseases are highly associated with the colonization of pathogenic microbes. However, current antibacterial treatments in the field of stomatology still lack a facile, safe, and universal approach. Herein, we report the controllable synthesis of copper aluminum-layered double hydroxides (CuAl-LDHs) with high Fenton-like catalytic activity, which can be utilized in the treatment of oral infectious diseases with negligible side effects. Our strategy can efficiently avoid the unwanted doping of other divalent metal ions in the synthesis of Cu-contained LDHs and result in the formation of binary CuAl-LDHs with high crystallinity and purity. Evidenced by experimental and theoretical results, CuAl-LDHs exhibit excellent catalytic ability toward the ·OH generation in the presence of H2O2 and hold strong affinity toward bacteria, endowing them with great catalytic sterilization against both Gram-positive and Gram-negative bacteria. As expected, these CuAl-LDHs provide outstanding treatments for mucosal infection and periodontitis by promoting wound healing and remodeling of the periodontal microenvironment. Moreover, toxicity investigation demonstrates the overall safety. Accordingly, the current study not only provides a convenient and economic strategy for treating oral infectious diseases but also extends the development of novel LDH-based Fenton or Fenton-like antibacterial reagents for further biomedical applications.
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Alumínio , Antibacterianos , Cobre , Peróxido de Hidrogênio , Cobre/química , Cobre/farmacologia , Catálise , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Alumínio/química , Alumínio/farmacologia , Hidróxidos/química , Hidróxidos/farmacologia , Testes de Sensibilidade Microbiana , Animais , Ferro/química , Ferro/farmacologia , Saúde Bucal , Camundongos , Humanos , Bactérias Gram-Negativas/efeitos dos fármacosRESUMO
Living cell-mediated nanodelivery system is considered a promising candidate for targeted antitumor therapy; however, their use is restricted by the adverse interactions between carrier cells and nanocargos. Herein, a novel erythrocyte-based nanodelivery system is developed by assembling renal-clearable copper sulfide (CuS) nanodots on the outer membranes of erythrocytes via a lipid fusion approach, and demonstrate that it is an efficient photothermal platform against hepatocellular carcinoma. After intravenous injection of the nanodelivery system, CuS nanodots assembled on erythrocytes can be released from the system, accumulate in tumors in response to the high shear stress of bloodstream, and show excellent photothermal antitumor effect under the near infrared laser irradiation. Therefore, the erythrocyte-mediated nanodelivery system holds many advantages including prolonged blood circulation duration and enhanced tumor accumulation. Significantly, the elimination half-life of the nanodelivery system is 74.75 ± 8.77 h, which is much longer than that of nanodots (33.56 ± 2.36 h). Moreover, the other two kinds of nanodots can be well assembled onto erythrocytes to produce other erythrocyte-based hitchhiking platforms. Together, the findings promote not only the development of novel erythrocyte-based nanodelivery systems as potential platforms for tumor treatment but also their further clinical translation toward personalized healthcare.
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Carcinoma Hepatocelular , Cobre , Eritrócitos , Neoplasias Hepáticas , Terapia Fototérmica , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Terapia Fototérmica/métodos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/tratamento farmacológico , Animais , Cobre/química , Humanos , Rim/patologia , Camundongos , Nanopartículas/química , Linhagem Celular TumoralRESUMO
BACKGROUND: Periodontitis (PD) may affect temporomandibular joint disorders (TMD) and TMD may influence PD in previous observational studies. Nevertheless, these studies were prone to confounders and reverse causation, leading to incorrect conclusions about causality and direction of association. This research investigates the associations between PD and TMD employing bidirectional two-sample Mendelian randomization (MR) analysis. METHODS: Single-nucleotide polymorphisms (SNPs) related to PD (p < 5 × 10-6) were selected from a genome-wide association study (GWAS) from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) consortium, and related these to SNPs from FinnGen and UK Biobank (UKB) consortia, and vice versa. We implemented the standard inverse variance weighted (IVW), weighted median (WM), MR-Egger regression, and MR-PRESSO methods to estimate the potential causality between PD and TMD. Sensitive tests were conducted using robust MR methods. Results from FinnGen and UKB were combined using the fixed model. RESULTS: PD did not appear to causally affect TMD. Additionally, the reverse MR analysis did not reveal a significant causal effect of TMD on PD. The results of other MR methods were similar to those of the IVW method. Sensitivity analyses addressed no potential pleiotropy in MR estimations. Results from the meta-analysis were consistent with the above-mentioned consequences. CONCLUSION: This research does not support a causal relationship between PD and TMD. PD does not appear to worsen TMD directly, and vice versa.
