Multidirectional characterization of cellular composition and spatial architecture in human multiple primary lung cancers.

Multiple primary lung cancers (MPLCs) pose diagnostic and therapeutic challenges in clinic. Here, we orchestrated the cellular and spatial architecture of MPLCs by combining single-cell RNA-sequencing and spatial transcriptomics. Notably, we identified a previously undescribed sub-population of epithelial cells termed as CLDN2+ alveolar type II (AT2) which was specifically enriched in MPLCs. This subtype was observed to possess a relatively stationary state, play a critical role in cellular communication, aggregate spatially in tumor tissues, and dominate the malignant histopathological patterns. The CLDN2 protein expression can help distinguish MPLCs from intrapulmonary metastasis and solitary lung cancer. Moreover, a cell surface receptor-TNFRSF18/GITR was highly expressed in T cells of MPLCs, suggesting TNFRSF18 as one potential immunotherapeutic target in MPLCs. Meanwhile, high inter-lesion heterogeneity was observed in MPLCs. These findings will provide insights into diagnostic biomarkers and therapeutic targets and advance our understanding of the cellular and spatial architecture of MPLCs.

Common variants of pro-inflammatory gene IL1B and interactions with PPP1R13L and POLR1G in relation to lung cancer among Northeast Chinese.

Lung cancer is a complex disease influenced by a variety of genetic and environmental factors. The cytokine interleukin 1 encoded by IL1B is an important mediator of the inflammatory response, and is involved in a variety of cellular activities. The effect of single nucleotide polymorphisms (SNP) at IL1B has been investigated in relation to cancer with inconsistent results. This Northeastern-Chinese case-control study involving 627 cases and 633 controls evaluated the role of three haplotype-tagging single nucleotide polymorphisms (htSNP) (rs1143633, rs3136558 and rs1143630) representing 95% of the common haplotype diversity across the IL1B gene and assessed interactions with IL1B, PPP1R13L, POLR1G and smoking duration in relation to lung cancer risk. The analyses of five genetic models showed associations with lung cancer risk for rs1143633 in the dominant model [adjusted-OR (95% CI) = 0.67 (0.52-0.85), P = 0.0012] and rs3136558 in the recessive model [adjusted-OR (95% CI) = 1.44 (1.05-1.98), P = 0.025]. Haplotype4 was associated with increased lung cancer risk [adjusted-OR (95% CI) = 1.55 (1.07-2.24), P = 0.021]. The variant G-allele of rs1143633 was protective in smoking sub-group of > 20 years. Using multifactor dimensionality reduction (MDR) analyses, we identified the three best candidate models of interactions and smoking-duration or IL1B rs1143633 as main effect. In conclusion, our findings suggest that IL1B SNP rs1143633 may associate with lower risk of lung cancer, confirming previously identified marker; IL1B SNP rs3136558 and haplotype4 consisting of IL1B htSNPs may associate with increasing risk of lung cancer; interactions of IL1B with POLR1G or PPP1R13L or smoking-duration, which is independent or combined, may involve in risk of lung cancer and lung squamous cell carcinoma.

Comparison of efficacy and safety of hybrid video-assisted thoracoscopic surgery vs. thoracotomy sleeve lobectomy for non-small cell lung cancer: a propensity score matching study.

