Siwen Liu

Cisplatin-resistant lung cancer cell–derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100–5p-dependent manner

Exosomes derived from lung cancer cells confer cisplatin (DDP) resistance to other cancer cells. However, the underlying mechanism is still unknown. A549 resistance to DDP (A549/DDP) was established. Microarray was used to analyze microRNA (miRNA) expression profiles of A549 cells, A549/DDP cells, A549 exosomes, and A549/DDP exosomes. There was a strong correlation of miRNA profiles between exosomes and their maternal cells. A total of 11 miRNAs were significantly upregulated both in A549/DDP cells compared with A549 cells and in exosomes derived from A549/DDP cells in contrast to exosomes from A549 cells. A total of 31 downregulated miRNAs were also observed. miR-100–5p was the most prominent decreased miRNA in DDP-resistant exosomes compared with the corresponding sensitive ones. Downregulated miR-100–5p was proved to be involved in DDP resistance in A549 cells, and mammalian target of rapamycin (mTOR) expression was reverse regulated by miR-100–5p. Exosomes confer recipient cells’ resistance to DDP in an exosomal miR-100–5p-dependent manner with mTOR as its potential target both in vitro and in vivo. Exosomes from DDP-resistant lung cancer cells A549 can alter other lung cancer cells’ sensitivity to DDP in exosomal miR-100–5p-dependent manner. Our study provides new insights into the molecular mechanism of DDP resistance in lung cancer.

MiR-138: A promising therapeutic target for cancer:

MicroRNAs are small noncoding RNAs which regulate gene expressions at post-transcriptional level by binding to the 3′-untranslated region of target messenger RNAs. Growing evidences highlight their pivotal roles in various biological processes of human cancers. Among them, miR-138, generating from two primary transcripts, pri-miR-138-1 and pri-miR-138-2, expresses aberrantly in different cancers and is extensively studied in cancer network. Importantly, studies have shown that miR-138 acts as a tumor suppressor by targeting many target genes, which are related to proliferation, apoptosis, invasion, and migration. Additionally, some researches also discover that miR-138 can sensitize tumors to chemotherapies. In this review, we summarize the expression of miR-138 on regulatory mechanisms and tumor biological processes, which will establish molecular basis on the usage of miR-138 in clinical applications in the future.

Chimaeric antigen receptor T-cell therapy for tumour immunotherapy

Chimaeric antigen receptor (CAR) T-cell therapies, as one of the cancer immunotherapies, have heralded a new era of treating cancer. The accumulating data, especially about CAR-modified T cells against CD19 support that CAR T-cell therapy is a highly effective immune therapy for B-cell malignancies. Apart from CD19, there have been many trials of CAR T cells directed other tumour specific or associated antigens (TSAs/TAAs) in haematologic malignancies and solid tumours. This review will briefly summarize basic CAR structure, parts of reported TSAs/TAAs, results of the clinical trials of CAR T-cell therapies as well as two life-threatening side effects. Experiments in vivo or in vitro, ongoing clinical trials and the outlook for CAR T-cell therapies also be included. Our future efforts will focus on identification of more viable cancer targets and more strategies to make CAR T-cell therapy safer.

Liver X receptors agonist GW3965 re-sensitizes gefitinib-resistant human non-small cell lung cancer cell to gefitinib treatment by inhibiting NF-κB in vitro

The recent research shows that the inhibition of the nuclear factor-κB (NF-κB) pathway is a promising therapeutic option for patients who progress after treatment with the novel mutant-selective EGFR-TKIs. For propose to find a nontoxic drug to reverse the acquired gefitinib resistance, we examined whether the Liver X Receptors agonist GW3965 affect gefitinib resistance of HCC827/GR-8-2 cells. Cell viability was measured by CCK-8 assay. Levels of NF-κB, p-AKT and caspases were detected by Western blot analysis. Immunocytochemical analysis was used to detect the expression of NF-κB, p-AKT intracellularly. Induction of apoptosis and cell cycle arrest was measured by Flow cytometry assay. And results revealed that more than 90% of HCC827/GR-8-2 cells lived upon treatment with gefitinib at a dose of 5μM for 48h. However, when under the combine treatment of GW3965 (5μM) & gefitinib(5μM), cell death rate was increased observably. Co-administration of gefitinib & GW3965 induced cell apoptosis and cell cycle arrest. Additionally, we observed a dose-dependent- down-regulation of NF-κB in HCC827/GR-8-2 cells treated with gefitinib & GW3965. GW3965 and gefitinib synergistically decreased cell proliferation and induced apoptosis by inhibiting NF-κB signaling pathway in gefitinib resistant cells. These findings support our hypothesis that GW3965 could act as a useful drug to reverse the gefitinib resistance.

