Exosomes from M1-polarized macrophages promote apoptosis in lung adenocarcinoma via the miR-181a-5p/ETS1/STK16 axis.

Serine/threonine kinase 16 (STK16) is crucial in on regulating tumor cell proliferation, apoptosis, and prognosis. Activated M1 macrophages regulate lung adenocarcinoma (LUAD) growth by releasing exosomes. This study aims to investigate the role of STK16 and then focus on the possible mechanisms through which exosomes derived from M1 macrophages play their roles in LUAD cells by targeting STK16. Clinical LUAD samples were used to evaluate the expression of STK16 and its association with prognosis. Exosomes were isolated from M0 and M1 macrophages by ultracentrifugation and were then identified by electron microscopy and western blotting. In vitro gain- and loss-of-function experiments with LUAD cells were performed to elucidate the functions of miR-181a-5p, ETS1, and STK16, and mouse xenograft models were used to verify the function of STK16 in vivo. Western blotting, quantitative real-time PCR, CCK-8 assay, cell apoptosis, immunohistochemistry staining, luciferase assay, ChIP assay, and bioinformatics analysis were performed to reveal the underlying mechanisms. High expression of STK16 was observed in LUAD tissues and cells, and higher expression of STK16 was associated with worse prognosis. Silencing STK16 expression inhibited cell proliferation and promoted apoptosis via the AKT1 pathway. Exosomes from M1 macrophages inhibited viability and promoted apoptosis by inhibiting STK16. Moreover, miR-181a-5p is the functional molecule in M1 macrophage-derived exosomes and plays a vital role in inhibiting cell proliferation and promoting apoptosis by targeting ETS1 and STK16. Hence, exosomes derived from M1 macrophages were capable of inhibiting viability and promoting apoptosis in LUAD via the miR-181a-5p/ETS1/STK16 axis.

Relationship of lymphovascular invasion with lymph node metastasis and prognosis in superficial esophageal carcinoma: systematic review and meta-analysis.

BACKGROUND: The development of tumor cells inside the lymphatics or blood vessels is known as lymphovascular invasion (LVI). The correlation between LVI, lymph node metastasis (LNM), and the diagnosis of superficial esophageal carcinoma (SEC) remains unclear. METHODS: We searched Embase, PubMed, Web of Science, and Cochrane Library databases for prospective articles to better understand the relationship between LVI, LNM, and SEC diagnosis. RESULTS: We included 23 articles containing data for 4749 patients (range: 54-598) in our meta-analysis. The hazard ratio between LVI and overall survival (OS) was 1.85 with 95% confidence interval (CI) (1.10-3.11, P = 0.02). LNM rate was higher in SEC patients with LVI than SEC patients without LVI (univariate: OR = 4.94, 95% CI: 3.74-6.53, P < 0.0001; multivariate: OR = 5.72, 95%CI: 4.38-7.4, P < 0.0001). No obvious publication was found. CONCLUSIONS: The results indicate that LVI plays a dominant role in the prognosis of LNM in SEC and in the prognostic prediction for SEC.

UPP1 Promotes Lung Adenocarcinoma Progression through Epigenetic Regulation of Glycolysis.

Uridine phosphorylase 1 (UPP1) is a dimeric enzyme that plays an indispensable role in pyrimidine salvage as well as uridine homeostasis and is upregulated in various cancers, including LUAD. However, the function and underlying mechanisms of UPP1 in mediating LUAD cell progression are still largely unknown. Single-cell RNA transcription analysis was applied to compare the expression of UPP1 in tumor tissues and adjacent tissue. In vitro gain- and loss-of-function experiments with LUAD cells were performed to elucidate the functions of UPP1. Western blotting, qRT-PCR, cell apoptosis, IHC staining, Seahorse XF24 Extracellular Flux analysis, chromatin immunoprecipitation (ChIP) assay, and bioinformatics analysis were performed to reveal the underlying mechanisms. In this study, UPP1 was found to be the top metabolism-related gene that was upregulated by single-cell transcriptomic profiling of LUAD. Next, we confirmed that UPP1 was highly expressed in LUAD tissues and cell lines and was correlated with poor overall survival in LUAD patients. UPP1 drove glycolytic metabolism and significantly regulated the sensitivity of tumors to glycolytic inhibitors in vitro and in vivo. UPP1 is subject to epigenetic regulation through histone acetylation. The CBP/p300 inhibitor SGC-CBP30 reduced the protein levels of UPP1, H3K27ac, and H3K9ac. ChIP assays revealed that acetyl-histone H3 and RNA polymerase II bind to the UPP1 promoter. UPP1 overexpression restored lactic acid production and glucose uptake compared to the SGC-CBP30 group. Our findings confirm UPP1 as a novel oncogene in LUAD, thus providing a potential novel diagnostic and therapeutic target for LUAD.