Background: It is unclear whether hybrid video-assisted thoracoscopic surgery (VATS) sleeve lobectomy (SL) could be an alternative to thoracotomy SL for non-small cell lung cancer (NSCLC) treatment. The aim of the study is to investigate the safety and efficacy of hybrid VATS SL. Methods: We collected 112 patients who received hybrid VATS SL or thoracotomy SL for primary treatment of NSCLC at Liaoning Cancer Hospital & Institute from November 2016 to September 2021. Perioperative and survival data were collected, and retrospective analysis was conducted on 91 thoracotomy and 21 hybrid VATS SL patients to evaluate the safety and efficacy of two approaches. Propensity score matching (PSM) was used to minimize selection bias. The Kaplan-Meier method was applied to compare overall survival (OS) and recurrence-free survival (RFS). Follow-up data were obtained by outpatient clinical visit and nurse-led telephone. Results: A total of 112 patients were included in this study, including thoracotomy patients (n=91) and hybrid VATS patients (n=21). In the non-match analysis, the baseline data of patients was similar between the two groups, except regarding the receipt of neoadjuvant therapy (P=0.087). After PSM (2:1), a total of 39 thoracotomy patients and 19 hybrid VATS patients were enrolled. The baseline variables were quite similar in both groups. In the hybrid group, the number of lymph nodes (25.9±8.5 vs. 32.9±9.7, P<0.01) and positive lymph nodes (3.7±2.9 vs. 5.6±4.0, P=0.045) were significantly higher than those in the thoracotomy group. The hybrid group was associated with significantly shorter postoperative hospital stay (9.5±3.5 vs. 7.3±2.9, P=0.021) and chest tube duration time (6.6±3.1 vs. 5.3±1.5, P=0.031). No statistical difference in complications, reoperation, and recurrence were observed between the hybrid VATS SL and thoracotomy SL (P=1.0, P=1.0, P=0.472). The 30- and 90-day mortalities showed no differences between approaches (2.6% vs. 0%, P=1.0; 5.1% vs. 5.3%, P=1.0). No significant differences were found between thoracotomy and hybrid VATS SL in 3-year OS (P=0.614) and 3-year RFS (P=0.750). Conclusions: Hybrid VATS SL lobectomy may be a safe and feasible approach associated with similar oncologic prognosis and better postoperative recovery compared with thoracotomy SL for NSCLC treatment.

Pembrolizumab Combined With Neoadjuvant Chemotherapy Versus Neoadjuvant Chemoradiotherapy Followed by Surgery for Locally Advanced Oesophageal Squamous Cell Carcinoma: Protocol for a Multicentre, Prospective, Randomized-Controlled, Phase III Clinical Study (Keystone-002).

Background: To compare the efficacy and safety of pembrolizumab combined with neoadjuvant chemotherapy (neoCT) versus neoadjuvant chemoradiotherapy (neoCRT) followed by surgery for locally advanced resectable oesophageal squamous cell carcinoma (ESCC). Methods: This study is a multicentre, prospective, randomized-controlled, phase III clinical study. Eligible ESCC (staging: cT1N2M0 or cT2-3N0-2M0 (stage II/III, high-risk lesions in T2N0M0)) patients will be randomly assigned to either the experimental group (pembrolizumab with neoCT, n = 228) or the control group (neoCRT, n = 114) at a ratio of 2:1. Within 4-6 weeks after preoperative therapy, the McKeown procedure will be performed. Patients in the experimental group will also receive pembrolizumab alone as adjuvant therapy after surgery until 1 year or until the radiographically confirmed PD or other condition indicated for premature termination is observed. The primary endpoint is event-free survival (EFS). The secondary endpoints are 1-, 3-, and 5-year overall survival (OS) and disease-free survival (DFS), short-term outcomes, and quality of life. Discussion: This is the first prospectively randomized controlled trial designed to compare pembrolizumab plus chemotherapy and chemoradiotherapy as neoadjuvant therapy for resectable ESCC. According to our hypothesis, preoperative pembrolizumab combined with chemotherapy will result in a better tumour response and prolong the survival of patients, with acceptable toxicity. This study started in December 2021, and the enrolment time is estimated to be 2 years. Trial Registration: This prospective study has been registered at ClinicalTrials.gov (NCT04807673), March 2021.

TP53 common variants and interaction with PPP1R13L and CD3EAP SNPs and lung cancer risk and smoking behavior in a Chinese population.

