PPARG Could Work as a Valid Therapeutic Strategy for the Treatment of Lung Squamous Cell Carcinoma.

Previous studies showed that PPAR-gamma (PPARG) ligands might serve as potential therapeutic agents for nonsmall cell lung cancer (NSCLC). However, a few studies reported the specific relationship between PPARG and lung squamous cell carcinoma (LSCC). Here, we made an effort to explore the relationship between PPARG and LSCC. First, we used mega-analysis and partial mega-analysis to analyze the effects of PPARG on LSCC by using 12 independent LSCC expression datasets (285 healthy controls and 375 LSCC cases). Then, literature-based molecular pathways between PPARG and LSCC were established. After that, a gene set enrichment analysis (GSEA) was conducted to study the functionalities of PPARG and PPARG-driven triggers within the molecular pathways. Finally, another mega-analysis was constructed to test the expression changes of PPARG and its driven targets. The partial mega-analysis showed a significant downregulated expression of PPARG in LSCC (LFC = -1.08, p value = 0.00073). Twelve diagnostic markers and four prognostic markers were identified within multiple PPARG-LSCC regulatory pathways. Our results suggested that the activation of PPARG expression may inhibit the development and progression of LSCC through the regulation of LSCC upstream regulators and downstream marker genes, which were involved in tumor cell proliferation and protein polyubiquitination/ubiquitination.

miR-938 promotes cell proliferation by regulating RBM5 in lung adenocarcinoma cells.

A growing body of research suggests that microRNAs (miRNAs) may play a key part in the progression of various cancers, including lung adenocarcinoma (LUAD). However, the expression and mechanism of miR-938 (microRNA-938) in LUAD have not been defined. Compared with adjacent tissues, the level of miR-938 was up-regulated in LUAD tissues. miR-938 expression was significantly associated with tumor size. In vitro assays indicated that miR-938 expression was also increased in the LUAD cell lines. Overexpression of miR-938 promoted LUAD cell proliferation, whereas down-regulation of miR-938 had the opposite effect. We identified RNA-binding protein 5 (RBM5) as a potential target gene of miR-938 in LUAD. Expression of RBM5 was down-regulated in LUAD tumor tissues and negatively correlated with expression of miR-938. Up-regulation of RBM5 reversed cell proliferation by inhibition of miR-938 expression in LUAD cells. These results showed that miR-938 may act as an oncogenic miRNA by targeting RBM5 in LUAD, indicating that miR-938 could be used as a potential therapeutic target for LUAD patients.

AGTR1 promoter hypermethylation in lung squamous cell carcinoma but not in lung adenocarcinoma.

Aberrant DNA methylation is associated with non-small cell lung cancer (NSCLC), suggesting that gene promoter methylation may be a potential biomarker for the detection or risk prediction of NSCLC. The present study aimed to evaluate the potential usage of angiotensin II receptor type 1 (AGTR1) methylation in two major pathologic subtypes: Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Quantitative methylation-specific polymerase chain reaction was used to investigate the effect of AGTR1 promoter methylation in the tumor and the paired adjacent non-tumor tissue samples from 42 patients with LUSC, and 69 with LUAD. The percentage of methylated reference was calculated and presented as the median (interquartile range 25th-75th percentile). The results of the current study revealed that there was significantly increased AGTR1 promoter methylation in the tumor tissues compared with the paired adjacent non-tumor tissue [97.4 (57.22-130.5) vs. 85 (48.25-123); P=0.024]. Furthermore, higher AGTR1 promoter methylation was observed in patients with LUSC compared with LUAD (odds ratio=2.483; 95% confidence interval=1.125-5.480; P=0.023). Significant differences were identified in AGTR1 methylation between non-tumor and the tumor tissues in LUSC [113.5 (68.33-148.73) vs. 93.04 (45.94-140); P=0.008]. In addition, the Cancer Genome Atlas data of 378 patients with LUSC and 477 with LUAD revealed an inverse correlation between gene expression and the methylation status of AGTR1 promoter.. These data suggest that AGTR1 hypermethylation is a promising biomarker to assist in LUSC detection and diagnosis.

