The FOXO1/G6PC axis promotes gastric cancer progression and mediates 5-fluorouracil resistance by targeting the PI3K/AKT/mTOR signaling pathway.

Gastric cancer (GC) is a prevalent malignancy of the digestive system. Distant metastasis and chemotherapy resistance are the crucial obstacles to prognosis in GC. Recent research has discovered that the glucose-6-phosphatase catalytic subunit (G6PC) plays an important role in tumor malignant development. However, little evidence has highlighted its role in GC. Herein, through a comprehensive analysis including profiling of tissue samples and functional validation in vivo and in vitro, we identify G6PC as a crucial factor in GC tumorigenesis. Importantly, we found that the FOXO1/G6PC axis could accelerate GC cell proliferation, metastasis, and 5-Fluorouracil (5-FU) resistance by targeting the PI3K/AKT/mTOR signaling pathway, implicating that as a prospective therapeutic approach in GC.

G6PC indicated poor prognosis in cervical cancer and promoted cervical carcinogenesis in vitro and in vivo.

BACKGROUND: The glucose-6-phosphatase catalytic subunit (G6PC) is a key enzyme that is involved in gluconeogenesis and glycogen decomposition during glycometabolism. Studies have shown that G6PC is abnormally expressed in various cancers and participates in the proliferation and metastasis of tumors. However, the role of G6PC in cervical cancer remains poorly established. METHODS: To analyze the expression of G6PC in cervical cancer tissues in patients by immunohistochemistry. Effects of G6PC deregulation on cervical cancer phenotype were determined using MTT, colony formation, transwell, and wound-healing assays. And constructed a nude mouse xenograft tumor model and CAM assay in vivo. The effect of G6PC on glycolysis in cervical cancer was also evaluated. Effect of G6PC on PI3K/AKT/mTOR pathway was detected by Western blot assay. RESULTS: In this study, G6PC expression was found to be upregulated in cervical cancer tissues, and this upregulated expression was associated with LN metastasis, clinical stage, recurrence, and disease-free survival and overall survival rates, indicating that G6PC could serve as a novel marker of early diagnosis in cervical cancer. G6PC promoted proliferation, invasion, epithelial mesenchymal transition (EMT) progression, and angiogenesis of cervical cancer cells. Mechanistically, G6PC activated PI3K/AKT/mTOR pathways. The PI3K/AKT pathway inhibitor, LY294002 could partially attenuate the effect. CONCLUSIONS: G6PC plays a key role in the progression of cervical cancer, and overexpressed G6PC is closely related to patient LN metastasis, clinical stage, recurrence and shortened survival. G6PC promoted cervical cancer proliferation, invasion, migration, EMT progression, and angiogenesis, partially through activating the PI3K/AKT pathway. G6PC, as a metabolic gene, not only plays a role in metabolism, but also participates in the development of cervical cancer. Its complex metabolic and non metabolic effects may be a potential therapeutic target and worthy of further study.

Genomic characterisation of pulmonary subsolid nodules: mutational landscape and radiological features.

BACKGROUND: Lung adenocarcinomas (LUADs) that display radiologically as subsolid nodules (SSNs) exhibit more indolent biological behaviour than solid LUADs. SSNs, commonly encompassing pre-invasive and invasive yet early-stage adenocarcinomas, can be categorised as pure ground-glass nodules and part-solid nodules. The genomic characteristics of SSNs remain poorly understood. METHODS: We subjected 154 SSN samples from 120 treatment-naïve Chinese patients to whole-exome sequencing. Clinical parameters and radiological features of these SSNs were collected. The genomic landscape of SSNs and differences from that of advanced-stage LUADs were defined. In addition, we investigated the intratumour heterogeneity and clonal relationship of multifocal SSNs and conducted radiogenomic analysis to link imaging and molecular characteristics of SSNs. Fisher's exact and Wilcoxon rank sum tests were used in the statistical analysis. RESULTS: The median somatic mutation rate across the SSN cohort was 1.12 mutations per Mb. Mutations in EGFR were the most prominent and significant variation, followed by those in RBM10, TP53, STK11 and KRAS. The differences between SSNs and advanced-stage LUADs at a genomic level were unravelled. Branched evolution and remarkable genomic heterogeneity were demonstrated in SSNs. Although multicentric origin was predominant, we also detected early metastatic events among multifocal SSNs. Using radiogenomic analysis, we found that higher ratios of solid components in SSNs were accompanied by significantly higher mutation frequencies in EGFR, TP53, RBM10 and ARID1B, suggesting that these genes play roles in the progression of LUADs. CONCLUSIONS: Our study provides the first comprehensive description of the mutational landscape and radiogenomic mapping of SSNs.

