An integrated analysis of the anticarcinogenic role of forkhead box protein 1 in oesophageal squamous cell carcinoma.

Forkhead box protein 1 (FOXP1) serves as a tumour promoter or suppressor depending on different cancers, but its effect in oesophageal squamous cell carcinoma has not been fully elucidated. This study investigated the role of FOXP1 in oesophageal squamous cell carcinoma through bioinformatics analysis and experimental verification. We determined through public databases that FOXP1 expresses low in oesophageal squamous cell carcinoma compared with normal tissues, while high expression of FOXP1 indicates a better prognosis. We identified potential target genes regulated by FOXP1, and explored the potential biological processes and signalling pathways involved in FOXP1 in oesophageal squamous cell carcinoma through GO and KEGG enrichment, gene co-expression analysis, and protein interaction network construction. We also analysed the correlation between FOXP1 and tumour immune infiltration levels. We further validated the inhibitory effect of FOXP1 on the proliferation of oesophageal squamous cell carcinoma cells through CCK-8, colony formation and subcutaneous tumour formation assays. This study revealed the anticarcinogenic effect of FOXP1 in oesophageal squamous cell carcinoma, which may serve as a novel biological target for the treatment of tumour.

PI3Kα inhibitor GNE-493 triggers antitumor immunity in murine lung cancer by inducing immunogenic cell death and activating T cells.

Phosphatidylinositol 3-kinase (PI3K) is frequently hyperactivated in cancer, playing pivotal roles in the pathophysiology of both malignant and immune cells. The impact of PI3K inhibitors on the tumor microenvironment (TME) within lung cancer remains largely unknown. In this study, we explored the regulatory effects of GNE-493, an innovative dual inhibitor of PI3K and mammalian target of rapamycin (mTOR), on the TME of lung cancer. First, through the analysis of The Cancer Genome Atlas-lung squamous cell carcinoma (LUSC) cohort, we found PIK3CA to be related to CD8 T cells, which may affect the overall survival rate of patients by affecting CD8 function. We herein demonstrated that GNE-493 can significantly inhibit tumor cell proliferation and promote cell apoptosis while increasing the expression of the immunogenic death-related molecules CRT and HSP70 using in vitro cell proliferation and apoptosis experiments on the murine KP lung cancer cell line and human A549 lung cancer cell line. Next, through the establishment of an orthotopic tumor model in vivo, it was found that after GNE-493 intervention, the infiltration of CD4+ and CD8+ T cells in mouse lung tumor was significantly increased, and the expression of CRT in tumors could be induced to increase. To explore the mechanisms underlying PI3K inhibition-induced changes in the TME, the gene expression differences of T cells in the control group versus GNE-493-treated KP tumors were analyzed by RNA-seq, and the main effector pathway of anti-tumor immunity was identified. The IFN/TNF family molecules were significantly upregulated after GNE-493 treatment. In summary, our findings indicate that GNE-493 promotes immunogenic cell death in lung cancer cells, and elucidates its regulatory impact on molecules associated with the adaptive immune response. Our study provides novel insights into how PI3K/mTOR inhibitors exert their activity by modulating the tumor-immune interaction.

Chinese never smokers with adenocarcinoma of the lung are younger and have fewer lymph node metastases than smokers.

