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1.
Purpose
Although overexpression of the eukaryotic translation initiation factor 4E (eIF4E) is detected in patients with renal cell carcinoma (RCC) and associated with poor prognosis, the possible roles of eIF4E in RCC have not been revealed.Methods
The effects of eIF4E inhibition on cell growth, migration, survival, chemo-/immunotherapy and eIF4E pathways via pharmacological inhibitor and genetic siRNA knockdown were analyzed in RCC cells.Results
In this work, we demonstrate that eIF4E is critically involved in multiple biological functions of RCC. We firstly inhibited eIF4E activity by ribavirin in two cell lines (Caki-1 and ACHN) representing RCC metastasis models. We demonstrated that ribavirin inhibited proliferation and migration and induced apoptosis in RCC in a dose-dependent manner. We further confirmed that the inhibitory effects of ribavirin were attributed to its ability in inhibiting eIF4E-regulated protein translation and activity. eIF4E inhibition using siRNA knockdown mimicked ribavirin’s effector in RCC cells. Importantly, eIF4E inhibition by both ribavirin and siRNA knockdown significantly sensitized RCC response to chemo- and immunotherapeutic agents in vitro as well as in vivo.Conclusions
Our findings clearly demonstrate the roles of eIF4E in RCC growth, survival, metastasis and resistance. Ribavirin is an antiviral drug, and its clinical efficacy is currently being investigated in the treatment of various cancers. Our findings support and provide a preclinical evidence for clinical trial for the combination of ribavirin with chemo-/immunotherapy in RCC.2.
Purpose
Cisplatin is commonly used in non-small-cell lung cancer (NSCLC) chemotherapy; however, chemoresistance to cisplatin remains a great clinical challenge. Octamer-binding protein 4 (OCT4) has been reported to be overexpressed in NSCLC. In this study, we aimed to investigate the potential role of OCT4 in NSCLC with chemoresistance to cisplatin.Methods
Expressions of OCT4 was detected in NSCLC tissues and cell lines. We utilized siRNA to knock down OCT4 expression in human NSCLC cells and analyzed their phenotypic changes.Results
We found that the difference of OCT4 expression between NSCLC and the adjacent non-tumourous tissues was statistically significant. Knockdown of OCT4 in NSCLC cells could decrease cell proliferation, and potentiate apoptosis induced by cisplatin, suggesting OCT4 may contribute to cisplatin resistance in NSCLC.Conclusion
Our findings indicate that targeting OCT4 could improve cisplatin effect in NSCLC, confirming their role in modulating cisplatin sensitivity.3.
Background
Ovarian cancer is the most lethal gynecologic malignancy worldwide with surgery as the only curative treatment. Long-term overall survival (OS) of ovarian cancer is far from satisfactory, even though significant improvement has been made in post-operative chemotherapy. One of the most important death cause is the chemoresistance due to consecutive chemotherapy. Therefore, understanding the molecular mechanisms involved in ovarian cancer development and identification of novel therapeutic targets are urgently required.Methods
Immunohistochemical (IHC) staining was used to explore the expression pattern of mitogen-activated protein kinase (MAPK)-interacting kinase 1 (MNK1) in tumor tissues from 138 epithelial ovarian cancer (EOC) patients. Clinicopathological data were subjected to Kaplan–Meier survival and Cox multivariate analyses to evaluate the prognostic value of MNK1 in EOC. Overexpression and silencing procedures were performed on OVCAR-5 cells to investigate the mechanisms of MNK1 in regulating EOC development. The anti-tumor effects of CGP57380, a specific MNK inhibitor, were examined by cell viability assay.Results
Higher MNK1 expression showed significant relationship with advanced FIGO stage and positive lymph node metastasis of EOC. Univariate and multivariate analyses revealed that MNK1 was an independent prognostic factor for OS of EOC patients. In vitro study demonstrated that MNK1 can promote cell proliferation through regulating the phosphorylation level of eukaryotic initiation factor 4E. In addition, inhibition of MNK1 by CGP57380 significantly down-regulated the OVCAR-5 cell viability.Conclusion
High MNK1 expression in EOC tissues indicates poor clinical outcomes, and MNK1 can act as a potential target for novel chemotherapy development towards EOC.4.
