ABSTRACT
Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.
Subject(s)
Humans , Esophageal Squamous Cell Carcinoma/drug therapy , Cisplatin/metabolism , Esophageal Neoplasms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Carcinoma, Squamous Cell/genetics , Growth Differentiation Factor 15/therapeutic use , Receptor, Transforming Growth Factor-beta Type II/therapeutic use , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, NeoplasticABSTRACT
Objective To construct a programmed cell death ligand 1(PD-L1) co-expression network in lung squamous cell carcinoma,screen potential PD-L1 co-expression biomarkers,and try to find the genes and pathways participating in PD-L1-regulated tumor immune response.Methods The lung squamous cell carcinoma dataset extracted from TCGA was used to screen the co-expression genes of PD-L 1 at the whole-genome transcriptional level by Venny analysis,and the target genes were screened by multiple types of cluster and molecular network analysis to construct a PD-L1 co-expression network.Results A total of 126 genes moderately co-expressed with PD-L1 were retrieved,most of them are plasma membrane targeting genes participating in immune response.Three transcription factors (IRF2/NFKB1/IRF1) were involved in more than 30％ the regulation of the PD-L1 genes transcription.By screening the core molecules of co-expression of PD-L1 gene set and analyzing the connectivity of network node,6 network nodes genes with the highest connectivity were retrieved as follows:IFNG,JAK2,STAT1,CTLA4,CD80 and CCR5.Analysis of the relations of the different expression levels of these genes to the survival situation of patients with lung cancer revealed that CCR5 was a significant prognostic marker.Analysis of the PD-L1 expression and CCR5 gene spectrum data showed the Pearson correlation coefficient is 0.47(P＜0.05);GO-BP cluster analysis showed that the function of CCR5 mainly focused on immune regulation,T cell regulation and signal transduction,in accordance with the PD-L1 function of network regulation.Conclusions The main nodes of PD-L1 co-expressing gene set are immune-related molecules,among which IFNG/CCR5/NFKB1 play the most significant regulatory effects in the gene network.This finding lays a foundation for the research and immunotherapy for lung squamous cell carcinoma.
ABSTRACT
Objective To compare the effect of single-tube drainage with that of two-tube drainange in non-small cell lung cancer(NSCLC) patients with VATS upper-lobectomy.Methods Between August 2012 and August 2014,100 NSCLC patients who had received VATS upper-lobectomy performed by a single surgeon were prospectively enrolled and randomly classified into a single-tube drainage group(A) and a two-tube drainage group(B),consisting of 49 and 51 patients respectively.Upper-lobectomy and systematic mediastinal node dissection or sampling were performed in all cases.Clinical and surgical variables were collected prospectively.Results There were no significant differences in demographic and pathologic features between two groups.The amount/duration of drainage,the postoperative hospitalization days,postoperative morbidity and mortality between two groups showed no significant difference either.Group A patients had significantly lower VAS pain scores in the second day (4.06 ± 0.97 vs 4.47 ± 0.86,P =0.027) and one month after surgery (1.31 ± 0.68 vs 1.61 ± 0.64,P =0.024)compared with group B patients.Conclusion Single-tube drainage is as safe and effective as the conventional use of two-tube drainage after VATS upper-lobectomy in NSCLC patients.Moreover,single-tube drainage can relieve the post-operative pain for the patients.
ABSTRACT
<p><b>BACKGROUND</b>In order to minimize the injury reaction during the surgery and reduce the morbidity rate, hence reducing the mortality rate of esophagectomy, minimally invasive esophagectomy (MIE) was introduced. The aim of this study was to compare the postoperative outcomes in patients with esophageal squamous cell carcinoma undergoing minimally invasive or open esophagectomy (OE).</p><p><b>METHODS</b>The medical records of 176 consecutive patients, who underwent minimally invasive esophagectomy (MIE) between January 2009 and August 2013 in Cancer Institute & Hospital, Chinese Academy of Medical Sciences, were retrospectively reviewed. In the same period, 142 patients who underwent OE, either Ivor Lewis or McKeown approach, were selected randomly as controls. The clinical variables of paired groups were compared, including age, sex, Charlson score, tumor location, duration of surgery, number of harvested lymph nodes, morbidity rate, the rate of leak, pulmonary morbidity rate, mortality rate, and hospital length of stay (LOS).</p><p><b>RESULTS</b>The number of harvested lymph nodes was not significantly different between MIE group and OE group (median 20 vs. 16, P = 0.740). However, patients who underwent MIE had longer operation time than the OE group (375 vs. 300 minutes, P < 0.001). Overall morbidity, pulmonary morbidity, the rate of leak, in-hospital death, and hospital LOS were not significantly different between MIE and OE groups. Morbidities including anastomotic leak and pulmonary morbidity, inhospital death, hospital LOS, and hospital expenses were not significantly different between MIE and OE groups as well.</p><p><b>CONCLUSIONS</b>MIE and OE appear equivalent with regard to early oncological outcomes. There is a trend that hospital LOS and hospital expenses are reduced in the MIE group than the OE group.</p>