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Periodontite , Transtornos da Articulação Temporomandibular , Humanos , Estudo de Associação Genômica Ampla , Periodontite/genética , Epistasia Genética , Estilo de Vida , Transtornos da Articulação Temporomandibular/epidemiologia , Transtornos da Articulação Temporomandibular/genéticaRESUMO
In this article, we consider conformable fractional stochastic differential equations (CFSDEs) driven by fBm with infinite delay via measures of noncompactness (MNC). As far as we know, there are few papers considering this issue. First, by virtue of a Mönch fixed point theorem and MNC, we explore the existence of solutions for CFSDEs. Subsequently, with the aid of Jensen inequality, Hölder inequality, stochastic analysis techniques, and semigroup theory, the controllability for this considered CFSDEs is investigated by employing a Mönch fixed point theorem. Thereafter, the controllability of CFSDEs with nonlocal conditions is discussed. Finally, the theoretical result is supported through an example.
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Objective: The aim of the present study was to determine overall survival (OS) and risk factors associated with early recurrence in patients with FIGO I-II stage endometrial carcinoma (EC). Methods: Clinical features were retrospectively extracted from the database of China Endometrial Cancer Consortium from January 2000 to December 2019. A total of 2,974 patients with Federation International of Gynecology and Obstetrics (FIGO) I-II stage endometrial cancer were included. Kaplan-Meier survival analysis was used to assess OS and disease-specific survival. Cox proportional hazard model and Fine-Gray model were used to determine the factors related to OS. Binary logistic regression model was used to determine independent predictors of early relapse patients. Results: Of these 2,974 ECs, 189 patients were confirmed to have relapse. The 5-year OS was significantly different between the recurrence and non-recurrence patients (p < 0.001). Three quarters of the relapse patients were reported in 36 months. The 5-year OS for early recurrence patients was shorter than late recurrence [relapse beyond 36 months, p < 0.001]. The grade 3 [odds ratio (OR) = 1.55, 95%CI 1.17-2.05, p = 0.002], lymphatic vascular infiltration (LVSI; OR = 3.36; 95%CI 1.50-7.54, p = 0.003), and myometrial infiltration (OR = 2.07, 95%CI 1.17-3.65, p = 0.012) were independent risk factors of early relapse. The protective factor of that is progesterone receptor (PR)-positive (OR = 0.50, 95%CI 0.27-0.92, p = 0.02). Bilateral ovariectomy could reduce recurrence risk rate (OR = 0.26, 95%CI 0.14-0.51, p < 0.001). Conclusion: The OS of early relapse EC is worse. Grade 3, LVSI, and myometrial infiltration are independent risk factors for early relapse EC. In addition, the protective factor is PR-positive for those people and bilateral salpingo-oophorectomy could reduce the risk of recurrence.
