ABSTRACT
The treatment of triple-negative breast cancer (TNBC) relies largely on chemotherapies. However, it is frequent that TNBC patients develop resistance to the chemotherapy drugs. Generation of drug-resistant cell lines facilitates the identification of drug resistance. Here, we established two paclitaxel (PTX)-resistant TNBC cancer cell lines using an intermittent and stepwise method and found that long non-coding RNA long intergenic non-protein-coding RNA p53-induced transcript (LINC-PINT) was significantly decreased in PTX-resistant cancer cells. Ectopic expression of LINC-PINT sensitized both PTX-resistant TNBC and wild-type TNBC to PTX. Moreover, RNA immunoprecipitation showed that LINC-PINT bound to RNA-binding protein NONO. Overexpression of LINC-PINT resulted in the degradation of NONO in a proteasome-dependent manner and vice versa. Knockdown of NONO with siRNA sensitized TNBC to PTX. We further analyzed the expression level of LINC-PINT and NONO in patient samples via online database and found that LINC-PINT and NONO may function antagonistically in all types of breast cancers. Taken together, our data illustrated a tumor suppressor role of LINC-PINT in sensitizing TNBC to chemotherapies via destabilizing NONO.
Subject(s)
DNA-Binding Proteins/metabolism , Neoplasm Proteins/metabolism , Paclitaxel , RNA, Long Noncoding/metabolism , RNA, Neoplasm/metabolism , RNA-Binding Proteins/metabolism , Triple Negative Breast Neoplasms/metabolism , Cell Line, Tumor , DNA-Binding Proteins/genetics , Female , Humans , Neoplasm Proteins/genetics , RNA, Long Noncoding/genetics , RNA, Neoplasm/genetics , RNA-Binding Proteins/genetics , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathologyABSTRACT
BACKGROUND: 18 F-FDG is a glucose analogue whose metabolic index SUV can effectively reflect the metabolic level of tumor microenvironment. Aspirin can affect the uptake of 18F-FDG by cancer cells, reducing the SUVmax value of primary tumors, exerting antitumor effect. This study aimed to evaluate the prognostic value of long-term aspirin and the relationship between aspirin intake and PET parameters value of primary tumor in non-small cell lung cancer (NSCLC). METHODS: Eighty-one NSCLC patients were recruited and divided into two groups: aspirin medication group and control group, who underwent surgery and had pathological diagnosis data between January 2012 and December 2016. Clinical characteristics were retrospective analyzed to evaluate the possibility of clinical prognosis, respectively. Kaplan-Meier curves and a Cox proportional hazard model were applied to evaluate the predictors of prognosis. RESULTS: The PET/CT SUVmax of the primary tumor in the aspirin group was lower than that in the control group (P < 0.05). Compared with the control group, the SUVmax, SUVmean and TLG of the primary tumor in aspirin group were lower, but the MTV value had no significant difference. Cox regression analysis showed that N stage and TNM stage were predictors of the prognosis. There was a significant difference in the use of aspirin in NSCLC patients. CONCLUSION: Aspirin can reduce SUVmax, SUVmean and TLG in primary tumor and aspirin can improve the prognosis of patients with NSCLC.
Subject(s)
Aspirin/administration & dosage , Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/therapy , Tumor Microenvironment/drug effects , Adult , Aged , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Disease-Free Survival , Female , Fluorodeoxyglucose F18/administration & dosage , Fluorodeoxyglucose F18/pharmacokinetics , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Lung/diagnostic imaging , Lung/drug effects , Lung/pathology , Lung/surgery , Lung Neoplasms/diagnosis , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Pneumonectomy , Positron Emission Tomography Computed Tomography , Prognosis , Radiopharmaceuticals/administration & dosage , Radiopharmaceuticals/pharmacokinetics , Retrospective Studies , Survival RateABSTRACT
BACKGROUND: Epidemiological studies have illustrated that regular aspirin consumption may decrease the risk of non-small cell lung cancer (NSCLC). The present study aims to investigate the mechanism of aspirin-induced inhibition of NSCLC development during hypoxia. METHODS: A549 cells were pre-treated with the vehicle control or aspirin and then subjected to hypoxic culture. Cell viability was monitored by CCK-8 assay, and flow cytometry was performed to detect cell cycle distributions, apoptosis, and proportion of cancer stem cells (CSCs). Flow cytometric cell sorting was used to separate CSCs. Quantitative reverse transcription-polymerase chain reaction and Western blot were used to detect the mRNA and protein levels of stem cell markers and the related signaling molecules. The abundance of prostaglandin E2 was detected by enzyme-linked immunosorbent assay. Exosomes in the cell culture medium were isolated using ExoQuick, and the number of exosomes was quantified by the EXOCET exosome quantification assay kit. Cell migration and angiogenesis were monitored by transwell migration assay and in vitro angiogenesis experiments. RESULTS: Aspirin inhibited cell proliferation and induced G2/M cell cycle arrest in hypoxic A549 cells; it also inhibited hypoxia-enhanced stemness in both A549 and ALDH+ cells. The drug reduced hypoxia-enhanced numbers of exosomes in A549 cells and exerted negative effects on the hypoxia-mediated up-regulation of exosomal HIF-1α/COX-2 and expression of exosomal miR-135b and miR-210. While hypoxic-induced exosomes can promote the proliferation, migration, and angiogenesis of other A549 cells, aspirin can weaken this promotion by reducing the amount of exosome secreted and changing exosome contents. CONCLUSIONS: Aspirin inhibits the hypoxia-induced stemness, hypoxic-mediated exosome release, and malignant paracrine effects of A549 cells.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Aspirin/pharmacology , Carcinoma, Non-Small-Cell Lung/pathology , Exosomes/drug effects , Lung Neoplasms/pathology , Neoplastic Stem Cells/drug effects , A549 Cells , Cell Hypoxia/drug effects , Cell Proliferation/drug effects , HumansABSTRACT
OBJECTIVE: To investigate the efficacy and adverse effect of DCF regimen with subsequent S-1 maintenance chemotherapy in patients with advanced gastric cancer (AGC). METHODS: Sixty AGC patients without disease progression after 4 to 6 cycles of DCF regimen as the first-line chemotherapy were randomized into maintenance group and control group (30 patients each). The patients in the maintenance group received maintenance chemotherapy with S-1 (40 mg/m(2), twice daily for 14 days; 21 days for a treatment cycle) until disease progression or with intolerant toxicity, and those in the control group received optimal supportive care. RESULTS: The response rate (CR+PR) was 33.3% in the maintenance group, significantly higher than that in the control group (3.33%, P<0.05), and the disease control rate (CR+PR+SD) also differed significantly between the two groups (73.3% vs 46.7%, P<0.05). The median time to progression was 7.9 months in the maintenance group and 6.8 months in the control group, with median overall survival time of 13.8 and 11.7 months, respectively (P>0.05). The most common adverse effect in the maintenance group included nausea, vomiting, leucocytopenia, and hand-foot syndrome; no death occurred in relation to the therapy. CONCLUSION: S-1 maintenance chemotherapy, with a tolerable toxicity profile, can improve the RR, DCR and median time to progression in AGC patients who respond to DCF regimen, but its efficacy still awaits further evaluation.