Development and validation of a nomogram to estimate the pretest probability of cancer in Chinese patients with solid solitary pulmonary nodules: A multi-institutional study.

OBJECTIVES: To develop and validate a nomogram to estimate the pretest probability of malignancy in Chinese patients with solid solitary pulmonary nodule (SPN). MATERIALS AND METHODS: A primary cohort of 1798 patients with pathologically confirmed solid SPNs after surgery was retrospectively studied at five institutions from January 2014 to December 2015. A nomogram based on independent prediction factors of malignant solid SPN was developed. Predictive performance also was evaluated using the calibration curve and the area under the receiver operating characteristic curve (AUC). RESULTS: The mean age of the cohort was 58.9 ± 10.7 years. In univariate and multivariate analysis, age; history of cancer; the log base 10 transformations of serum carcinoembryonic antigen value; nodule diameter; the presence of spiculation, pleural indentation, and calcification remained the predictive factors of malignancy. A nomogram was developed, and the AUC value (0.85; 95%CI, 0.83-0.88) was significantly higher than other three models. The calibration cure showed optimal agreement between the malignant probability as predicted by nomogram and the actual probability. CONCLUSIONS: We developed and validated a nomogram that can estimate the pretest probability of malignant solid SPNs, which can assist clinical physicians to select and interpret the results of subsequent diagnostic tests.

Supplement CT-Guided Microcoil Placement for Localising Ground-glass Opacity (GGO) Lesions at "Blind Areas" of the Conventional Hook-Wire Technique.

BACKGROUND: In the conventional hook-wire technique of pulmonary nodular localisations there are several "blind areas", including the mediastinum-vicinity region, interlobar fissure-neighbouring areas and scapulae-shadowed areas. The present study aims to summarise the experiences of CT-guided microcoil placement as an alternative method for localising pulmonary ground-glass opacity (GGO) lesions before thoracoscopic wedge resections. METHODS: Sixteen GGO lesions at "blind areas" in 16 patients were localised with platinum-fibered microcoils under CT assistance before undergoing video-assisted thoracoscopic surgical resections. Information regarding coil placement, operations and complications was recorded. RESULTS: Of all lesions, 1 was in the mediastinum-vicinity region, 8 were covered by the scapulae, and 7 were close to interlobar fissures (3 horizontal fissures, 4 oblique fissures). All 16 (100%) lesions had been successfully marked with microcoils. No major complications of the puncture procedure occurred; there were only minor pneumothorax (n=2) and haemoptysis (n=1) complications, which required no intervention before operations. All GGO lesions and microcoils were successfully removed by initial wedge resections. Of the 16 lesions in "blind areas", 8 were adenocarcinoma in situ (AIS), 4 were minimally invasive adenocarcinoma (MIA), 3 were atypical adenomatous hyperplasia (AAH), and 1 was interstitial fibrous tissue proliferation. No major complications occurred postoperatively. CONCLUSIONS: For the "blind areas" of the hook-wire technique, CT-guided microcoil placement is an effective method of marking GGO lesions that makes thoracoscopic wedge resection easier.

Preoperative nomogram for identifying invasive pulmonary adenocarcinoma in patients with pure ground-glass nodule: A multi-institutional study.

PURPOSE: To construct a preoperative nomogram to differentiate invasive pulmonary adenocarcinomas (IPAs) from preinvasive lesions in patients with solitary pure ground-glass nodules (GGN). METHODS: A primary cohort of patients with pathologically confirmed pulmonary solitary pure GGN after surgery were retrospectively studied at five institutions from January 2009 to September 2015. Half of the patients were randomly selected and assigned to a model-development cohort, and the remaining patients were assigned to a validation cohort. A nomogram predicting the invasive extent of the solitary GGNs was constructed based on the independent risk factors. Predictive performance was evaluated by concordance index (C-index) and calibration curve. RESULTS: Out of 898 cases included in the study, 501 (55.8%) were preinvasive lesions and 397 (44.2%) were IPAs. In the univariate analysis, lesion size (p < 0.001), lesion margin (p = 0.041), lesion shape (p < 0.001), mean computed tomography (CT) value (p = 0.018), presence of pleural indentation (p = 0.017), and smoking status (p = 0.014) were significantly associated with invasive extent. In multivariate analysis, lesion size (p < 0.001), lesion margin (p = 0.042), lesion shape (p < 0.001), mean CT value (p = 0.014), presence of pleural indentation (p = 0.026), and smoking status (p = 0.004) remained the predictive factors of invasive extent. A nomogram was developed and validation results showed a C-index of 0.94, demonstrating excellent concordance between predicted and observed results. CONCLUSIONS: We established and validated a novel nomogram that can identify IPAs from preinvasive lesions in patients with solitary pure GGN.