Comparison of nedaplatin-based versus cisplatin-based chemotherapy for advanced non-small cell lung cancer among East Asian populations: A meta-analysis

Whether nedaplatin and cisplatin are equally effective for advanced non-small cell lung cancer (NSCLC) remains uncertain. Therefore, we performed a meta-analysis of trials to compare nedaplatin-based chemotherapy with cisplatin-based chemotherapy. We conducted a literature search to identify trials that had investigated the substitution of nedaplatin for cisplatin in the treatment of advanced NSCLC. Fourteen randomized controlled trials were included. We found equivalent overall response, overall survival, and survival probability (0.5-year, 1-year). Considering the toxicity profiles, nausea and vomiting were common in the cisplatin group (OR = 0.28, 95% CI = 0.20–0.40, P < 0.001), whereas severe thrombocytopenia was common in the nedaplatin group (OR = 1.68, 95% CI = 1.18–2.40, P = 0.005). A subgroup analysis of grades 1–4 nephrotoxicity showed that cisplatin-based chemotherapy resulted in more renal toxicity (OR = 0.40, 95% CI = 0.24–0.68, P = 0.001). No significant heterogeneity and publication bias were observed. Cumulative analysis found a stable time-dependent trend. Consistent results stratified by age, regimen, and country were observed. Cisplatin-based chemotherapy was associated with non-inferior antitumor efficacy compared with nedaplatin-based therapy. Therefore, the toxicity profile might play an important role in choosing between cisplatin-based or nedaplatin-based regimens.

Cytokine-induced killer cells as a feasible adoptive immunotherapy for the treatment of lung cancer

Most of the patients with lung cancer are diagnosed at advanced stage, and they often lose the opportunity of surgical therapy, most of whom fail to reach good prognosis after chemotherapy. Recently, a few clinical studies have confirmed the role of adoptive T-cell transfer in the maintenance therapy of cancer patients. Here, we provided statistical insights into the role of CIKs in advanced lung cancer from three different levels, cell model (in vitro co-culture system), mice model (in situ lung cancer), and clinical research (in lung cancer patients of different progression stages). We optimized the components of supplements and cytokines on activating and expanding CIK cells. Based on this, we explored a new serum-free medium for in vitro activation and expansion of CIK cells. Moreover, we found that activated CIK cells could efficiently kill lung cancer cells in cell-to-cell model in vitro and significantly reduce the tumor growth in mice. For the clinical research, the OS rates of patients received combination of chemotherapy and CIK treatment were significantly improved compared to the OS rates of patients only received chemotherapy. Additionally, CIK therapy represented good toleration in our study. All the results suggested that combination of immunotherapy with traditional therapy will be a feasible and promising method for the treatment of lung cancer.

Genome-wide profiling of micro-RNA expression in gefitinib-resistant human lung adenocarcinoma using microarray for the identification of miR-149-5p modulation

To understand the mechanism involved in gefitinib resistance, we established gefitinib-resistant human HCC827/GR-8-1 cell line from the parental HCC827 cell line. We compared the micro-RNA expression profiles of the HCC827 cells HCC827/GR-8-1 using Agilent micro-RNA microarrays. The micro-RNAs, such as the miR-149-5p, were up- or downregulated and associated with acquired gefitinib resistance. Quantitative real-time polymerase chain reaction was then performed to verify the expression patterns of different micro-RNAs. The result showed that miR-149-5p was upregulated in the HCC827/GR-8-1 cell line. To investigate the biological function of miR-149-5p in non–small cell lung cancer cells acquired gefitinib resistance, we examined cell proliferation using a cell counting kit-8 assay. Cell viability was evaluated after the miR-149-5p mimics, inhibitors, and negative control were separately transfected into the non–small cell lung cancer cells. The results showed that the non–small cell lung cancer cells transfected with miR-149-5p mimics exhibited reduced cell motility. The drug-sensitivity assay results revealed that the overexpression of miR-149-5p effectively evaluates the half maximal inhibitory concentration values of the cell in response to gefitinib, and the downregulation of miR-149-5p can attenuate the half maximal inhibitory concentration values of the cell lines in response to gefitinib. Furthermore, the levels of miR-149-5p in the HCC827 and HCC827/GR-8-1 cells were inversely correlated with caspase-3 expression. In conclusion, this study revealed that miR-149-5p is upregulated in the HCC827/GR-8-1 cells and involved in the acquired gefitinib resistance.

