BackgroundEpidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are approved for patients with recurrent non-small cell lung cancer (NSCLC). However, the efficacy of EGFR-TKIs in NSCLC therapy is limited by primary and acquired resistance. Recent studies have revealed that long non-coding RNAs (LncRNA) may be involved in EGFR-TKI resistance. Therefore, a better understanding of the interactive mechanisms underlying LncRNA-mediated EGFR-TKIs resistance may help us to improve clinical response rates.MethodTo investigate the expression of growth arrest-specific 5 (GAS5) in lung adenocarcinoma, we performed real-time reverse-transcriptase polymerase chain reaction. The correlation between GAS5 expression levels and the samples’ clinicopathological features was also analyzed. Primary resistance to EGFR-TKIs was identified in the human lung adenocarcinoma cell line A549. Plasmid vectors were used to overexpress GAS5 in A549 cells. MTT (3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide) colony formation assays and EdU (5-ethynyl-2’-deoxyuridine) assays were used to assess cell proliferation, and flow-cytometric analysis was used to evaluate the apoptosis rate. The expression levels of our target proteins, namely, EGFR, p-EGFR, ERK, p-ERK, Akt, p-Akt, IGF-1R (insulin-like growth factor 1 receptor), and p-IGF-1R, were analyzed by western blotting. A549 cells transfected with pcDNA-GAS5 were injected into nude mice. The transplanted mice were treated with gefitinib to study the effect of GAS5 on the resistance to EGFR-TKIs in vivo.ResultsOur results showed that GAS5 was significantly downregulated in lung adenocarcinoma tissues compared with the paired adjacent non-tumorous tissue samples. Furthermore, lower GAS5 expression levels were associated with larger tumor sizes, poor tumor differentiation, and advanced pathological stages. However, GAS5 was almost equally expressed between benign tumors compared with the adjacent normal tissues. GAS5 was also overexpressed in EGFR-TKI sensitive cell lines compared with the resistant cell line. Using MTT, EdU incorporation, and colony formation assays, we showed that GAS5-expressing A549 cells displayed an elevated level of cell death. In addition to its pro-apoptotic effect in the A549 cell line, GAS5 overexpression also suppressed the growth of A549-derived tumors in nude mice treated with gefitinib. GAS5 overexpression was inversely correlated with the expression of the EGFR pathway and IGF-1R proteins.ConclusionsCollectively, our results indicated that GAS5 LncRNA may represent a potential biomarker for the diagnosis of lung adenocarcinoma and that GAS5 might play a novel role in the development of the resistance to gefitinib, which could be reversed by overexpressing GAS5.

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Background: As one of the most aggressive malignancies, esophageal squamous cell carcinoma(ESCC) remains one of the leading causes of cancer related death worldwide. The majority of ESCCs are diagnosed at advanced stages with poor five-year survival rate, making it urgent to identify specific genes and pathways associated with its initiation and prognosis. Materials and Methods: The differentially expressed genes in TCGA were analysed to construct a co-expression network by WGCNA. Gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis were performed for the selected genes. Moduleclinical trait relationships were analyzed to explore the genes and pathways that associated with clinicopathological parameters of ESCC. Log-rank tests and COX regression were used to identify the prognosis-related genes. Results: The brown module containing 716 genes which most significantly contributed to ESCC. GO analysis suggested enrichment of adaptive immune response, cyclin−dependent protein serine, regeneration and mRNA metabolic process. KEGG analysis indicated pathways including Cellular senescence, Ribosome biogenesis, Proteasome, Base excision repair and p53 signaling pathway. Clinical stage was associated with cyan module; clinical M was associated with grey60 module; clinical T was associated with darkturquoise module; while clinical N, histological type and cancer location were associated with turquoise module. Key genes of TCP1, COQ3, PTMA and MAPRE1 might be potential prognostic markers for ESCC. Discussion: Differentially expressed genes and key modules contributing to initiation and progression in ESCC were identified by WGCNA. These findings provide novel insights into the mechanisms underlying the initiation, prognosis and treatment of ESCC.

Backgrounds:The 2 isoforms of paired-related homeobox 1 (PRRX1), PRRX1A and PRRX1B, are critical in regulating several kinds of cancers, and figure prominently in the maintenance of stemness and progression of epithelial-mesenchymal transition (EMT). However their differential expression in non-small cell lung cancer (NSCLC) clinical samples and exact regulatory roles in cancer stem-like cells (CSCs) remain unknown.Methods: In vitro and in vivo experiments were employed to investigate the molecular mechanism. Using CSCs, mouse models, and clinical tissues, we obtained a general picture of the relatively higher level of PRRX1A compared to PRRX1B, and PRRX1A thus promoting EMT and maintaining stemness of CSCs.Results: PRRX1A but not PRRX1B was upregulated in lung cancer tissues and was positively correlated with TGF-β expression. In CSCs, overexpressed PRRX1A promoted malignant behaviors via transcriptional activation of TGF-β depending on TGF-β/TGF-βR signaling pathway. PRRX1A knockdown decreased selfrenewal capacity accompanied by a decrease in stemness factor expression independent of the TGF-β/TGF-βR signaling pathway. Furthermore, PRRX1A was found to tightly bind to and stabilize SOX2. PRRX1A promoted sphere formation not only by enhancing stemness via stabilizing SOX2 but also by promoting cell proliferation.Conclusions: PRRX1A, but not PRRX1B, was demonstrated to have important roles in the regulation of the stemness and metastatic potential of lung cancer, which suggests the potential application of PRRX1A in cancer treatment.