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OBJECTIVE: The prognostic impact and treatment responses among cervical cancer patients with different histological types remains inconclusive. To determine the prognostic effects of different histologic types, we identified 39,088 patients with a diagnosis of cervical cancer between 2004 and 2016 from the Surveillance, Epidemiology, and End Results program. METHODS: Variables related to the prognosis of cervical cancer were evaluated using log-rank method and univariate/multivariate Cox models before and after propensity score matching. RESULT: Of the 36,310 patients, Squamous cell carcinoma (SCC) was the most common histological type (n = 27,043, 74.5%), followed by adenocarcinoma (AC, n = 7755, 21.4%) and adenosquamous carcinoma (ASC, n = 1512, 4.1%). Compared to SCC patients, patients with AC (HR = 1.14, 95%CI = 1.09-1.20, P < 0.01) and ASC (HR = 1.28, 95%CI = 1.18-1.40, P < 0.01) showed significantly poorer prognosis. Subgroup analyses indicated that the differences in prognosis between AC and SCC were only observed in stage II and III patients (P < 0.01). In patients with concurrent chemoradiotherapy, survival rates of patients with AC were significantly worse compared with similar patients with SCC (HR = 1.14, 95%CI = 1.03-1.27; P < 0.01). CONCLUSION: The prognostic impact of histologic types among patients with cervical cancer depends on tumor stages and therapeutic approaches. Tailored treatment and follow-up planning need to be developed across patients with different histological types and stages.
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Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia , Adenocarcinoma/epidemiologia , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Pontuação de Propensão , Modelos de Riscos Proporcionais , Programa de SEER , Estados Unidos/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/terapiaRESUMO
Purpose: To evaluate the value of C1QC+ and SPP1+ TAMs gene signatures in patients with cervical cancer. Methods: We compare the C1QC+ and SPP1+ TAMs gene signatures with the M1/M2 gene signatures at single cell level and bulk RNA-seq level and evaluate which gene signature can clearly divide TAMs and patients with cervical cancer into distinct clinical subclusters better. Results: At single-cell level, C1QC+ and SPP1+ TAMs gene signatures, but not M1 and M2 gene signatures, could clearly divided TAMs into two subclusters in a colon cancer data set and an advanced basal cell data set. For cervical cancer data from TCGA, patients with C1QChigh and SPP1low TAMs gene signatures have the best prognosis, lowest proportion (34.21%) of locally advanced cervical cancer (LACC), and highest immune cell infiltration, whereas patients with C1QClow and SPP1high TAMs gene signatures have the worst prognosis, highest proportion (71.79%) of LACC and lowest immune cell infiltration. Patients with C1QChigh and SPP1low TAMs gene signature have higher expression of most of the Immune checkpoint molecules (ICMs) than patients with C1QClow and SPP1high TAMs gene signatures. The GSEA results suggested that subgroups of patients divided by C1QC+ and SPP1+ TAMs gene signatures showed different anti- or pro-tumor state. Conclusion: C1QC+ and SPP1+ TAMs gene signatures, but not M1/M2 gene signatures, can divide cervical patients into subgroups with different prognosis, tumor stage, different immune cell infiltration, and ICMs expression. Our findings may help to find suitable treatment strategy for cervical cancer patients with different TAMs gene signatures.