BACKGROUND: Lung cancers arising in never smokers have been suggested to be substantially different from lung cancers in smokers at an epidemiological, genetic and molecular level. Focusing on non-small cell lung cancer (NSCLC), we characterized lung cancer patients in China looking for demographic and clinical differences between the smoking and never-smoking subgroups. METHODS: In total, 891 patients with NSCLC, including 841 with adenocarcinoma and 50 with squamous cell carcinoma, were recruited in this study. Association of smoking status with demographic and clinical features of NSCLC was determined, and risk factors for lymph node metastasis and TNM stage were evaluated using Multivariate logistic regression analysis. RESULTS: In patients with adenocarcinoma, never smokers showed a younger age at diagnosis (54.2 ± 12.7vs. 59.3 ± 9.4, padjusted<0.001), a lower risk for lymph node metastasis than smokers (7,6% vs. 19.5%, padjusted<0.001) and less severe disease as indicated by lower percentages of patients with TNM stage of III or IV (5.5% vs. 14.7%, padjusted<0.001 ). By contrast, these associations were not observed in 50 patients with squamous cell carcinoma. Multivariate logistic regression analysis showed that smoking status was a risk factor for lymph node metastasis (OR = 2.70, 95% CI: 1.39-5.31, p = 0.004) but not for TNM stage (OR = 1.18, 95% CI: 0.09-14.43, p = 0.896) in adenocarcinoma. CONCLUSION: This study demonstrates that lung adenocarcinoma in never smokers significantly differ from those in smokers regarding both age at diagnosis and risk of lymph node metastasis, supporting the notion that they are distinct entries with different etiology and pathogenesis.

An NF-κB/OVOL2 circuit regulates glucose import and cell survival in non-small cell lung cancer.

BACKGROUND: Tumor cells tend to utilize glycolysis rather than aerobic respiration even under aerobic conditions. OVOL2, an inhibitory C2H2 zinc finger transcription factor, is a potential tumor suppressor in cancers. However, the association between OVOL2 and tumor energy metabolism is unknown. METHODS: Western blotting was used to determine the expression of OVOL2 in different non-small cell lung cancer (NSCLC) cell lines and mouse models. The metabolic parameters in NSCLC cells following overexpression or knockdown OVOL2 were examined. To define the mechanism by which OVOL2 regulates aerobic glycolysis, interacting protein of OVOl2 and downstream molecular events were identified by luciferase assay and co-immunoprecipitation. We documented the regulatory mechanism in mouse xenograft models. Finally, clinical relevance of OVOL2, NF-κB signaling and GLUT1 was measured by immunostaining. RESULTS: OVOL2 is downregulated in NSCLC and overexpression of OVOL2 inhibits the survival of cancer cells. Moreover, OVOL2 directly binds to P65 and inhibits the recruitment of P300 but facilitates the binding of HDAC1 to P65, which in turn negatively regulates NF-κB signaling to suppress GLUT1 translocation and glucose import. In contrast, OVOL2 expression is negatively regulated by NF-κB signaling in NSCLC cells via the ubiquitin-proteasome pathway. Re-expression of OVOL2 significantly compromise NF-κB signaling-induced GLUT1 translocation, aerobic glycolysis in NSCLC cells and mouse models. Immunostaining revealed inverse correlations between the OVOL2 and phosphorylated P65 levels and between the OVOL2 and membrane GLUT1 levels, and a strong correlation between the phosphorylated P65 and membrane GLUT1 levels. CONCLUSIONS: These results suggest a regulatory circuit linking NF-κB and OVOL2, which highlights the role of NF-κB signaling and OVOL2 in the modulation of glucose metabolism in NSCLC. Video Abstract.

Skip N2 Metastasis in Pulmonary Adenocarcinoma: Good Prognosis Similar to N1 Disease.