Heterogeneity of Lipid Metabolism and its Clinical and Immune Correlation in Lung Adenocarcinoma.

INTRODUCTION: The role of lipid metabolism in lung adenocarcinoma (LUAD) is not completely researched. Lipid metabolism reprogramming is a characteristic of malignancies and contributes to carcinogenesis and progression. The transcriptome and scRNA- seq data and clinical information were downloaded from the public databases. METHODS: Lipid metabolism pathways were collected from the MSigDB database, and molecular subtypes were classified based on lipid metabolism features via consensus clustering. The bidirectional crosstalk between immune cells and malignant cells was analyzed. Differences in lipid metabolism at the single-cell level and their correlation with the tumor microenvironment (TME) were also studied. LUAD patients were classified into two subtypes, showing distinct mutation and lipid metabolism features based on lipid metabolism characteristics. Meanwhile, significant differences in the overall survival, clinical characteristics, and immune landscape were observed between the two subtypes. We also found that clust1 had higher oxidative stress status. There were 116 differentially expressed genes between the two subtypes, which were significantly associated with cell cycle progression. We identified 4001 immune cells, including 483 malignant cells and 3518 normal cells, and found active intercellular communication and significant differences in lipid metabolism characteristics between the malignant cells and normal cells. Furthermore, several lipid metabolism pathways were found to be associated with TME factors, including hypoxia and angiogenesis. RESULT: The current findings indicated that lipid metabolism was involved in the development and cellular heterogeneity of LUAD and revealed widespread reprogramming across multiple cellular elements in the TME of LUAD. CONCLUSION: This characterization improved the current understanding of tumor biology and enabled the identification of novel targets for immunotherapy.

Functional exploration and drug prediction on programmed cell death-related biomarkers in lung adenocarcinoma.

Background: Our study aims to perform functional exploration and drug prediction of programmed cell death (PCD)-related biomarkers in lung adenocarcinoma (LUAD). Methods: UCSC-Xena obtained LUAD-related genes. DESeq2 screened PCD-specific differentially expressed genes (DEGs), and these DEGs were intersected with genes identified by weighted gene co-expression network analysis (WGCNA) to pinpoint the key genes. KOBAS-i was used for enrichment analysis. String and GeneMania were used to construct protein interaction networks and gene-gene interaction networks, respectively. Using two machine learning algorithms to screen for key genes, and taking the intersection as biomarkers, validating via receiver operating characteristic (ROC) and in vitro experiments. Building a diagnostic model with a nomogram. Construct transcription factor (TF) regulatory network. CIBERSORT was used for immune infiltration analysis. Enrichr predicts targeted drugs and AutodockTools simulates molecular docking. Results: 120 hub genes related to PCD were identified, and an intersection of these genes with DEGs yielded 10 key genes, which were enriched in apoptosis-related pathways. Further machine learning screening of these genes led to the selection of 7 genes, among which 6 genes (FGR, LAPTM5, SIRPA, TLR4, ZEB2, and NLRC4) exhibited significant differences upon ROC validation, ultimately serving as biomarkers, in vitro experiments also confirmed. A nomogram demonstrated their excellent diagnostic performance. These six biomarkers are correlated with the infiltration status of most immune cells, suggesting that they affect LUAD through the immune system. TF regulation analysis identified the upstream miRNAs. Finally, drug prediction yielded three potential drugs: Lenvatinib, methadone, and trimethoprim. Conclusion: PCD-related biomarkers in LUAD were explored, which may contribute to further understanding on PCD in LUAD.