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Biomarcadores Tumorais/genética , Complemento C1q/genética , Perfilação da Expressão Gênica , Osteopontina/genética , Transcriptoma , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismo , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Tomada de Decisão Clínica , Bases de Dados Genéticas , Feminino , Humanos , Proteínas de Checkpoint Imunológico/genética , Imunoterapia , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , RNA-Seq , Análise de Célula Única , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/terapia , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Cisplatin-paclitaxel (TP) combination chemotherapy as the first-line therapy for numerous cancers is hindered by its inadequate accumulation in tumors and severe side effects resulting from non-specific distribution. The aim of this study is to explore whether TMTP1-modified, cisplatin and paclitaxel prodrugs co-loaded nanodrug could improve cervical cancer chemotherapy and relieve its side effects through active and passive tumor targeting accumulation and controlled drug release. METHODS: TDNP, with capacities of active targeting for tumors and controlled drug release, was prepared to co-deliver cisplatin and paclitaxel prodrugs. The characteristics were investigated, including the diameter, surface zeta potential, stability and tumor microenvironment (TME) dependent drug release profiles. Cellular uptake, cytotoxicity, drug accumulation in tumors, antitumor effects and safety analysis were evaluated in vitro and in vivo. RESULTS: The oxidized cisplatin and the paclitaxel linked to the polymer achieved a high loading effciency of over 80% and TME-dependent sustained drug release. Moreover, TMTP1 modification enhanced cellular uptake of TDNP and further improved the cytotoxicity of TDNP in vitro. In vivo, TDNP showed an extended blood circulation and increased accumulation in SiHa xenograft models with the aid of TMTP1. More importantly, TDNP controlled tumor growth without life-threatening side effects. CONCLUSION: Our study provided a novel TP co-delivery platform for targeted chemotherapy of cervical cancer, which was promising to improve the therapeutic effcacy of TP and may also have application in other tumors.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Portadores de Fármacos/química , Nanopartículas/química , Pró-Fármacos/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/metabolismo , Cisplatino/farmacologia , Feminino , Humanos , Paclitaxel/administração & dosagem , Paclitaxel/metabolismo , Paclitaxel/farmacologia , Polímeros/química , Neoplasias do Colo do Útero/tratamento farmacológico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Metastasis is one of the most threatening aspects of cervical cancer. We developed a method to intraoperatively map the primary tumor, metastasis and metastatic sentinel lymph nodes (SLNs), providing real-time intraoperative guidance in cervical cancer. Methods: TMTP1, a tumor metastasis targeting peptide, was employed to modify the indocyanine green (ICG)-loaded poly (ethylene glycol)- poly (lactic-co-glycolic acid) (PEG-PLGA) micelles. The cervical cancer subcutaneous tumor model and lung metastasis model were established to determine the active targeting of ICG-loaded TMTP1-PEG-PLGA micelles (ITM) for the primary tumor and occult metastasis of cervical cancer. Human cervical cancer HeLa cells engineered by firefly luciferase were injected into the right hocks of BALB/c nude mice to develop the SLN metastasis model. The ITM and control ICG-loaded PEG-PLGA micelles (IM) were injected into the right hind footpads in the SLN metastasis model, and the migration and retention of micelles were recorded under near-infrared fluorescence. K14-HPV16 transgenic mice were also used to detect the image capability of ITM to target cancerous lesions. Results: ITM could actively target imaging of the primary tumor and cervical cancer metastasis. ITM quickly diffused from the injection site to SLNs along lymphatic capillaries and remained in the SLNs for 12 h. Moreover, ITM specifically accumulated in the tumor metastatic SLNs (T-SLNs), which could be successfully distinguished from normal SLNs (N-SLNs). Conclusion: ITM could achieve active targeting of the primary tumor, metastasis and T-SLNs, providing precise and real-time intraoperative guidance for cervical cancer.