INTRODUCTION: The prognostic effect and mechanism of skip N2 lung cancer remain unclear. Our study aimed to elucidate the influence of skip N2 on overall survival (OS) and disease-free survival (DFS) compared with N1 and non-skip N2 in patients with lung adenocarcinoma. PATIENTS AND METHODS: Patients with lung adenocarcinoma and lymph node involvement between May 2011 and December 2015 were retrospectively analyzed. The outcomes of skip N2 patients were compared with N1 and non-skip N2 patients. Prognosis was further investigated according to the N status in different adenocarcinoma subtypes. Univariate and multivariate analyses were carried out to define independent risk factors for OS and DFS. RESULTS: A total of 456 patients with lung adenocarcinoma, 169 with N1 disease, 81 with skip N2 disease, and 206 with non-skip N2 disease, were enrolled in this study. All tumors were invasive adenocarcinoma, and the predominant subtypes were acinar in 252, papillary in 42, solid in 119, micropapillary in 20, and invasive mucinous adenocarcinoma in 23 patients. The DFS and OS of N1 and skip N2 diseases were similar and significantly better than those of patients with non-skip N2 disease. The prognosis according to lymph node status was significantly different in acinar-predominant subtypes in terms of both OS and DFS. CONCLUSIONS: Skip N2 disease has a similar prognosis to N1 disease and is significantly better than that of non-skip N2 disease in relation to OS and DFS. Skip N2 has a prognostic advantage in patients with the acinar-predominant subtype.

Log odds of positive lymph nodes predicts survival in patients treated with neoadjuvant therapy followed by esophagectomy.

BACKGROUND AND OBJECTIVES: We aimed to evaluate the efficacy of the log odds of positive lymph nodes (LODDS) in survival prediction of patients with esophageal carcinoma receiving neoadjuvant therapy, compared with N descriptor and positive lymph node ratio (LNR). METHODS: Patients with esophageal carcinoma receiving neoadjuvant therapy from 2004 to 2015 were reviewed in Surveillance, Epidemiology, and End Results database. The receiver operating characteristics curve and area under the curve (AUC) were used to compare discriminatory power among N descriptor, LNR, and LODDS. The goodness of fit was measured using the -2 log-likelihood ratio (-2LLR). RESULTS: About 2239 patients with a 22 months median follow-up and a 37.8% 5-year overall survival rate were included. LODDS had the best discriminatory power and goodness of fit (LODDS vs N descriptor, AUC 0.666 vs 0.626, -2LLR 15 680.402 vs 15 746.162; LODDS vs LNR, AUC 0.666 vs 0.635, -2LLR 15 680.402 vs 15 712.379; all P < .001). LODDS was the best for fewer than 15 lymph nodes retrieved (LODDS vs N descriptor, AUC 0.652 vs 0.618, P < .001; LODDS vs LNR, AUC 0.652 vs 0.625, P = .005). The prognosis of patients without metastatic nodes could be discriminated by LODDS. CONCLUSIONS: LODDS could better predict survival of patients with esophageal carcinoma receiving neoadjuvant therapy.

Clinical characteristics, diagnosis, treatment, and prognostic factors of pulmonary mucosa-associated lymphoid tissue-derived lymphoma.

Primary pulmonary mucosa-associated lymphoid tissue-derived (MALT) lymphoma is a rare disease with a favorable prognosis. However, its clinical characteristics, diagnosis, treatment, and prognoses remain unclear. We retrospectively analyzed 80 patients with pathologically confirmed MALT lymphoma from 2006 to 2018. The clinical characteristics, diagnosis, treatments, and prognoses of all the 80 patients were recorded. Patients were stratified into surgery and biopsy groups, respectively, to evaluate the role of surgery in the diagnosis and treatment of MALT lymphoma. The prognoses were compared between different clinical characteristics and treatments. Pathological diagnoses were confirmed by surgery, bronchoscopy, and percutaneous biopsy. Thirty patients were treated by surgery. While MALT lymphoma was only diagnosed by bronchofiberoscopy or bercutaneous biopsy in four of 18 patients in the surgery group who underwent the procedure. Six patients received adjuvant chemotherapy and one patient received involved-field radiotherapy in surgery group. Thirty-one patients were treated with chemotherapy alone, one patient was treated with radiotherapy, one patient received only symptomatic and supportive treatment, and waiting and watching without treatment were recommended in 17 patients in biopsy group. Eight patients died during follow-up and the 5-year survival rate was 87.1%. Tumor number, treatment, and age were prognostic factors for overall survival (OS), but age was the only independent prognostic factor according to multivariate analysis. While, tumor number was the only prognostic factor in the analysis about progression-free survival (PFS). No significant difference was found in OS or PFS between patients treated with and without surgical resection. MALT lymphoma is an indolent disease with favorable treatment outcome. Tumor number is associated with PFS and age is the only significant prognostic factor for pulmonary MALT lymphoma patients because of its indolent nature, but surgery still plays an important role in the diagnosis and treatment of MALT lymphoma.