Hu YiRen Yu YingCong You Sunwu Li Keqin Tong Xiaochun Chen Senrui Chen Ende Lin XiZhou Chen Yanfan 《Molecular cancer》2017,16(1):174
Background
Chemoresistance has long been recognized as a major obstacle in cancer therapy. Clarifying the underlying mechanism of chemoresistance would result in novel strategies to improve patient’s response to chemotherapeutics.Methods
lncRNA expression levels in gastric cancer (GC) cells was detected by quantitative real-time PCR (qPCR). MALAT1 shRNAs and overexpression vector were transfected into GC cells to down-regulate or up-regulate MALAT1 expression. In vitro and in vivo assays were performed to investigate the functional role of MALAT1 in autophagy associated chemoresistance.Results
We showed that chemoresistant GC cells had higher levels of MALAT1 and increased autophagy compared with parental cells. Silencing of MALAT1 inhibited chemo-induced autophagy, whereas MALAT1 promoted autophagy in gastric cancer cells. Knockdown of MALAT1 sensitized GC cells to chemotherapeutics. MALAT1 acts as a competing endogenous RNA for miR-23b-3p and attenuates the inhibitory effect of miR-23b-3p on ATG12, leading to chemo-induced autophagy and chemoresistance in GC cells.Conclusions
Taken together, our study revealed a novel mechanism of lncRNA-regulated autophagy-related chemoresistance in GC, casting new lights on the understanding of chemoresistance.5.
Background and aim
The concepts of the pathogenesis of epithelial ovarian tumors have significantly changed during the last decade. The aim of this review is to briefly present the current concepts on this topic.Methods
This work is based on a selective PubMed search using the terms “ovarian” cancer and “origin”.Results
Numerous studies have shown that the histological subtypes of ovarian cancer greatly differ in molecular features, etiology, therapy response, and prognosis. Correlations between histopathological and molecular characteristics revealed that serous tubal intraepithelial carcinoma (STIC) is probably the precursor of high grade serous carcinoma, and that endometrioid and clear cell carcinomas arise in ovarian endometriosis cysts. Preliminary data also point to a tubal origin of low grade serous carcinoma while the pathogenesis of rare mucinous neoplasia is currently unclear.Conclusions
The histological subtypes of ovarian cancer should be considered as separate entities. The origin of most epithelial ovarian neoplasia very probably lies in extraovarian organs.6.
Yan Gao Jacson Shen Edwin Choy Henry Mankin Francis Hornicek Zhenfeng Duan 《Cellular oncology (Dordrecht)》2017,40(3):209-218
Purpose
Overexpression of cyclin-dependent kinase (CDK) 4 has been observed in a variety of cancers and has been found to contribute to tumor cell growth and proliferation. However, the effect of inhibition of CDK4 in ovarian cancer is unknown. We investigated the therapeutic effect of the CDK4 inhibitor palbociclib in combination with paclitaxel in ovarian cancer cells.Methods
Cell viabilities were determined by MTT assay after exposure to different dosages of palbociclib and/or paclitaxel. Western blot, immunofluorescence, and Calcein AM assays were conducted to determine the mechanisms underlying the cytotoxic effects of palbociclib in combination with paclitaxel. CDK4 siRNA was used to validate the outcome of targeting CDK4 by palbociclib in ovarian cancer cells.Results
We found that combinations of palbociclib and paclitaxel significantly enhanced drug sensitivity in both Rb-positive (SKOV3TR) and Rb-negative (OVCAR8TR) ovarian cancer-derived cells. When combined with paclitaxel, palbociclib induced apoptosis in both SKOV3TR and OVCAR8TR cells. We also found that palbociclib inhibited the activity of P-glycoprotein (Pgp), and that siRNA-mediated CDK4 knockdown sensitized multidrug resistant (MDR) SKOV3TR and OVCAR8TR cells to paclitaxel.Conclusions
Inhibition of CDK4 by palbociclib can enhance paclitaxel sensitivity in both Rb-positive and Rb-negative MDR ovarian cancer cells by increasing apoptosis. CDK4 may serve as a promising target in the treatment of ovarian cancer.7.