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Oligopeptídeos/química , Imagem Óptica/métodos , Linfonodo Sentinela/diagnóstico por imagem , Neoplasias do Colo do Útero/diagnóstico por imagem , Animais , Feminino , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Humanos , Verde de Indocianina/química , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Metástase Linfática/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oligopeptídeos/metabolismo , Imagem Óptica/instrumentação , Polímeros/química , Polímeros/metabolismo , Linfonodo Sentinela/patologia , Neoplasias do Colo do Útero/patologiaRESUMO
As we reported in our previous studies, TMTP1, a tumor-homing peptide, selectively targets highly metastatic tumors and their metastatic foci. Aminopeptidase P2 (XPNPEP2) is a receptor for TMTP1 tumor-homing peptide. However, the biological and clinical significance of Aminopeptidase P2 in human cancers remains unknown. In this study, the high-density multiple organ tumor tissue array was employed for the analysis of XPNPEP2 expression profiles in human specimens. The results showed that XPNPEP2 was moderately expressed in the normal prostate tissues, but significantly decreased in the prostate cancer. Hence we used TCGA, IHC, and ELISA to further analyze the expression of XPNPEP2 in tissues and serum of prostate cancer patients. In general, XPNPEP2 expression was lower in prostate cancer tissue than in normal prostate tissue, but was higher in prostate cancer tissues with local invasion and LN metastasis than in tissues with localized Pca. Western blot clarified XPNPEP2 had a secreted form in the serum. Then the serums of 128 Pca patients, 70 healthy males and 40 prostate hyperplasia patients were obtained for detecting serum XPNPEP2 levels.The results indicated that the concentration of XPNPEP2 in serums of Pca patients with LN metastasis (142.7 ± 14.40 ng/mL) were significantly higher than levels in Pca patients without LN metastasis (61.63 ± 5.50 ng/mL) (p < 0.01). An ROC analysis revealed that the combination of PSA and XPNPEP2 was more efficient than PSA or XPNPEP2 alone for predicting LN metastasis, especially for Pca patients with low serum PSA levels. In summary, serum XPNPEP2 levels when combined with PSA levels may result in increased sensitivity for predicting LN metastasis in Pca patients, especially for patients with low serum PSA levels.
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Aminopeptidases/metabolismo , Biomarcadores Tumorais/metabolismo , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Idoso , Idoso de 80 Anos ou mais , Aminopeptidases/genética , Regulação para Baixo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Oligopeptídeos , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
AIM: To investigate the influence of tissue mechanics on the cellular uptake efficiency of nanoparticles (NPs) in cancer. MATERIALS & METHODS: Collagen-coated polyacrylamide gels were prepared as model substrates. Coumarin 6-loaded poly(lactic-co-glycolic) acid micelles (C6-NPs) were prepared to investigate the cellular uptake of NPs. RESULTS: We demonstrated that substrate stiffness modulated the cellular uptake of NPs of cancer. Mechanistically, mechanical cues exerted influence on the clathrin-mediated endocytosis and caveolae-mediated endocytosis pathways, which mediated stiffness-regulated cellular uptake of NPs. CONCLUSION: Our findings shed light on the regulatory role of the mechanical cues on the cellular uptake of NPs and will facilitate the selection of clinical patients who might benefit from a given nanotherapy.
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Cavéolas/metabolismo , Clatrina/metabolismo , Células A549 , Resinas Acrílicas/química , Animais , Western Blotting , Linhagem Celular Tumoral , Endocitose/fisiologia , Feminino , Células HeLa , Humanos , Camundongos , Nanopartículas/químicaRESUMO
Despite an improvement in the efficacy of chemotherapeutic agents, the outcome of patients with prostate cancer remains poor. MicroRNA (miRNA/miR)-139 expression is often downregulated in multiple types of tumor, including in prostate cancer. The aim of the present study was to investigate the inhibitory effect of miR-139 on the PC-3, C4-2B and LNCaP prostate cancer cell lines. Analysis of the cell cycle of PC-3, C4-2B and LNCaP cells transfected with miR-139 revealed a significantly increased percentage of cells in the G1 phase and a decreased percentage in the S and G2 phases compared with those transfected with a negative control miRNA. The growth inhibitory rate of miR-139-transfected cells 24, 48 and 72 h after transfection were 32.83±2.61, 52.58±3.2 and 62.36±4.55% in PC-3 cells; 30.28±2.25, 51.74±3.27 and 60.80±3.58% in C4-2B cells; and 33.20±2.67, 51.83±3.59 and 61.79±4.85% in LNCaP cells, respectively. The present study revealed that miR-139 inhibited the proliferation of prostate cancer cells by interfering with the cell cycle. Further study into the mechanism by which this happened suggested that miR-139 reduced cyclin D1 expression and inhibited cell proliferation through targeting Notch1.