BACKGROUND: TP53 encodes a tumor suppressor protein containing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. The effect of TP53 inactivation is well-known, and genetically determined smaller variations in TP53 activity are related to cancer. Lung cancer causes the highest rates of morbidity and mortality in the world. Epidemiology studies have assessed the association of TP53 single nucleotide polymorphisms with lung cancer. METHODS: We systematically examined the association of five htSNPs (haplotype-tagging single nucleotide polymorphism) (rs12951053, rs1042522, rs8079544, rs12602273 and rs8064946) across the entire TP53 locus and interaction between genes TP53 and PPP1R13L and CD3EAP and smoking-duration related to lung cancer risk in this Chinese study including 544 cases and 550 controls. RESULTS: No significant associations were observed in analysis of alleles and genotypes with co-dominant, dominant, recessive, and log-additive models after adjustment for smoking status. Haplotype analysis showed that haplotype9 (rs12951053A-rs1042522C-rs8079544C-rs12602273G-rs8064946C) [OR (95% CI) = 0.13 (0.03-0.59), p = 0.0079] was associated with decreased risk of lung cancer after adjusted for smoking-duration. The analysis of smoking-duration within TP53 haplotypes showed that there were more carriers of haplotype1 (AGCCG), 2 (CCCGC) and 4 (CCCCG) in smoking-subgroup of >20 (years) (all p < 0.05). MDR testing analysis identified two significant models (both p < 0.0010) of gene-gene-environment interaction in relation to lung cancer risk in whole study group. CONCLUSION: The present results provide novel evidence that the haplotype of TP53 htSNPs and interaction between genetic variation in TP53 and CD3EAP and smoking-duration may associate with lung cancer risk, and provide additional evidence of association between TP53 htSNP haplotypes and long-term smoking-related behavior.

E2F transcription factor 1 is involved in the phenotypic modulation of esophageal squamous cell carcinoma cells via microRNA-375.

E2F family of transcription factors modulates multiple cellular functions associated with cell cycle and apoptosis. Here, we focused on the relevance of E2F1 to esophageal squamous cell carcinoma (ESCC) and identification of E2F1-mediated network in this study. Query of Gene Expression Omnibus database revealed that E2F1 was the core gene that was upregulated in ESCC. E2F1 downregulation inhibited ESCC cell activity. microRNA (miR)-375 was confirmed to be a downstream target of E2F1. E2F1 bound to miR-375 promoter and inhibited miR-375 transcription. Moreover, miR-375 inhibitor mitigated the repressive impacts of si-E2F1 on ESCC cells in part. Further study showed that sestrin 3 (SESN3) could interact with miR-375, and its knockdown annulled the stimulative effect of miR-375 inhibitor on ESCC development. Finally, E2F1 and SESN3 downregulation inhibited the phosphatidylinositol 3 kinase (PI3K)/AKT pathway activity in cells, while miR-375 inhibitor promoted PI3K/AKT pathway activation. These findings suggest that E2F1 inhibited miR-375 expression and promoted SESN3 expression to activate the PI3K/AKT pathway in ESCC.

Metabolomic Characterization Reveals ILF2 and ILF3 Affected Metabolic Adaptions in Esophageal Squamous Cell Carcinoma.

Esophageal cancer (EC) is a common malignant disease in eastern countries. However, a study of the metabolomic characteristics associated with other biological factors in esophageal squamous cell carcinoma (ESCC) is limited. Interleukin enhancer binding factor 2 (ILF2) and ILF3, double-stranded RNA-binding proteins, have been reported to contribute to the occurrence and development of various types of malignancy. Nevertheless, the underlying functions of ILF2 and ILF3 in ESCC metabolic reprogramming have never been reported. This study aimed to contribute to the metabolic characterization of ESCC and to investigate the metabolomic alterations associated with ILF2 and ILF3 in ESCC tissues. Here, we identified 112 differential metabolites, which were mainly enriched in phosphatidylcholine biosynthesis, fatty acid metabolism, and amino acid metabolism pathways, based on liquid chromatography-mass spectrometry and capillary electrophoresis-mass spectrometry approaches using ESCC tissues and paired para-cancer tissues from twenty-eight ESCC patients. In addition, ILF2 and ILF3 expression were significantly elevated in EC tissues compared to the histologically normal samples, and closely associated with PI3K/AKT and MAPK signaling pathways in ESCC. Moreover, in ESCC tissues with a high ILF2 expression, several short-chain acyl-carnitines (C3:0, C4:0, and C5:0) related to the BCAA metabolic pathway and long-chain acyl-carnitines (C14:0, C16:0, C16:0-OH, and C18:0) involved in the oxidation of fatty acids were obviously upregulated. Additionally, a series of intermediate metabolites involved in the glycolysis pathway, including G6P/F6P, F1,6BP, DHAP, G3P, and 2,3BPG, were remarkably downregulated in highly ILF3-expressed ESCC tissues compared with the corresponding para-cancer tissues. Overall, these findings may provide evidence for the roles of ILF2 and ILF3 during the process of ESCC metabolic alterations, and new insights into the development of early diagnosis and treatment for ESCC. Further investigation is needed to clarify the underlying mechanism of ILF2 and ILF3 on acyl-carnitines and the glycolysis pathway, respectively.