Risk and prognostic nomograms for hepatocellular carcinoma with newly-diagnosed pulmonary metastasis using SEER data.

PURPOSE: This research aimed to identify risk factors of pulmonary metastasis (PM) from hepatocellular carcinoma (HCC) and prognostic factors of patients with PM from HCC at initial diagnosis. METHODS: Patients diagnosed with HCC between 2010 and 2015 were reviewed retrospectively in the Surveillance, Epidemiology, and End Results (SEER) database. Patients with PM from HCC at initial diagnosis were identified from the entire cohort. Predictors for PM from HCC were identified by multivariate logistic regression analysis. Independent prognostic factors for patients with PM were determined by univariate and multivariate Cox regression analysis. Nomograms were also constructed for quantifying risk of metastasis and overall survival estimation visually. RESULTS: Our research included 30,641 patients diagnosed with HCC, of whom 1,732 cases were with PM from HCC at initial diagnosis. The risk factors causing PM from HCC were age (P = 0.001), race (P < 0.001), primary tumor size (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), alpha-fetoprotein (P < 0.001), bone metastasis (P < 0.001), brain metastasis (P < 0.001), and intrahepatic metastasis (P < 0.001). The significantly prognostic factors for overall survival were age (P = 0.014), T stage (P = 0.009), surgical approach (P < 0.001), and chemotherapy (P < 0.001). Harrell's C-index statistics of two nomograms were 0.768 and 0.687 respectively, indicating satisfactory predictive power. CONCLUSIONS: This research provided evaluation of risk factors and prognosis for patients with PM from HCC. Two nomograms we developed can be convenient individualized tools to facilitate clinical decision-making.

Clinical Factors Predictive of a Better Prognosis of Pulmonary Metastasectomy for Hepatocellular Carcinoma.

BACKGROUND: The lung is the most common site of extrahepatic metastasis of hepatocellular carcinoma (HCC). The aim of this study was to identify prognostic factors for pulmonary metastasectomy of HCC. METHODS: One hundred three patients who underwent pulmonary metastasectomy for HCC between January 2005 and December 2016 were retrospectively evaluated. Patient demographic data and characteristics of the primary tumors and pulmonary metastasis were investigated to identify factors significantly correlated with prognosis. RESULTS: Of 103 patients, 75 (72.8%) had 1 site pulmonary metastasis, 22 (21.4%) had 2, and 6 (5.8%) had 3 or more. Liver recurrence at the time of pulmonary metastasectomy was noted in 34 patients. The estimated 5-year overall survival rate was 38.5% after pulmonary metastasectomy. Univariate prognostic analysis showed that liver recurrence at the time of pulmonary metastasectomy, extent of resection, laterality of pulmonary metastasis, tumor location, number of metastatic sites, and metastatic tumor size were significantly associated with favorable overall survival after pulmonary metastasectomy. Multivariate analysis revealed that liver recurrence at the time of pulmonary metastasectomy and the number of metastatic sites were independent prognostic factors. Subgroup analysis with a combination of these 2 independent prognostic factors revealed 5-year overall survival rates for patients with 0, 1, and 2 risk factors of 58.5%, 23.8%, and 0.0%, respectively. CONCLUSIONS: Pulmonary metastasectomy is a safe and effective treatment for well-selected patients with pulmonary metastasis of HCC. Liver recurrence at the time of pulmonary metastasectomy and the number of metastatic sites were identified as independent prognostic factors. The number of risk factors significantly influenced patient survival.