Liver X receptor agonist T0901317 reverses resistance of A549 human lung cancer cells to EGFR-TKI treatment.

Epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) is effective in lung cancer patients carrying sensitive EGFR mutations. In this study, we investigated if liver X receptor (LXR) agonist T0901317 could reverse the resistance of lung cancer cell lines A549 and H1650 to EGFR‐TKI treatment. We found that T0901317 could make natural EGFR‐TKI‐resistant A549 human lung cancer cells sensitive to EGFR‐TKI treatment and that this was dependent on LXRβ expression. However, T0901317 does not have a similar effect on another natural EGFR‐TKI‐resistant cell line H1650.

PPARγ agonist efatutazone and gefitinib synergistically inhibit the proliferation of EGFR-TKI-resistant lung adenocarcinoma cells via the PPARγ/PTEN/Akt pathway

ABSTRACT Development of acquired resistance to EGFR‐TKI therapy continues to be a serious clinical problem in Lung adenocarcinoma management. Peroxisome proliferator‐activated receptor gamma (PPAR&ggr;) agonists demonstrate anti‐tumor activity likely via transactivating genes that regulate cell proliferation, differentiation and apoptosis. Efatutazone, a novel later generation PPAR&ggr; agonist, selectively activates PPAR&ggr; target genes and has antiproliferative effects in a range of malignancies. However, the exact function and molecular mechanism of PPAR&ggr; agonists efatutazone in EGFR‐TKI gefitinib‐resistance of Lung adenocarcinoma has not been determined. In this study, we studied the development of acquired resistance to an EGFR‐TKI gefitinib in lung adenocarcinoma cells and investigated the antiproliferative effects of efatutazone in the acquired resistant cells. The treatment of gefitinib‐resistant cells with efatutazone reduced the growth of gefitinib‐resistant cells in a dose‐ and time‐dependent manner, and facilitated the anti‐proliferative effects of gefitinib. Mechanistic investigations suggested that efatutazone acted by upregulating protein expression of PPAR&ggr;, phosphatase and tensin homolog (PTEN), inactivating the Akt pathway, followed by dephosphorylation of p21Cip1 at Thr145 without affecting the transcriptional levels. Our results suggested that efatutazone, alone or in combination with gefitinib, might offer therapeutic effects in lung adenocarcinoma. HIGHLIGHTSThe low expression of PPARG predicts poor overall survival for patients with lung adenocarcinoma.Treatment with efatutazone and gefitinib produced a synergistic effect on inhibiting proliferation of EGFR‐TKI‐resistant cells.The PPAR&ggr;/PTEN/Akt/p21 signaling pathway might be involved in above synergistic effect.Efatutazone is a potential therapeutic agent for the NSCLC patients who develop acquired resistance to EGFRT‐KI.

Elevated serum levels of vascular endothelial growth factor predict a poor prognosis of platinum-based chemotherapy in non-small cell lung cancer.

Aim This study was designed to investigate the predictive and prognostic values of serum vascular endothelial growth factor (VEGF) level in non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. Methods Patients’ peripheral blood samples were collected prior to chemotherapy and after 1 week of the third cycle of combination chemotherapy. Serum VEGF levels were evaluated through Luminex multiplex technique. Between September 2011 and August 2015, a total of 135 consecutive advanced or recurrent histologically verified NSCLC patients were enrolled in the study. Moreover, all the patients received platinum-based combination chemotherapy as a first-line treatment. Results No significant associations were found between pretreatment serum VEGF levels and clinical characteristics, such as sex (P=0.0975), age (P=0.2522), stage (P=0.1407), lymph node metastasis (P=0.6409), tumor location (P=0.3520), differentiated degree (P=0.5608), pathological (histological) type (P=0.4885), and response to treatment (P=0.9859). The VEGF load per platelet (VEGFPLT) levels were not correlated with sex, age, primary tumor site, and pathological type in NSCLC patients (all P>0.05). The median survival time of progression-free survival (PFS) was 6.407 and 5.29 months in the low and high groups, respectively, when using 280 pg/mL VEGF level as the cutoff point (P=0.024). Conclusion In conclusion, the serum VEGF levels were found to be a poor prognostic biomarker for the efficacy of platinum-based chemotherapy in terms of PFS, but it was not shown to be a suitable predictive marker for clinical response to platinum-based chemotherapy.