Fast-track surgery in single-hole thoracoscopic radical resection of lung cancer.

PURPOSE: To explore the efficacy and safety of fast-track surgery (FTS) in the perioperative period of single-hole thoracoscopic radical resection of lung cancer. METHODS: The clinical data of 152 lung cancer patients undergoing single-hole thoracoscopic radical resection of lung cancer in our hospital from October 2016 to March 2019 were collected. Among them, 76 patients were treated with perioperative FTS (FTS group) following in-depth information and education, effective analgesia, early ambulation and early extubation, while the other 76 patients received conventional perioperative treatments (Control group). RESULTS: The intraoperative volumes of blood loss and fluid infusion in FTS group were smaller than those in Control group. Moreover, the mean time to postoperative drainage tube removal, time to the first postoperative ambulation and length of postoperative hospital stay in FTS group were substantially shorter than those in Control group. Moreover, the visual analog scale (VAS) scores of patients at 48 and 72 h after operation in FTS group were considerably lower than those in Control group. Besides, the total incidence rate of postoperative complications in FTS group was considerably lower than that in Control group. Compared with those before operation, all pulmonary function indicators declined substantially after operation, and the postoperative forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and maximum voluntary ventilation (MVV) in FTS group were remarkably higher than those in Control group. CONCLUSION: FTS in the perioperative period of single-hole thoracoscopic radical resection of lung cancer can effectively accelerate the recovery of patients, alleviate their pain, shorten the length of hospital stay, reduce hospitalization expense and improve patient's satisfaction, so it is worth clinically applying.

ARHGAP6 Promotes Apoptosis and Inhibits Glycolysis in Lung Adenocarcinoma Through STAT3 Signaling Pathway.

OBJECTIVE: Constitutively activated signal transducer and activator of transcription 3 (STAT3) has been linked to cisplatin (DDP)-resistance in a wide range of cancers. Recent work has indicated that Rho GTPase-activating protein 6 (ARHGAP6) promotes cell cycle arrest and apoptosis in cervical and breast cancers. However, the role of ARHGAP6 in lung adenocarcinoma and DDP-resistance remains unknown. MATERIALS AND METHODS: Bioinformatic analysis, quantitative RT-PCR and IHC staining were used to explore ARHGAP6 expression patterns in The Cancer Genome Atlas (TCGA) dataset and patient samples. Statistical analysis was performed to establish the association of ARHGAP6 expression with the resistance to DDP-based chemotherapy in lung adenocarcinoma patients. Functional assays were then conducted to examine the effect of ARHGAP6 on the apoptosis and glycolysis in DDP-resistant/sensitive A549/DPP cells in vitro. Finally, the effects of ARHGAP6 on the chemosensitivity of DDP were explored in vivo. RESULTS: We show that decreased ARHGAP6 levels are a reliable marker of lung adenocarcinoma across published datasets, cell culture lines, and clinical samples. Low ARHGAP6 expression was linked to decreased apoptosis and increased metabolic activity, which highlights ARHGAP6's role as a tumor suppressor. Furthermore, activated p-STAT3 levels increased dramatically in the absence of ARHGAP6, which suggests that ARHGAP6 can inhibit the STAT3 pathway. In agreement with previous studies that linked p-STAT3 levels to DDP-resistance, our in vitro and in vivo data indicate that tumors became more resistant to DDP-therapy with reduced ARHGAP6 levels and an associated increase in p-STAT3. CONCLUSION: ARHGAP6 presents a novel study target for overcoming p-STAT3-associated DDP-resistance in lung adenocarcinoma and potentially other cancers.

Interaction between common variants of MDM2 and PPP1R13L and CD3EAP and TP53 SNPs in relation to lung cancer risk among Chinese.