Silencing Aurora-A with siRNA inhibits cell proliferation in human lung adenocarcinoma cells.

Aurora kinase A (AURKA) is an oncogenic serine/threonine kinase, it plays important roles in tumorigenesis and chemoresistance. In this study, we investigated the expression of AURKA in lung adenocarcinoma tissues, the role of small interference RNA targeting AURKA on growth, cell cycle, and apoptosis of lung adenocarcinoma cell lines in vitro. The AURKA is highly expressed in lung adenocarcinoma tissues and human lung adenocarcinoma cell lines. Lentivirus-mediated short hairpin RNA (shRNA) was used to knock down AURKA expression in human lung adenocarcinoma cell lines H1299 and A549. The results indicated that depletion of AURKA could inhibit cell growth, cause cell cycle arrest and apoptosis. The potential mechanisms of AURKA inhibition induced cell cycle arrest and apoptosis are associated with downregulated RAF-1, CCND2, CCND3, CDK4, PAK4, EGFR and upregulated WEE1 expression. Furthermore, AURKA knockdown cooperated with vincristine (VCR) to repress A549 cell proliferation. Therefore, AURKA plays important roles in the proliferation of human lung adenocarcinoma cells, which suggests that AURKA could be a promising tool for lung adenocarcinoma therapy.

Knocking down the expression of Aurora-A gene inhibits cell proliferation and induces G2/M phase arrest in human small cell lung cancer cells.

A hallmark of small cell lung cancer (SCLC) is frequent relapse characterized by newfound resistance to formerly efficacious chemotherapies. The prognosis for SCLC patients is particularly unfavorable. Aurora kinase A (AURKA), a member of the serine/threonine kinase family, is overexpressed across many types of human tumors. Recent studies have identified AURKA as an important factor in tumorigenesis, but little is known regarding its specific roles in SCLC. The aim of the present study was to establish the roles of AURKA in the molecular pathogenesis of human SCLC. In the present study, we constructed a lentiviral vector to express siRNA against AURKA (LV-AURKA siRNA). As we expected, the viral construct effectively suppressed the expression of the AURKA gene and protein in H446 and H1688 cell lines. Additionally, RNA interference of AURKA inhibited the colony formation and subsequent growth of H446 and H1688 cell lines by increasing the incidence of cell cycle arrest in the G2/M phase. Furthermore, suppression of AURKA by LV-AURKA siRNA also increased apoptosis of SCLC cells. A potential mechanism for the increase of apoptosis is the downregulation of Bcl-2 and upregulation of Bax. AURKA gene suppression may provide a novel, effective therapy for SCLC patients by inhibiting cell division and increasing the rate of apoptosis of SCLC cells.

Mesenchymal stem-like cells isolated from human esophageal carcinoma and adjacent non-cancerous tissues.

Mesenchymal stem cells (MSCs) or MSC-like cells have now been isolated from various sites, including different types of tumor tissues. Whether MSCs or MSC-like cells in different tumor tissues possess differentiated biological characteristics remains unclear, and the correlation between MSCs or MSC-like cells and tumors has been a controversial topic. In the present study, we isolated MSC-like cells from human esophageal carcinoma (hEC-MSCs) and adjacent non-cancerous tissues (hECN-MSCs). Although the two types of MSC-like cells were in different microenvironments and had certain differences, they possessed similar morphological properties and surface antigens, including CD13, CD29, CD44 and CD105. Our results indicated that hEC-MSCs and hECN-MSCs are similar in a number of ways. This may have implications for further research on the esophageal carcinoma microenvironment and its pathological mechanism.