Purpose of review
The purpose of this review is to describe the role of D-type cyclins and cyclin-dependent kinases (CDKs) 4 and 6 in breast cancer and to discuss potential biomarkers for sensitivity or resistance to CDK4/6 inhibitors.Recent findings
A small number of preclinical and clinical studies have explored potential mechanisms of CDK4/6 inhibitor response and resistance in breast cancer. Putative markers of response include estrogen receptor positivity, luminal patterns of gene expression, high cyclin D1 levels, and low p16 levels. Possible resistance mechanisms include loss of Rb function, overexpression/amplification of cyclin E, and CDK6 amplification. Most of these remain speculative and have not been validated in clinical specimens.Summary
If early successes with CDK4/6 inhibitors are to be capitalized upon, it is critical that our understanding of CDK4/6 biology in breast cancer extends beyond its current rudimentary state. Only then, we will be able to develop rational therapeutic combinations that further enhance the efficacy of these agents.8.
Eun-Sun Choi Sejun Oh Boonsil Jang Hyun-Ju Yu Ji-Ae Shin Nam-Pyo Cho In-Hyoung Yang Dong-Hoon Won Hye-Jeong Kwon Seong Doo Hong Sung-Dae Cho 《Cellular oncology (Dordrecht)》2017,40(3):235-246
Purpose
Approximately 20% of all salivary gland cancer patients who are treated with current treatment modalities will ultimately develop metastases. Its most common form, mucoepidermoid carcinoma (MEC) is a highly aggressive tumor with an overall 5-year survival rate of ~30%. Until now, several chemotherapeutic drugs have been tested for the treatment of salivary gland tumors, but the results have been disappointing and the drugs often cause unwanted side effects. Therefore, several recent studies have focused on the potential of alternative and/or complementary therapeutic options, including the use of silymarin.Methods
The effects of silymarin and its active component silibinin on salivary gland cancer-derived MC3 and HN22 cells and their underlying molecular mechanisms were examined using trypan blue exclusion, 4′-6-diamidino-2-phenylindole (DAPI) staining, Live/Dead, Annexin V/PI staining, mitochondrial membrane potential (ΔΨm) measurement, quantitative RT-PCR, soft agar colony formation and Western blotting analyses.Results
We found that silymarin and silibinin dramatically increased the expression of the pro-apoptotic protein Bim in a concentration- and time-dependent manner and, concomitantly, induced apoptosis in MC3 and HN22 cells. We also found that ERK1/2 signaling inhibition successfully sensitized these cells to the apoptotic effects of silymarin and silibinin, which indicates that the ERK1/2 signaling pathway may act as an upstream regulator that modulates the silymarin/silibinin-induced Bim signaling pathway.Conclusions
Taken together, we conclude that ERK1/2 signaling pathway inhibition by silymarin and silibinin increases the expression of the pro-apoptotic Bcl-2 family member Bim which, subsequently, induces mitochondria-mediated apoptosis in salivary gland cancer-derived cells.9.
10.
Shigekazu Ukawa Akiko Tamakoshi Mitsuru Mori Satoyo Ikehara Toru Shirakawa Hiroshi Yatsuya Hiroyasu Iso JACC study group 《Cancer causes & control : CCC》2018,29(2):213-219
Purpose
Seventy-five percent of epidemiological studies have reported that sedentary behavior is associated with ovarian cancer incidence. Although Japan has one of the most sedentary populations, with median sitting times of 7 h/day, this association has not been investigated. This study aimed to elucidate the association between average daily television (TV) viewing time, which is a major sedentary behavior, and the incidence of ovarian cancer in a large-scale nationwide cohort study in Japan.Methods
A total of 34,758 female participants aged 40–79 years without a history of cancer at baseline were included in the study. The inverse probability weighted competing risk model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for the incidence of ovarian cancer.Results
During a median follow-up of 19.4 years, 59 participants developed ovarian cancer (ICD-10: C56), 2,706 participants developed other types of cancer, and 4,318 participants died. Participants who watched TV for ≥?5 h/day were more likely to develop ovarian cancer than those who watched TV for <?2 h/day (HR 2.15; 95% CI 1.54–2.99).Conclusion
Our findings suggest that reducing the amount of time spent sedentarily may be beneficial for preventing ovarian cancer.11.
12.