Individualized Treatment for Advanced Non-Small Cell Lung Cancer: A Case Report and Literature Review.

The incidence of lung cancer is high and about 75% of the patients with lung cancer are found in the middle and advanced stage, which has a limited treatment strategy. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. In this article, we delineate the treatment process of a middle-aged male patient with advanced-stage lung cancer to explain the significance of individualized chemotherapy combined with immunotherapy and surgery. This patient has extensive bone metastasis with PS scores of 2. After nine cycles of preoperative neoadjuvant chemotherapy, surgery, and two cycles of postoperative adjuvant chemotherapy, the patient achieved complete response (CR) and his PS score was 0. Although there is a standard chemotherapy regimen for lung adenocarcinoma, the treatment effect varies because of individual differences. Comprehensive analysis of the characteristics of patients through a variety of means to develop a precise individualized chemotherapy plan will be a major direction of lung cancer treatment in the future. Additionally, surgical treatment for advanced lung cancer patients after chemotherapy can effectively reduce the primary lesion and prolong the survival time of patients.

Total nodule number as an independent prognostic factor in resected stage III non-small cell lung cancer: a deep learning-powered study.

Background: Almost every patient with lung cancer has multiple pulmonary nodules; however, the significance of nodule multiplicity in locally advanced non-small cell lung cancer (NSCLC) remains unclear. Methods: We identified patients who had undergone surgical resection for stage I-III NSCLC at the Peking University People's Hospital from 2005 to 2018 for whom preoperative chest computed tomography (CT) scans were available. Deep learning-based artificial intelligence (AI) algorithms using convolutional neural networks (CNN) were applied to detect and classify pulmonary nodules (PNs). Maximally selected log-rank statistics were used to determine the optimal cutoff value of the total nodule number (TNN) for predicting survival. Results: A total of 33,410 PNs were detected by AI among the 2,126 participants. The median TNN detected per person was 12 [interquartile range (IQR) 7-20]. It was revealed that AI-detected TNN (analyzed as a continuous variable) was an independent prognostic factor for both recurrence-free survival (RFS) [hazard ratio (HR) 1.012, 95% confidence interval (CI): 1.002 to 1.022, P=0.021] and overall survival (OS) (HR 1.013, 95% CI: 1.002 to 1.025, P=0.021) in multivariate analyses of the stage III cohort. In contrast, AI-detected TNN was not significantly associated with survival in the stage I and II cohorts. In a survival tree analysis, rather than using traditional IIIA and IIIB classifications, the model grouped cases according to AI-detected TNN (lower vs. higher: log-rank P<0.001), which led to a more effective determination of survival rates in the stage III cohort. Conclusions: The AI-detected TNN is significantly associated with survival rates in patients with surgically resected stage III NSCLC. A lower TNN detected on preoperative CT scans indicates a better prognosis for patients who have undergone complete surgical resection.

[G6PC knockdown blocks AKT/mTOR pathway to inhibit proliferation, invasion and migration of cervical cancer HeLa cells].