BACKGROUND: Lung cancer is a complex disease that diagnosed the most common cancer and led cause of cancer death. MDM2 (MDM2 proto-oncogene) encodes a nuclear-localized E3 ubiquitin ligase. The encoded protein can promote tumor formation by targeting tumor suppressor proteins, such as TP53, for proteasomal degradation. Epidemiology studies have investigated the association of MDM2 single nucleotide polymorphisms (SNP) and interaction between genetic and environmental factors with lung cancer. METHODS: This Chinese case-control study comprised 627 cases and 633 controls explored the role of MDM2 five htSNPs (rs1690924, rs1846402, rs2291857, rs3730581 and rs3730635, haplotype-tagging SNP) tagging 95% of the common haplotypes across the gene and the interactions of MDM2, PPP1R13L, CD3EAP and TP53 in the same pathological pathway on lung cancer risk, together with smoking-duration. RESULTS: None of the htSNPs in MDM2 were associated with lung cancer risk in co-dominant, dominant, recessive, and log-additive models (adjusted for smoking-duration). Haplotype analysis showed that global haplotype association was statistically significant (P=0.0036, adjusted for smoking-duration) and haplotype5 (rs1690924A-rs1846402G-rs2291857C-rs3730581G-rs3730635A) was associated with reduced risk of lung cancer [OR (95%) =0.52 (0.33-0.82), P=0.0053, adjusted for smoking-duration]. MDR interaction analysis showed that two the best significant models and strong synergy between MDM2 and TP53. CONCLUSIONS: MDM2 five-htSNPs haplotype exhibited association with lung cancer susceptibility, interaction of MDM2 and TP53 htSNPs and smoking-duration contributed to lung cancer risk and strong synergy between MDM2 and TP53 htSNPs influenced lung cancer predisposition. Our results suggest that MDM2, TP53 and smoking-duration interact in relation to lung carcinogenesis.

The tumor suppressive roles of ARHGAP25 in lung cancer cells.

AIM: Several Rho GTPase-activating proteins (Rho GAPs) have been proved to serve as tumor suppressors in diverse human cancers. Among them, ARHGAP25 has also been found to be associated with hematopoietic cells and regulate phagocytosis. Little is known about the role of ARHGAP25 in lung cancer cells. METHODS: Quantitative real-time PCR and Western blot were used to measure the expression levels of ARHGAP25. The ability of cell growth and mobility were measured by cell proliferation and Transwell assays. Chromatin immunoprecipitation and luciferase assay were conducted to identify the transcriptional regulation. RESULTS: Lung cancer tissues had much lower expression level of ARHGAP25 compared to non-cancerous specimens as well as for lung cancer cells. Cell growth and mobility were strongly reduced when ARHGAP25 was overexpressed. Further, significantly negative correlation between ARHGAP25 expression and Wnt signaling pathway was observed. Overexpression of ARHGAP25 reduced the expression of ß-catenin and matrix metalloproteinase-7. ARHGAP25 knockdown effect of increased abilities of cell proliferation, migration and invasion could be reversed by adding XAV939 inhibitor. The promoter site of ARHGAP25 could be bound with HOXA4. HOXA4 could regulate the transcriptional activity of ARHGAP25. CONCLUSIONS: This study suggests that ARHGAP25 may inhibit lung cancer cell growth, migration and invasion through Wnt/ß-catenin signaling pathway and its transcriptional activity can be regulated by HOXA4.

Methylation status of the PPP1R13L promoter region among lung cancer patients and healthy controls. Analytical cross-sectional study.