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Cancer-associated fibroblasts (CAFs) play a pivotal role in the development and progression of many human cancers. Recent studies have shown that Hedgehog (Hh) signalling modulates the stromal microenvironment and prepares a suitable niche for tumour metastasis. However, the detailed molecular mechanisms underlying CAF-mediated lymphangiogenesis have not been fully elucidated. Therefore, our goal is to illustrate whether Hh ligands can activate Hh signalling in CAFs in a paracrine fashion and elucidate the effect of CAFs on lymphangiogenesis. We determined here that Sonic Hedgehog (SHH) secreted by ovarian cancer (OC) cells activated Hh signalling in CAFs and promoted the proliferation of CAFs. Moreover, we co-injected SHH-overexpressing OC cells and CAFs in a xenograft model and found that the CAFs accelerated tumourigenesis and lymphangiogenesis in OC. Mechanistically, we found that SHH secreted by the OC cells induced VEGF-C expression in CAFs. Inhibition of Hh signalling in CAFs decreased VEGF-C expression and diminished the positive role of CAFs in supporting tumourigenesis and lymphangiogenesis in a murine xenograft model. Our results demonstrate that CAFs constitute a supportive niche for cancer lymphangiogenesis via the Hh/VEGF-C signalling axis and provide evidence for the clinical application of Hh inhibitors in the treatment of OC.
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XPNPEP2 is a proline hydrolytic enzyme that hydrolyzes several biologically active peptides and causes a loss of substrate activity. However, its function in cancer is still unknown. Our study showed that XPNPEP2 expression was significantly upregulated in cervical cancer tissues compared with normal cervical tissues and cervical intraepithelial neoplasm tissues. Statistical analysis showed that XPNPEP2 expression was associated with the International Federation of Gynecology and Obstetrics stage and lymph node metastasis. Overexpression of XPNPEP2 in SiHa and HeLa cells promoted cell invasion and migration without affecting cell proliferation and apoptosis. Mechanistically, we found that XPNPEP2 facilitated cervical cancer cell invasion and migration by inducing epithelial-mesenchymal transition. Furthermore, we demonstrated that XPNPEP2 had significant effects on the metastasis of xenografted tumors in vivo. Collectively, our findings identify the novel function of XPNPEP2 in the metastasis of cervical cancer and suggest that XPNPEP2 could be a novel potential therapeutic target for the treatment of cervical cancer.
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Aminopeptidases/biossíntese , Proliferação de Células/genética , Prognóstico , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Aminopeptidases/genética , Animais , Apoptose/genética , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Metástase Linfática/genética , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Serous ovarian cancer (SOC) is the most lethal gynecological cancer. Clinical studies have revealed an association between tumor stage and grade and clinical prognosis. Identification of meaningful clusters of co-expressed genes or representative biomarkers related to stage or grade may help to reveal mechanisms of tumorigenesis and cancer development, and aid in predicting SOC patient prognosis. We therefore performed a weighted gene co-expression network analysis (WGCNA) and calculated module-trait correlations based on three public microarray datasets (GSE26193, GSE9891, and TCGA), which included 788 samples and 10402 genes. We detected four modules related to one or more clinical features significantly shared across all modeling datasets, and identified one stage-associated module and one grade-associated module. Our analysis showed that MMP2, COL3A1, COL1A2, FBN1, COL5A1, COL5A2, and AEBP1 are top hub genes related to stage, while CDK1, BUB1, BUB1B, BIRC5, AURKB, CENPA, and CDC20 are top hub genes related to grade. Gene and pathway enrichment analyses of the regulatory networks involving hub genes suggest that extracellular matrix interactions and mitotic signaling pathways are crucial determinants of tumor stage and grade. The relationships between gene expression modules and tumor stage or grade were validated in five independent datasets. These results could potentially be developed into a more objective scoring system to improve prediction of SOC outcomes.