Seyyed Mehdi Jafari Hamid Reza Joshaghani Mojtaba Panjehpour Mahmoud Aghaei 《Cellular oncology (Dordrecht)》2018,41(1):61-72
Purpose
It has been reported that cancer stem cells (CSCs) may play a crucial role in the development, recurrence and metastasis of breast cancer. Targeting signaling pathways in CSCs is considered to be a promising strategy for the treatment of cancer. Here, we investigated the role of the A2B adenosine receptor (A2BAR) and its associated signaling pathways in governing the proliferation and viability of breast cancer cell line derived CSCs.Methods
CSCs were isolated from the breast cancer cell lines MCF-7 and MDA-MB-231 using a mammosphere assay. The effect of the A2BAR agonist BAY606583 on cell proliferation was evaluated using XTT and mammosphere formation assays, respectively. Apoptosis was assessed using Annexin-V staining and cell cycle analyses were performed using flow cytometry. The expression levels of Bax, Bcl-2, cyclin-D1, CDK-4 and (phosphorylated) ERK1/2 were assessed using Western blotting.Results
Our data revealed that the breast cancer cell line derived mammospheres were enriched for CSCs. We also found that A2BAR stimulation with its agonist BAY606583 inhibited mammosphere formation and CSC viability. In addition, we found that the application of BAY606583 led to CSC cell cycle arrest and apoptosis through the cyclin-D1/Cdk-4 and Bax/Bcl-2 pathways, respectively. Notably, we found that BAY606583 significantly down-regulated ERK1/2 phosphorylation in the breast cancer cell line derived CSCs.Conclusions
From our results we conclude that A2BAR induces breast CSC cell cycle arrest and apoptosis through downregulation of the ERK1/2 cascade. As such, A2BAR may be considered as a novel target for the treatment of breast cancer.13.
Naoyuki Yamamoto Shozo Yokoyama Junji Ieda Yasuyuki Mitani Shunsuke Yamaguchi Katsunari Takifuji Tsukasa Hotta Kenji Matsuda Takashi Watanabe John E. Shively Hiroki Yamaue 《Cancer chemotherapy and pharmacology》2015,75(2):421-430
Purpose
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) re-expressed and promoted hollow spheroid (HS) formation beyond the invasion front of colorectal cancer. The aim of the present study was to clarify whether CEACAM1 cytoplasmic domain isoform balance and HS are associated with resistance to 5-fluorouracil (5FU).Methods
Two-dimensional (D) or 3D culture systems were employed to evaluate the effects of CEACAM1 cytoplasmic isoform balance and HS formation on the chemosensitivity of colorectal cancer cells to 5FU. The risk factors for postoperative recurrence were calculated based on the presence of HS and various clinicopathological characteristics in 82 patients with Stage III colorectal cancer who had undergone curative surgery followed by 5FU-based chemotherapy.Results
CEACAM1-4L-transfected HT29 and CEACAM1-4L and 4S expressing parental LS174T cells had significantly higher resistance to 5FU in comparison with CEACAM1-4S- or vector control-transfected cells. In 3D culture, HS formation induced by CEACAM1-4L induced chemoresistance to 5FU, whereas the solid spheres formed in response to CEACAM1-4S were destroyed by 5FU treatment. HS was identified as an independent factor for recurrence of Stage III colorectal cancer after curative resection followed by 5FU-based chemotherapy. Kaplan–Meier survival curves demonstrated that patients with HS had lower recurrence-free survival rate.Conclusions
CEACAM1 long cytoplasmic domain isoform dominance and HS formation are phenotypes associated with chemoresistance to 5FU.14.