BACKGROUND: There is evidence that genetic predisposition and epigenetic alteration (e.g. DNA methylation) play major roles in lung cancer. In our genetic epidemiological studies, rs1970764 in oncogene PPP1R13L was most consistently associated with lung cancer risk. Here, we explored the role of PPP1R13L methylation in lung cancer development. DESIGN AND SETTING: Analytical cross-sectional study (45 lung cancer cases and 45 controls), conducted in China. METHODS: We investigated the DNA methylation status of 2,160 cytosine-phosphate-guanine (CpG) sites in the PPP1R13L promoter region using the EpiTYPER assay of the Sequenom MassARRAY platform. RESULTS: In the whole study group, the methylation levels of CpG-6, CpG-9, CpG-20 and CpG-21 were significantly lower and those of CpG-16 were significantly higher in cases than in controls. Among smokers, the methylation levels at five CpG sites (CpG-6, CpG-11, CpG-15, CpG-20 and CpG-21) were statistically significantly lower among cases. Among men, the methylation levels at four CpG sites (CpG-11, CpG-15, CpG-20 and CpG-21) were significantly lower among cases. Regarding smokers, the methylation levels at CpG-7.8 and CpG-21 among cases and at CpG-22 among controls were significantly lower, compared with nonsmokers. The frequency of positivity for methylation was not significantly different between lung cancer cases and controls (68.22% for cases and 71.87% for controls; P = 0.119). CONCLUSION: Our study on a Chinese population suggests that lung cancer patients have aberrant methylation status (hypomethylation tended to be more frequent) in peripheral blood leukocytes at several CpG sites in the PPP1R13L promoter region and that exposure to smoking may influence methylation status.

Methylation status of the PPP1R13L promoter region among lung cancer patients and healthy controls. Analytical cross-sectional study

ABSTRACT BACKGROUND: There is evidence that genetic predisposition and epigenetic alteration (e.g. DNA methylation) play major roles in lung cancer. In our genetic epidemiological studies, rs1970764 in oncogene PPP1R13L was most consistently associated with lung cancer risk. Here, we explored the role of PPP1R13L methylation in lung cancer development. DESIGN AND SETTING: Analytical cross-sectional study (45 lung cancer cases and 45 controls), conducted in China. METHODS: We investigated the DNA methylation status of 2,160 cytosine-phosphate-guanine (CpG) sites in the PPP1R13L promoter region using the EpiTYPER assay of the Sequenom MassARRAY platform. RESULTS: In the whole study group, the methylation levels of CpG-6, CpG-9, CpG-20 and CpG-21 were significantly lower and those of CpG-16 were significantly higher in cases than in controls. Among smokers, the methylation levels at five CpG sites (CpG-6, CpG-11, CpG-15, CpG-20 and CpG-21) were statistically significantly lower among cases. Among men, the methylation levels at four CpG sites (CpG-11, CpG-15, CpG-20 and CpG-21) were significantly lower among cases. Regarding smokers, the methylation levels at CpG-7.8 and CpG-21 among cases and at CpG-22 among controls were significantly lower, compared with nonsmokers. The frequency of positivity for methylation was not significantly different between lung cancer cases and controls (68.22% for cases and 71.87% for controls; P = 0.119). CONCLUSION: Our study on a Chinese population suggests that lung cancer patients have aberrant methylation status (hypomethylation tended to be more frequent) in peripheral blood leukocytes at several CpG sites in the PPP1R13L promoter region and that exposure to smoking may influence methylation status.

ARHGAP6 regulates the proliferation, migration and invasion of lung cancer cells.

Lung cancer, a leading cause of cancer­related deaths, is frequently diagnosed in both males and females worldwide. In the present study, the Ras homologue GTPase activation protein 6 (ARHGAP6), which belongs to the Rho GTPase­activating protein (RhoGAP) family, was found to have low expression in tumor tissues from patients with lung cancer, accompanied by high expression of matrix metalloproteinase­9 (MMP9) and vascular endothelial growth factor (VEGF). In A549 and H1299 cells, upregulation of ARHGAP6 inhibited tumor growth and metastasis and reduced the levels of MMP9, VEGF and p­STAT3, while the levels STAT3 were unchanged, as demonstrated by CCK­8, migration and invasion assays as well as western blot analysis. In addition, interleukin 6 (IL­6)­induced migration, invasion and MMP9 and VEGF expression, and STAT3 signaling activity were suppressed by ARHGAP6 upregulation. Based on these data, we concluded that ARHGAP6 is critically important in lung cancer progression and that upregulation of ARHGAP6 benefits the treatment and prevention of lung cancer, possibly through the suppression of MMP9, VEGF and STAT3 signaling activation.

Efficacy of on-pump coronary artery bypass grafting and stent implantation combined with surgery on lung cancer.