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Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Expressão Gênica , Redes Reguladoras de Genes , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Biologia Computacional , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Estudos de Associação Genética , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Característica Quantitativa Herdável , Reprodutibilidade dos TestesRESUMO
Approximately 50-75% of patients with serous ovarian carcinoma (SOC) experience recurrence within 18 months after first-line treatment. Current clinical indicators are inadequate for predicting the risk of recurrence. In this study, we used 7 publicly available microarray datasets to identify gene signatures related to recurrence in optimally debulked SOC patients, and validated their expressions in an independent clinic cohort of 127 patients using immunohistochemistry (IHC). We identified a two-gene signature including KCNN4 and S100A14 which was related to recurrence in optimally debulked SOC patients. Their mRNA expression levels were positively correlated and regulated by DNA copy number alterations (CNA) (KCNN4: p=1.918e-05) and DNA promotermethylation (KCNN4: p=0.0179; S100A14: p=2.787e-13). Recurrence prediction models built in the TCGA dataset based on KCNN4 and S100A14 individually and in combination showed good prediction performance in the other 6 datasets (AUC:0.5442-0.9524). The independent cohort supported the expression difference between SOC recurrences. Also, a KCNN4 and S100A14-centered protein interaction subnetwork was built from the STRING database, and the shortest regulation path between them, called the KCNN4-UBA52-KLF4-S100A14 axis, was identified. This discovery might facilitate individualized treatment of SOC.
Assuntos
Biomarcadores Tumorais/análise , Cistadenocarcinoma Seroso/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação ao Cálcio/análise , Proteínas de Ligação ao Cálcio/biossíntese , Carcinoma Epitelial do Ovário , Cistadenocarcinoma Seroso/mortalidade , Feminino , Perfilação da Expressão Gênica , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/análise , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/biossíntese , Estimativa de Kaplan-Meier , Fator 4 Semelhante a Kruppel , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Prognóstico , TranscriptomaRESUMO
Growing evidences have shown that the IL-6/IL-6R signal pathway promotes the tumor growth, angiogenesis, invasion and migration in various cancers, especially for epithelial ovarian cancer. Hence, including anti-IL-6 antibody (Siltuximab) and anti-IL-6R antibody (Tocilizumab), more and more therapeutic drugs targeting IL-6/IL-6R pathway were developed to block their activity. The molecular imaging of IL-6R is a significant factor for predicting tumor response to IL-6/IL-6R targeted drugs. However, few probes targeting IL-6R were designed and used for the specific detection. The purpose of this study was to develop and evaluate a novel radiotracer, (99m)Tc-HYNIC-Aca-LSLITRL, for SPECT imaging of interleukin-6 receptor. The expression of IL-6R was determined by western blot, immunofluorescence and immunohistochemistry. HYNIC-Aca-LSLITRL and HYNIC-Aca-TLQASIL were synthesized, and then were labeled with 99mTc. The stability and the cell-binding assay were performed. Ovarian tumor xenografts were established and subjected to SPECT imaging after injection of these two radiopharmaceuticals with or without excess primary peptides. The biodistribution of these two radiotracers was performed in nude mice bearing C13K tumors. (99m)Tc-HYNIC-Aca-LSLITRL and (99m)Tc-HYNIC-Aca-TLQASIL were obtained in >95 % labeling yield with favorably stability. In vitro studies demonstrated that the interleukin-6 receptor was overexpressed in ovarian cancer C13K cells. The SPECT imaging of interleukin-6 receptor and biodistribution studies showed that (99m)Tc-HYNIC-Aca-LSLITRL had higher tumor uptake and significantly lower kidney accumulation compared to (99m)Tc-HYNIC-Aca-TLQASIL. (99m)Tc-HYNIC-Aca-LSLITRL could be a promising agent for SPECT imaging of interleukin-6 receptor of ovarian cancer especially for those anti-IL-6R drugs under clinical trials, such as tocilizumab.