Xihui Wang Rui Yang Chunyan Yuan Yanli An Qiusha Tang Daozhen Chen 《Targeted oncology》2018,13(4):481-494
Background
Ovarian cancer is a common gynecologic malignancy with poor prognosis, requiring innovative new therapeutic strategies. Temperature-controlled drug delivery to cancer cells represents a novel, promising, targeted treatment approach.Objective
We prepared folate receptor-targeted thermosensitive liposomes wrapped with the HSP90 inhibitor 17-AAG and superparamagnetic material (17-AAG/MTSLs-FA), and tested the efficacy of these targeted magnetoliposomes in vitro and in vivo.Methods
Magnetic thermosensitive liposomes wrapped with 17-AAG were coprecipitated with Fe3O4 magnetic nanoparticles and prepared by a rotary evaporation method. Experiments were conducted with SKOV3 human ovarian cancer cells and MCF7 human breast carcinoma cells to evaluate the anti-tumor effects.Results
17-AAG/MTSLs-FA prepared in this study met the basic requirements for therapeutic application. The preparation method is relatively simple and the raw materials are readily available. The product exhibited strong magnetism, high encapsulation efficiencies, and satisfactory performance. The liposomes combined with hyperthermia significantly inhibited the proliferation of SKOV3 cells and induced apoptosis. Experiments using a mouse subcutaneous model as well as an ascites tumor xenograft model indicated that 17-AAG/MTSLs-FA was stable in vivo and effectively targeted tumor tissues expressing the folate receptor.Conclusions
Folic acid-conjugated 17-AAG magnetic thermosensitive liposomes in combination with an alternating magnetic field for heating can achieve a synergistic anti-tumor effect of chemotherapy and heat treatment, potentially offering a new method for ovarian cancer treatment.15.
16.
Justyna Mikuła-Pietrasik Paweł Uruski Kinga Matuszkiewicz Sebastian Szubert Rafał Moszyński Dariusz Szpurek Stefan Sajdak Andrzej Tykarski Krzysztof Książek 《Cellular oncology (Dordrecht)》2016,39(5):473-481
Purpose
After the seeding ovarian cancer cells into the peritoneal cavity, ascitic fluid creates a microenvironment in which these cells can survive and disseminate. The exact nature of the interactions between malignant ascitic fluids and peritoneal mesothelial cells (HPMCs) in ovarian cancer progression has so far remained elusive. Here we assessed whether malignant ascitic fluids may promote the senescence of HPMCs and, by doing so, enhance the acquisition of their pro-cancerogenic phenotype.Methods
Primary omentum-derived HPMCs, ovarian cancer-derived cell lines (A2780, OVCAR-3, SKOV-3), malignant ascitic fluids and benign ascitic fluids from non-cancerous patients were used in this study. Ovarian cancer cell proliferation, as well as HPMC proliferation and senescence, were determined using flow cytometry and β-galactosidase assays, respectively. Ovarian cancer cell migration was quantified using a Transwell assay. The concentrations of soluble agents in ascitic fluids, conditioned media and cell lysates were measured using DuoSet® Immunoassay Development kits.Results
We found that HPMCs, when exposed to malignant ascitic fluids, exhibited decreased proliferation and increased senescence rates. The malignant ascitic fluids were found to contain elevated levels of HGF, TGF-β1 and GRO-1, of which HGF and GRO-1 were able to induce senescence in HPMCs. We also found that HPMCs subjected to malignant ascitic fluids or exogenously added HGF and GRO-1 stimulated ovarian cancer cell progression, which was manifested by an increased production of HA (adhesion), uPA (proliferation), IL-8 and MCP-1 (migration).Conclusion
Our results indicate that malignant ascitic fluids may contribute to ovarian cancer progression by accelerating the senescence of HPMCs.17.
Elizabeth M. Poole Laura D. Kubzansky Anil K. Sood Olivia I. Okereke Shelley S. Tworoger 《Cancer causes & control : CCC》2016,27(5):661-668
Purpose
In ovarian cancer patients and mouse models, psychosocial stress is associated with higher circulating markers of angiogenesis and cell migration, impaired immune response, and increasing tumor burden and aggressiveness. In the Nurses’ Health Studies (NHS/NHSII), we assessed whether phobic anxiety, a marker of chronic distress, was associated with risk of incident ovarian cancer as well as survival among ovarian cancer patients.Methods
We used Cox proportional hazards regression to model the relative risks (RRs) and 95 % confidence intervals (CI) of ovarian cancer incidence and survival by categories of the Crown–Crisp phobic anxiety index (CCI).Results
We identified 779 cases of ovarian cancer during 2,497,892 person-years of follow-up. For baseline CCI (NHS: 1988; NHSII: 1993), we observed a statistically nonsignificant increased risk of epithelial ovarian cancer (RR for CCI ≥ 4 vs. 0 or 1: 1.14; 95 % CI 0.96–1.36). However, when we updated CCI (NHS: 2004; NHSII: 2005), the associations were attenuated. Pre-diagnosis CCI was not associated with ovarian cancer survival (RR for ≥4 vs. 0 or 1: 1.00; 95 % CI 0.77–1.31); results were similar for post-diagnosis CCI.Conclusions
Distress, as measured by phobic anxiety symptoms, was not associated with ovarian cancer risk, although we cannot rule out a modest association. Future research should explore the role of phobic anxiety and other forms of psychological distress and ovarian cancer risk and survival.18.