Patterns of Extrathoracic Metastases in Different Histological Types of Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths mainly attributable to metastasis, especially extrathoracic metastasis. This large-cohort research is aimed to explore metastatic profiles in different histological types of lung cancer, as well as to assess clinicopathological and survival significance of diverse metastatic lesions. Lung cancer cases were extracted and enrolled from the Surveillance, Epidemiology, and End Results (SEER) database. χ2-tests were conducted to make comparisons of metastatic distribution among different histological types and odds ratios were calculated to analyze co-occurrence relationships between different metastatic lesions. Kaplan-Meier methods were performed to analyze survival outcomes according to different metastatic sites and Cox regression models were conducted to identify independent prognostic factors. In total, we included 159,241 lung cancer cases with detailed metastatic status and complete follow-up information. In order to understand their metastatic patterns, we elucidated the following points in this research: (1) Comparing the frequencies of different metastatic lesions in different histological types. The frequency of bone metastasis was highest in adenocarcinoma, squamous cell carcinoma, LCLC and NSCLC/NOS, while liver was the most common metastatic site in SCLC. (2) Elaborating the tendency of combined metastases. Bi-site metastases occurred more common than tri-site and tetra-site metastases. And several metastatic sites, such as bone and liver, intended to co-metastasize preferentially. (3) Clarifying the prognostic significance of single-site and bi-site metastases. All single-site metastases were independent prognostic factors and co-metastases ended up with even worse survival outcomes. Thus, our findings would be beneficial for research design and clinical practice.

Quantitative assessment of the diagnostic role of FHIT promoter methylation in non-small cell lung cancer.

Aberrant methylation of CpG islands acquired in promoter regions plays an important role in carcinogenesis. Accumulated evidence demonstrates FHIT gene promoter hyper-methylation is involved in non-small cell lung cancer (NSCLC). To test the diagnostic ability of FHIT methylation status on NSCLC, thirteen studies, including 2,119 samples were included in our meta-analysis. Simultaneously, four independent DNA methylation datasets from TCGA and GEO database were analyzed for validation. The pooled odds ratio of FHIT promoter methylation in cancer samples was 3.43 (95% CI: 1.85 to 6.36) compared with that in controls. In subgroup analysis, significant difference of FHIT gene promoter methylation status in NSCLC and controls was found in Asians but not in Caucasian population. In validation stage, 950 Caucasian samples, including 126 paired samples from TCGA, 568 cancer tissues and 256 normal controls from GEO database were analyzed, and all 8 CpG sites near the promoter region of FHIT gene were not significantly differentially methylated. Thus the diagnostic role of FHIT gene in the lung cancer may be relatively limited in the Caucasian population but useful in the Asians.

Aberrant methylation of CDH13 can be a diagnostic biomarker for lung adenocarcinoma.

Background: Aberrant methylation of CpG islands in tumor cells in promoter regions is a critical event in non-small cell lung carcinoma (NSCLC) tumorigenesis and can be a potential diagnostic biomarker for NSCLC patients. The present study systemically and quantitatively reviewed the diagnostic ability of CDH13 methylation in NSCLC as well as in its subsets. Eligible studies were identified through searching PubMed, Web of Science, Cochrane Library and Embase. The pooled odds of CDH13 promoter methylation in lung cancer tissues versus normal controls were calculated by meta-analysis method. Simultaneously, four independent DNA methylation datasets of NSCLC from TCGA and GEO database were downloaded and analyzed to validate the results from meta-analysis. Results: Thirteen studies, including 1850 samples were included in this meta-analysis. The pooled odds ratio of CDH13 promoter methylation in cancer tissues was 7.41 (95% CI: 5.34 to 10.29, P < 0.00001) compared with that in controls under fixed-effect model. In validation stage, 126 paired samples from TCGA were analyzed and 5 out of the 6 CpG sites in the CpG island of CDH13 were significantly hypermethylated in lung adenocarcinoma tissues but none of the 6 CpG sites was hypermethylated in squamous cell carcinoma tissues. Concordantly, the results from other three datasets, which were subsequently obtained from GEO database consisting of 568 tumors and 256 normal tissues, also consisted with those from TCGA dataset. Conclusion: The pooled data showed that the methylation status of the CDH13 promoter is strongly associated with lung adenocarcinoma. The CDH13 methylation status could be a promising diagnostic biomarker for diagnosis of lung adenocarcinoma.