Paraneoplastic Cushing's syndrome (CushingPS) caused by bronchopulmonary carcinoid tumors presents a diagnostic challenge for clinicians. The present study reports the case of an 18-year-old male patient presenting with rapid weight gain, polyuria, polydipsia and progressive muscle weakness. Chemical and imaging findings suggested ectopic secretion of adrenocorticotropin. Whole-body 18fluorine-fluorodeoxyglucose (18FDG-PET/CT) positron-emission tomography revealed an increased uptake of 18FDG-PET/CT in the right middle lung mass and lobar lymph node. Postoperative pathology confirmed the presence of a typical carcinoid, as well as a lobar lymph node metastasis. The patient underwent a right middle lobectomy with mediastinal lymph node resection, which resulted in symptom clearance, followed by rapid weight loss. No CushingPS or tumor recurrence was observed at the 3-month postoperative follow-up.

ObjectivesIt is not clear whether being overweight or obese influences postoperative complications in myasthenia gravis (MG) patients. We retrospectively investigated an association between body mass index (BMI) and postoperative complications in MG.Materials and MethodsFifty-nine MG patients who had undergone transsternal thymectomy were classified as low or high BMI based on the criteria for Asian-Pacific populations. An association between BMI and complications was analyzed.ResultsMG patients with high BMI had significantly higher rates of major adverse complications (P = 0.033), postoperative respiratory failure (P = 0.045), and longer postoperative hospitalization (P = 0.005). The optimal cutoff value of BMI for postoperative respiratory failure was 23.3 kg/m2, with a sensitivity of 75.0% and a specificity of 64.7% (P = 0.046).ConclusionsMG patients with a BMI indicating overweight or obesity have a higher risk of postoperative complications after thymectomy. Thus, close monitoring must be performed when surgery is necessary.

Background Neoadjuvant chemoradiotherapy (nCRT) followed by surgery benefits survival for patients with esophageal squamous cell carcinomas (ESCC) compared with surgery alone, but the clinical outcomes of nCRT are heterogeneous. This study aimed to elucidate transcriptional factor (TF) regulation network and competitive endogenous RNA (ceRNA) network determining response of ESCC to nCRT. Materials and Methods RNA microarray data of GSE59974 and GSE45670 were analyzed to investigate the significant changes of lincRNAs, miRNAs, mRNAs in responders and non-responders of nCRT in ESCC. Functional and enrichment analyses were conducted by clusterProfiler. The target lincRNAs and mRNAs of miRNAs were predicted by miRWalk. The ceRNA and TF regulatory networks were constructed using Cytoscape. Results Differentially expressed genes between responders and non-responders mainly enriched in biological process including Wnt signaling pathway and regulation of cell development and morphogenesis involved in differentiation. Besides, these genes showed enrichment in molecular function of glycosaminoglycan binding, metalloendopeptidase inhibitor and growth factor activity. KEGG analysis enriched these genes in pathways of neurotrophin signaling pathway, cell adhesion molecules and Wnt signaling pathway. We also constructed ceRNA network and TF network regulating response of ESCC to nCRT. Core regulatory miRNAs were miR-520a, miR-548am, miR-3184, miR-548d, miR-4725, miR-148a, miR-4659a and key regulatory TFs included MBNL1, SLC26A3, BMP4, ZIC1 and ANKRD7. Conclusion We identified significantly altered lincRNAs, miRNAs and mRNAs involved in the nCRT response of ESCC. In addition, the ceRNA regulatory network of lincRNA-miRNA-mRNA and TF regulatory network were constructed, which would elucidate novel molecular mechanisms determining nCRT response of ESCC, thus providing promising clues for clinical therapy.

Reactive oxygen species (ROS) play a crucial role in the regulation of tumor occurrence and development. As a main source of ROS, NADPH oxidases are key enzymes that mediate electron transport within intracellular membranes. Of the NOX members that have been reported to be dysregulated in a wide variety of tumors, NOX4 is the member to be most frequently expressed. Numerous studies have elucidated that NOX4 gets involved in the regulation of tumor proliferation, metastasis, therapy resistance, tumor-stromal interaction and dysregulated tumor metabolism. In this review, we primarily discussed the biological function of NOX4 in tumorigenesis and progression of multiple cancer models, including its role in activating oncogenic signaling pathways, rewiring the metabolic phenotype and mediating immune response. Besides, the development of NOX4 inhibitors has also been unraveled. Herein, we discussed the interplay between NOX4 and tumorigenesis, proposing NOX4 as a promising therapeutic target waiting for further exploration.