PURPOSE: Diaphragmatic hernia following an esophagectomy for esophageal cancer (EC) can be both an early and late complication. The esophageal hiatus within the diaphragm is disrupted during the operation. However, the incidence of Post-Esophagectomy Diaphragmatic Hernia (PEDH) is unknown. PEDH can be life-threatening and surgical treatment is challenging. However, all PEDH do not require surgery. The rate of EC diagnosis is rising. Therefore, esophageal surgery, particularly esophagectomy, is gradually increasing. Undoubtedly, the numbers of PEDH increase as well. METHODS: This review describes the presentation and diagnosis of PEDH after surgery for esophageal malignancy, as well as the management options for PEDH. RESULTS: Fifteen papers regarding PEDH have been published. There are many different surgical approaches to complete an esophagectomy, while there are different approaches to repair PEDH. CONCLUSION: Upper GI surgeons need to have an index of suspicion for PEDH. They must investigate and operate these patients if this complication develops, since an immediate surgery has a high mortality and poor outcome.

Reduced miR-125a-5p level in non-small-cell lung cancer is associated with tumour progression.

Emerging evidence suggests that microRNAs (miRNAs) serve an important role in tumourigenesis and development. Although the low expression of miR-125a-5p in non-small-cell lung cancer (NSCLC) has been reported, the underlying mechanism remains unknown. In the current study, the low expression of miR-125a-5p in NSCLC was verified in paired cancer tissues and adjacent non-tumour tissues. Furthermore, the CpG island in the miR-125a-5p region was hypermethylated in the tumour tissues, and the hypermethylation was negatively correlated with miR-125a-5p expression. Target gene screening showed that the histone methyltransferase Suv39H1 was one of the potential target genes. In vitro studies showed that miR-125a-5p could directly suppress Suv39H1 expression and decrease the H3K9me3 levels. On the other hand, Suv39H1 could induce demethylation of miR-125a-5p, resulting in re-activation of miR-125a-5p. What is more, overexpessing miR-125a-5p could also self-activate the silenced miR-125a-5p in NSCLC cells, which suppressed cell migration, invasion and proliferation in vitro and inhibited cancer progression in vivo Thus, we found that the epigenetic silenced miR-125a-5p could be self-activated through targeting Suv39H1 in NSCLC, suggesting that miR-125a-5p might not only have the potential prognostic value as a tumour biomarker but also be a potential therapeutic target in NSCLC.

A novel SWIM domain protein ZSWIM5 inhibits the malignant progression of non-small-cell lung cancer.

PURPOSE: Zinc finger SWIM-type containing 5 (ZSWIM5) is a newly discovered protein, which contains a novel zinc-chelating domain SWIM (CxCxnCxH), and is predicted to interact with DNA or proteins. Currently, the knowledge of functions of ZSWIM5 remains limited. In this study, we aimed to elucidate the biological functions of ZSWIM5 and their mechanisms. PATIENTS AND METHODS: We detected the expression of ZSWIM5 in samples from 139 cases of non-small-cell lung cancer (NSCLC) patients and six cell lines using immunohistochemistry and Western blot. Moreover, we explored the biological functions of ZSWIM5 in lung cancer cells by siRNA interference and cDNA transfection of ZSWIM5. RESULTS: The results showed that compared with adjacent non-tumor lung tissues, ZSWIM5 expression was significantly decreased in NSCLC tissues (P=0.0199) and that the ZSWIM5-positive rate in non-tumor tissues (76.67%) was notably higher than that in NSCLC tissues (40.29%). ZSWIM5 expression in human normal bronchial epithelial cells was also much higher than that in lung cancer lines (P<0.001). ZSWIM5-negative expression was significantly related to TNM stage (P<0.001), lymph node metastasis (P=0.002), and poor prognosis (P<0.001) of NSCLC patients. MTT and colony formation assays showed that ZSWIM5 could inhibit the proliferation and colony formation abilities of lung cancer cells. Meanwhile, the results of transwell and wound healing assays showed that ZSWIM5 could suppress the invasion and migration of lung cancer cells. Further investigation revealed that ZSWIM5 could downregulate cyclin D1, cyclin E, cyclin A2, MMP2, and MMP9 expression, which affected the proliferation, invasion, and migration abilities of lung cancer cells. CONCLUSION: ZSWIM5 could inhibit the malignant progression of NSCLC by affecting the expression of cyclins and MMPs.