Objective To explore the effect of glucose-6-phsophatase, catalytic subunit (G6PC) on the proliferation, migration and invasion of cervical cancer HeLa cells and the possible molecular mechanism. Methods RNA interfering (RNAi) was used to knockdown the expression of G6PC in HeLa cells, and the silencing effect of protein was confirmed by Western blotting. MTT assay and plate clony formation assay were performed to detect the effect of G6PC knockdown on the proliferation of HeLa cells; scratch healing assay and TranswellTM chamber assay were applied to observe the effect of G6PC knockdown on the invasion and migration abilities of HeLa cells; the tube-formation assay was used to detect the effect of G6PC knockdown on the angiogenesis ability of HeLa cells; the expression levels of epithelial-mesenchymal transition (EMT)-related proteins and AKT/mTOR signaling pathway-related proteins were determined by Western blotting. Results The expression of G6PC was effectively silenced by RNAi technology. G6PC knockdown obviously inhibited the proliferation, migration and angiogenesis of HeLa cells. Meanwhile, G6PC knockdown suppressed the EMT process, the phosphorylation of AKT and mTOR proteins. Conclusion G6PC knockdown can effectively inhibit the proliferation, migration, angiogenesis and EMT process of HeLa cells, which is related to the blocked AKT/mTOR signaling pathway.

Development and External Validation of a Nomogram for Predicting Cancer-Specific Survival of Non-Small Cell Lung Cancer Patients With Ipsilateral Pleural Dissemination.

BACKGROUND: Non-small-cell lung cancer (NSCLC) patients with ipsilateral pleural dissemination are defined as M1a in the eighth of American Joint Committee on Cancer (AJCC) TNM staging. We aimed to build a nomogram to predict lung cancer specific survival (LCSS) of NSCLC patients with ipsilateral pleural dissemination and to compare the impact of primary tumor resection (PTR) on LCSS among patients with different features. METHODS: A total of 3,918 NSCLC patients with ipsilateral pleural dissemination were identified from the Surveillance, Epidemiology, and End Results (SEER) database. We selected and integrated significant prognostic factors based on competing risk regression to build a nomogram. The model was subjected to internal validation within SEER cohort and external validation with the cohort of 97 patients from Peking University People's Hospital. RESULTS: Age (P < 0.001), gender (P = 0.037), T stage (P = 0.002), N stage (P < 0.001), metastasis pattern (P = 0.005), chemotherapy (P < 0.001), and PTR (P < 0.001) were independent prognostic factors. The calibration curves presented a good consistency and the Harrell's C-index of nomogram were 0.682 (95%CI: 0.673-0.691), 0.687 (95%CI: 0.670-0.704) and 0.667 (95%CI: 0.584-0.750) in training, internal, and external validation cohort, respectively. Interaction tests suggested a greater LCSS difference caused by PTR in patients without chemotherapy (P < 0.001). CONCLUSIONS: We developed a nomogram based on competing risk regression to reliably predict prognosis of NSCLC patients with ipsilateral pleural dissemination and validated this nomogram in an external Chinese cohort. This novel nomogram might be a practical tool for clinicians to anticipate the 1-, 3- and 5-year LCSS for NSCLC patients with pleural dissemination. Subgroup analysis indicated that patients without chemotherapy could get more benefit from PTR. In order to assess the role of PTR in the management of M1a patients more accurately, further prospective study would be urgently required.

New horizons in non-small-cell lung cancer patients with ipsilateral pleural dissemination (M1a): review of the literature.

Non-small cell lung cancer (NSCLC) with ipsilateral pleural dissemination (pM1a) is generally contraindicated for surgery owing to the extremely poor survival. However, some studies have demonstrated that primary tumor resection (PTR) may prolong the survival of these patients. Besides, with the development of systemic therapy, it is still hard to decide the best therapy model for pM1a patients. Thus, we reviewed essential studies about NSCLC with pleural disease and summarized the progress of new techniques in recent years, trying to provide promising new horizons about the management of pM1a patients. Firstly, we suggest performing PTR for highly selected pM1a patients, combined with appropriate systemic therapies and follow-up strategies. Secondly, hyperthermic intrathoracic chemotherapy (HITHOC) can control the symptoms and prolong the survival of NSCLC patients with malignant pleural effusion (MPE). It could also combine with PTR together. Finally, application of genetic testing and circulating tumor DNA (ctDNA) monitoring may furthermore make it possible for personalized management of pM1a patients in the future.