Andris Gardovskis Arvids Irmejs Edvins Miklasevics Viktors Borosenko Marianna Bitina Inga Melbarde-Gorkusa Andrejs Vanags Grzegorz Kurzawski Janina Suchy Bohdan Górski Janis Gardovskis 《Hereditary cancer in clinical practice》2005,3(2):71-76
Introduction
The aim of the study is to evaluate the incidence and phenotype-genotype characteristics of hereditary breast and ovarian cancer syndromes in Latvia in order to develop the basis of clinical management for patients and their relatives affected by this syndrome.Materials and methods
In 2002-2004 in two Latvian oncology hospitals (Liepãja Oncology Hospital and Daugavpils Oncology Hospital) cancer family histories were collected from 287 consecutive patients with breast and ovarian cancer. In all cases, when it was possible to obtain the blood sample, DNA testing for founder mutations in the BRCA1 gene was performed.Results
Among 287 family cancer histories analysed in 8 (2.8%) cases criteria of hereditary breast cancer (HBC) were fulfilled and in 5 (1.7%) cases hereditary breast and ovarian cancer (HBOC) was diagnosed. In 50 (17.4%) cases we have suspicion of hereditary breast cancer (HBC susp.) and in 8 (2.8%) cases - suspicion of hereditary breast and ovarian cancer (HBOC susp.). We have one (0.3%) case with hereditary ovarian cancer (HOC). DNA testing of founder mutations in the BRCA1 gene (exon 20 (5382 insC) exon 5 (300T/G), exon 11, 17 (4153delA)) for 178/287 (62%) patients was performed. In 9/287 (4.9%) cases we found a mutation in the BRCA1 gene. 4 mutations were detected in exon 11, 17 (4153delA) and 4 mutations in exon 20 (5382 insC) and 1 in exon 5.Conclusions
Existing pedigree/clinical data suggest that in Latvia the clinical frequency of hereditary breast and ovarian cancer is around 5% of consecutive breast and ovarian cancer patients and suspicion of the syndrome is observed in another 20% of cases. Frequency of BRCA1 founder mutations is 5% of all consecutive breast and ovarian cancers. Considerable geographical differences in the clinical and molecular frequency of hereditary breast ovarian cancer have been observed in Latvia.19.
Steffen?D?rfel Claus-Christoph?Steffens Dirk?Meyer Hans?Tesch Lisa?Kruggel Melanie?Frank Martina?J?nicke Norbert?Marschner The TMK-Group 《Breast cancer (Tokyo, Japan)》2018,25(3):275-283
Background
Several regimens for which efficacy was established in randomized controlled trials are recommended in current treatment guidelines for early breast cancer. However, knowledge on use and effectiveness of commonly administered chemotherapeutic agents in real-life care and across all breast cancer subtypes is limited.Methods
The prospective, multicentre German TMK cohort study (Tumour Registry Breast Cancer) recruited patients in 148 oncology outpatient-centres. Data from 1650 patients who completed adjuvant chemotherapy were analysed regarding treatment regimens and taxane use from 2007 to 2014. The association of patient characteristics with application of taxane-free regimens was examined with a multivariate regression model.Results
The preferred adjuvant treatment shifted from fluorouracil, anthracycline and cyclophosphamide containing regimens to anthracycline/taxane combinations. Taxane use increased for all subtypes, and the greatest rise was among node-negative patients. Older age, node-negativity, lower grading, HR-positive/HER2-negative subtype and earlier start year of therapy were significantly associated with taxane-free therapy.Conclusions
Treatment with anthracycline/taxane-based chemotherapy in Germany has been rising for every subtype. The increased taxane use reflects updated guideline recommendations over the past decade. Cohort studies like the TMK provide insight into real-life treatment of patients outside of clinical trials.20.