GLTSCR1, ATM, PPP1R13L and CD3EAP Genetic Variants and Lung Cancer Risk in a Chinese Population.

Genetic variants in glioma tumor suppressor candidate region gene 1 (GLTSCR1) and ATM serine/threonine kinase (ATM) have been associated with various cancer risks. Epidemiological studies also revealed the association of variants of GLTSCR1 and ATM genes with different brain tumors. However, little is known about the relationship between both gene polymorphisms and lung cancer risk. We conducted a Chinese hospital-based casecontrol study involving 384 lung cancer cases and 387 cancer-free controls. No significant differences in the single polymorphism (GLTSCR1 rs1035938 and ATM rs11212592) association were found in five genetic models (co-dominant, dominant, recessive, overdominant and log-additive models) (adjusted by smoking duration). Join effect of three SNPs (PPP1R13L rs1970764, CD3EAP rs967591, GLTSCR1 rs1035938) on chromosome 19q13.3 showed that the designated haplotype8 (rs 1970764G-rs967591A-rs1035938C) [OR (95% CI)=1.60(1.11-2.32), P/0.012] andhaplotype8 (rs1970764G-rs967591G-rs1035938T) [OR (95% CI)=2.45 (1.17-5.12), P=0.018] were associated with increased risk of lung cancer (adjusted by smoking duration). The analysis of multifactor dimensionality reduction revealed that two 3-way models were the best fit models in analyses of 2 loci (P<0.001) or 4 loci (Р=0.015-0.016). The entropy-based analysis indicated the strongest synergistic effect between PPP1R13L rs1970764 and ATM rs11212592 in analysis of four genes. In conclusion, our study suggests that haplotypes consisting of PPP1R13L rs1970764-CD3EAP rs961591-GLTSCR1 rs1035938 on Chr19q13.3, interaction of smoking and GLTSCR1 rs1035938-ATM rs11212592, and synergistic action of PPP1R13L rs1970764 and ATM rs11212592 may associate with lung cancer risk in the Chinese population.

Fine-mapping markers of lung cancer susceptibility in a sub-region of chromosome 19q13.3 among Chinese.

Linkage disequilibrium-mapping studies in Caucasians have indicated anassociation of Chr19q13.3 sub-region spanning ERCC2, PPP1R13L, CD3EAP and ERCC1 with several cancers. To refine the region of association and identify potential causal variations among Asians, we performed a fine-mapping study using 32 (39) SNPs in a 71.654kb sub-region. The study included 384 Chinese lung cancer cases and 387 controls. Seven closely situated SNPs showed significant associations with lung cancer risk in five different genetic models of single-locus associations (adjusted for smoking duration). These were PPP1R13L rs1970764 [OR (95% CI) = 1.58 (1.09-2.29), P = 0.014] in a recessive model and PPP1R13L rs1005165 [OR (95% CI) = 1.25 (1.01-1.54), P = 0.036], CD3EAP rs967591 [OR (95% CI) = 1.40 (1.13-1.75), P = 0.0023], rs735482 [OR (95% CI) = 1.29 (1.03-1.61), P = 0.026], rs1007616 [OR (95% CI) = 0.78 (0.61-1.00), P = 0.046], and rs62109563 [OR (95% CI) = 1.28 (1.03-1.59), P = 0.024] in a log-additive model and ERCC1 rs3212965 [OR (95% CI) = 0.70 (0.52-0.94), P = 0.019] in an over-dominant model. Six-haplotype blocks were determined in the sub-region. Using an alternative approach where we performed a haplotype analysis of all significant polymorphisms, rs1970764 was found to be most consistently associated with lung cancer risk. The combined data suggest that the sub-region with the strongest association to lung cancer susceptibility might locate to the 23.173kb from PPP1R13L intron8 rs1970764 to rs62109563 3' to CD3EAP. Limited risk loci and span on lung cancer in this sub-region are initially defined among Asians.