Primary tumor resection of non-small cell lung cancer patients with ipsilateral pleural dissemination (M1a) in the era of targeted therapy.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with ipsilateral pleural dissemination (M1a) are generally contraindicated for surgery. Recently, several studies have demonstrated that these patients might benefit from primary tumor resection (PTR). However, whether PTR is beneficial for driver oncogene-positive patients treated with targeted therapy, remains unclear. Here, we investigated the effects of PTR on survival in the era of targeted therapy. METHODS: In total, 105 NSCLC patients with ipsilateral pleural dissemination were identified. The mode of systemic treatment was assessed in this study. Survival analysis was performed with the Kaplan-Meier method and Cox proportional hazards regression. The overall survival (OS) of patients with or without PTR was compared between propensity score-matched groups (caliper: 0.02). RESULTS: In the entire cohort, PTR was associated with improved OS in both unmatched (median survival time [MST]: 50.0 vs. 29.6 months, P = 0.019) and matched (MST: 50.0 vs. 34.4 months, P = 0.052) cohorts. Multivariate regression models showed that surgery was an independent favorable prognostic factor for OS. A total of 70 patients underwent genetic testing, and targeted therapies, such as EGFR-TKIs or ALK-TKIs, were used in the driver oncogene-positive patients. Subgroup analysis showed that PTR did not improve OS in the targeted therapy group (MST: 57.1 months vs. 50.4 months, P = 0.840). However, surgery significantly prolonged survival in the nontargeted therapy group (MST: 39.8 vs. 14.2 months, P = 0.002). CONCLUSIONS: The results of this study indicated that PTR could prolong OS in stage IV NSCLC patients with ipsilateral pleural dissemination, especially in patients who are not candidates for targeted therapy. KEY POINTS: Non-small cell lung cancer patients with ipsilateral pleural dissemination can benefit from primary tumor resection. Primary tumor resection could prolong overall survival (OS) in non-small cell lung cancer patients with ipsilateral pleural dissemination who are not candidates for targeted therapy.

Primary tumour resection in non-small-cell lung cancer patients with ipsilateral pleural dissemination (M1a): a population-based study.

OBJECTIVES: Non-small-cell lung cancer (NSCLC) patients with ipsilateral pleural dissemination (M1a) are generally contraindicated for surgery. However, several small-sample studies have demonstrated that they might benefit from surgery. We investigated the effects of primary tumour resection on survival in these patients. METHODS: Stage IV NSCLC patients with ipsilateral pleural dissemination were identified from the US National Cancer Institute Surveillance, Epidemiology and End Results database entries from 2010 to 2015. Survival analysis was performed before and after matching. Multivariable regression models were built to identify prognostic factors. RESULTS: Of the 5513 patients with ipsilateral pleural dissemination, 309 underwent primary tumour resection. In the entire cohort, surgery was associated with improved overall survival (OS) in both the unmatched and matched cohorts (both log rank, P < 0.001). In the surgery-recommended cohort, patients treated with surgery also had significantly longer OS before and after matching. Multivariable regression models showed that surgery was an independent favourable prognostic factor for OS [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.48-0.65; P < 0.001] and lung cancer-specific mortality (subhazard ratio 0.60, 95% CI 0.51-0.70; P < 0.001). Surgery was independently associated with improved survival in all subgroups except for those with pericardial effusion (P = 0.065) or N3 disease (P = 0.17). In the surgical cohort, patients who underwent lobe/bilobectomy had significantly better OS than those who underwent sublobar resection (log rank, P < 0.001). CONCLUSIONS: Inclusion of primary tumour resection in multimodal therapy of NSCLC was associated with improved survival in selected patients with ipsilateral pleural dissemination, except for those with pericardial effusion or N3 disease.