ABSTRACT
NDFIP1 has been previously reported as a tumor suppressor in multiple solid tumors, but the function of NDFIP1 in NSCLC and the underlying mechanism are still unknown. Besides, the WW domain containing proteins can be recognized by NDFIP1, resulted in the loading of the target proteins into exosomes. However, whether WW domain-containing transcription regulator 1 (WWTR1, also known as TAZ) can be packaged into exosomes by NDFIP1 and if so, whether the release of this oncogenic protein via exosomes has an effect on tumor development has not been investigated to any extent. Here, we first found that NDFIP1 was low expressed in NSCLC samples and cell lines, which is associated with shorter OS. Then, we confirmed the interaction between TAZ and NDFIP1, and the existence of TAZ in exosomes, which requires NDFIP1. Critically, knockout of NDFIP1 led to TAZ accumulation with no change in its mRNA level and degradation rate. And the cellular TAZ level could be altered by exosome secretion. Furthermore, NDFIP1 inhibited proliferation in vitro and in vivo, and silencing TAZ eliminated the increase of proliferation caused by NDFIP1 knockout. Moreover, TAZ was negatively correlated with NDFIP1 in subcutaneous xenograft model and clinical samples, and the serum exosomal TAZ level was lower in NSCLC patients. In summary, our data uncover a new tumor suppressor, NDFIP1 in NSCLC, and a new exosome-related regulatory mechanism of TAZ.
Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung/metabolism , Carrier Proteins/metabolism , Cell Line , Cell Proliferation , Exosomes/metabolism , Lung Neoplasms/genetics , Membrane Proteins/metabolism , Transcriptional Coactivator with PDZ-Binding Motif Proteins/metabolismABSTRACT
Objective To explore the mechanism of gefitinib in the treatment of non-small cell lung cancer (NSCLC) cell lines in vitro. Methods The effects of the gefitinib in five human NSCLC cell lines (A549, SPC-A-1, H460, H1229, 95D) were studied. The inhibition of cell proliferation in each group were measured by CCK8;The status of apoptosis cells were observed using flow cytometry after PI marked;invasion of lung cancer cell inhibited by gefitinib were assessed by transwell technique;The drug was detected by western blot on the proliferation-related signaling protein. Results The proliferation and invasive capacity of NSCLC cells were inhibited by gefitinib (P < 0.05). In gefitinib group, the apoptosis rates of A549 [(9.6±0.73) %]and SPC-A-1[(14.3±1.12) %]were higher than that of control group[(3.1±0.29) %](t =11.16,P =0.001;t =4.726, P =0.009). Expression of p-AKT, p-EGFR, p-MAPK protein levels were significantly down regulated in A549 cells when gefitinib was given after 72 hours (t =6.656, P =0.003;t =16.441, P =0.0001;t =3.736, P =0.020). Conclusion Gefitinib can inhibit the proliferation and invasion of lung cancer cell, also can induce apoptosis in vitro and most likely to contribute to the inhibition of key enzymes in EGFR signaling transduction pathway.
ABSTRACT
Recent progress in molecular biology has enabled us to better understand the molecular mechanism underlying pathogenesis of human malignancy including lung cancer, the advent of therapies based on mechanisms that target critical molecular pathways of tumors has evoked considerable interest. The therapeutic index is high, and optimally effective treatment can be achieved at a dose below the maximal tolerated dose,giving us a better understanding of the human lung cancer. This review focuses on the advance of targeted therapy for the first-line, second-line treatment or the maintenance treatment of non-small cell lung cancer.
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Objective To observe the short-term efficacy and safety of sequential administration of erlotinib and chemotherapy in unselected, chemonaive patients with advanced non-small-cell lung cancer (NSCLC). Methods Previously-untreated patients (n=23) with stage Ⅲ_B/Ⅳ NSCLC and ECOG PS of 0/1 received erlotinib (150 mg/d) on days 15-28 of a 4-week cycle that included gemcitabine (1250 mg/m~2, days 1 and 8), and either cisplatin (75 mg/m~2, day 1) or carboplatin (AUC=5, day 1). The primary end points were tumor response rate and safety. Results 23 patients received a total of 95 cycles of treatment, and all were evaluable for efficacy and toxicity. The overall response rate was 30.4%, 0 case achieved complete responses (CR), 7 cases (30.4%) achieved partial responses (PR), 14 cases (60.9 %) achieved stable disease (SD), 2 cases (8.7 %) achieved progression disease (PD). The disease control rate was 91.3 %. The sequential administration of erlotinib following gemcitabine/platinum chemotherapy was well tolerated. The major grade 3 treatment-related adverse events were eutropenia (13.4%), rash (8.7%), nausea (8.7%) and thrombocytopenia (8.7%). No treatment-related interstitial lung disease. Conclusion equential administration of erlotinib following gemcitabine/platinum chemotherapy was effective, and the toxicity was tolerable. This treatment strategy warrants further investigation.
ABSTRACT
As a hot topic, biomarkers can provide reliable evidence for the individualized treatment of non-small cell lung cancer. With the further study of molecular biology and development of new drugs,biomarkers have shown a broad prospect in clinical application. Combining with the research in recent years,this review describes the progress in biomarkers for non-small-cell lung cancer.
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Objective To determine the efficacy and toxicity of docetaxel in patients with paclitaxel-resistant advanced non-small cell lung cancer (NSCLC). Methods The clinical data from 15 patients with NSCLC who were admitted in the Shanghai Chest Hospital from January 2005 to May 2008 were retrospectively analyzed. The effects and toxicities of the second-line treatment were assessed. The progression-free survival time(PFS) and overall survival time(OS) were analyzed. Results The disease control rate was 66.7 %, with a progression-free survival time of 6 months, and a overall survival time of 17.3 months. The 1-year survival rate was 63.3 %. The toxic effects were as expected. Conclusion The doeetaxel-based agent is active in patients with paelitaxel-resistant advanced NSCLC.
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A platinum-based doublet with a third-generation agent represents the standard first-line treatment for advanced non-small cell lung cancer patients with good performance status (PS). Traditional chemotherapy provides response rates of 20 %-40 % and a median survival of 8-10 months. In an attempt to improve its outcome, alternative schedules have been proposed, namely sequential, alternating, and maintenance therapy. Sequential chemotherapy with a platinum-based doublet followed by a single agent is feasible in patients with good PS; The use of sequential single agents is an option for elderly and frail patients unsuitable for a platinum-based combination. Based on trials published so far, it is unlikely that an alternating chemotherapy strategy will be proved superior to standard chemotherapy in patients with good PS.Consolidation chemotherapy may provide additional benefit for patients achieving disease control after standard first-line chemotherapy.
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For advanced lung cancer,multimodality treatment is the main stream.Patients with locally advanced disease may have long-term survival rate with radiation therapy combined with chemotherapy.Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy.Here we reviewed the recent development in treatment for advanced non-small cell lung cancer.
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3 months. Female gender, adenocarcinoma history, non-smoking history, good PS and the presence of multiple lung metastases are associated with improved responsiveness to Gefitinib. Reflecting the results of previous clinical trials, the reports indicate that Gefitinib is generally well tolerated by Asian patients. The incidence of interstitial lung disease appears to be higher in Japanese than non-Japanese patients, although the reason for this is not clear. Recent findings regarding Erlotinib and other targeted therapy among Asian patients are discussed.