Progranulin modulates the progression of non-small cell lung cancer through lncRNA H19.

OBJECTIVE: This study aimed to explore the specific mechanism of action of Progranulin (PGRN) in non-small cell lung cancer (NSCLC) and its interaction with lncRNA H19. METHODS: Normal and cancerous lung tissues were collected from patients with NSCLC and healthy volunteers. We assessed the expression of PGRN in both groups using immunohistochemistry, quantitative-reverse transcription-polymerase chain reaction (qRT-PCR), and western blotting (WB). RESULTS: Compared to the controls, PGRN expression was noticeably higher in tumor tissues. The high expression of PGRN in patients with NSCLC was inversely correlated to the prognosis and strongly associated with the biological features and clinicopathologic data. High PGRN expression significantly improved the ability of NSCLC cells to proliferate and migrate and was positively correlated with tumor formation, based on in vitro and in vivo cellular tests. Expression of lncRNA H19 was also found to be elevated in NSCLC tissue and cells. The expression of H19 was correlated with tumor growth in vivo and in vitro, and H19 regulated PGRN by mediating the expression of miR-29b-3p. CONCLUSIONS: H19 and PGRN can serve as biomarkers and therapeutic targets in NSCLC.

The impact of surgery and age on mortality with primary trachea malignant tumors: a retrospective study based on propensity-score matching analysis.

PURPOSE: This study aimed to explore the survival significance of surgery and age on the prognosis of patients with primary trachea malignancies. METHODS: The entire cohort of 637 patients with primary malignant trachea tumors was used to perform the main analyses. The data of those patients were from a public database. Overall survival (OS) curves were drawn by the Kaplan-Meier method and compared by the Log-rank test. The univariable and multivariable Cox regression analyses calculated the hazard ratio (HR) and 95% confidence interval (CI) for overall mortality. The propensity-score matching analysis was used to reduce the selection bias. RESULTS: Age, surgery, histological type, N classification, M classification, marital status, and tumor grading were identified as independent prognostic factors after eliminating confounding factors. The results of the Kaplan-Meier method revealed that patients with age < 65 had a survival advantage over those with age ≥ 65 (HR = 1.908, 95% CI 1.549-2.348, P < 0.001). The 5-year OS rates were 28% and 8% in the group with age < 65 and age ≥ 65, respectively (P < 0.001). Cases with surgery had better survival over patients without surgery (HR = 0.372, 95% CI 0.265-0.522, P < 0.001). Compared with patients who did not undergo operations, patients with surgery had a higher median survival time (20 vs. 174 months). For patients with surgery, young age was considered a survival-promoting factor (HR 2.484; 95% CI 1.238-4.983, P = 0.010). CONCLUSION: We suggested that age and surgery were the independent prognostic factors in patients with primary malignant trachea tumors. Besides, age serves as an essential indicator for evaluating the prognosis of postoperative patients.

Histone lysine methyltransferase SETDB2 suppresses NRF2 to restrict tumor progression and modulates chemotherapy sensitivity in lung adenocarcinoma.

OBJECTIVE: Aberrant epigenetic remodeling represents a molecular hallmark in lung adenocarcinoma (LUAD). We aim to investigate the biological roles of SETDB2 and its underlying associations with oxidative stress, providing therapeutic targets for individualized treatment of LUAD. METHODS: Differential analysis was conducted via Limma package, and Kaplan-Meier analysis was performed with survival package. CCK-8, cell proliferation assay, transwell assay, and in vivo assays were conducted to assess the function of SETDB2. Western blot assay, RT-qPCR, and immunohistochemistry (IHC) were conducted to assess the expression levels of SETDB2/NRF2. Chromatin immunoprecipitation (ChIP) assay and ChIP-qPCR were conducted to assess the epigenetic roles of SETDB2. RESULTS: We found that SETDB2 expression is decreased in tumor samples versus normal tissues in TCGA-LUAD cohort, LUAD-EAS cohort, GSE72094 dataset, and independent Soochow-LUAD dataset. Patients with low SETDB2 levels had a worse prognosis relative to those with high SETDB2. SETDB2 inhibition could significantly promote cell growth, migration ability, and stemness maintenance. Gene set enrichment analysis (GSEA) suggested that SETDB2 correlated with oxidative stress crosstalk and regulated NRF2 mRNA levels. ChIP assay suggested that SETDB2 mainly recruited the H3K9me3 enrichment at the NRF2 promoter region to suppress the mRNA levels of NRF2. Downregulated SETDB2 could activate NRF2 transcription and expression, thereby promoting its downstream targets, like NQO1, FTH1, and ME1. Functional experiments demonstrated that low SETDB2 allowed NRF2 to drive malignant processes of LUAD. SETDB2 overexpression attenuated the ability of NRF2 signaling to neutralize cellular reactive oxygen species (ROS) levels, leading to enhanced cell apoptosis. Overexpressed SETDB2 could inhibit tumor progression in vivo and further render LUAD cells sensitive to chemotherapy. CONCLUSIONS: In conclusion, these findings uncovered the suppressive role of SETDB2 in LUAD. SETDB2 negatively regulates NRF2 signaling to modulate tumor progression, which creates a therapeutic vulnerability in LUAD.

Research on the application of uniportal video-assisted thoracoscopic segmental resection of the lung in elderly patients with non-small cell lung cancer aged over 65 years.

INTRODUCTION: The literature regarding the application of uniportal video-assisted thoracoscopic segmental resection of the lung in patients aged over 65 years with non-small cell lung cancer (NSCLC) is sparse. This paper reports 175 cases of uniportal video-assisted thoracoscopic segmental resection of the lung performed at one center, of which 63 patients were over 65 years old. AIM: To investigate the safety and feasibility of uniportal video-assisted thoracoscopic segmental resection of the lung in elderly patients aged over 65 years with NSCLC. MATERIAL AND METHODS: A retrospective analysis of 175 NSCLC patients who underwent uniport video-assisted thoracoscopic segmental resection of the lung in the center from August 2018 to August 2020 was conducted, and based on the age of 65 years, patients were divided into elderly and non-elderly groups. The general data and perioperative indicators of the two groups were compared. RESULTS: The procedures were completed in all patients without death or conversion to open surgery. In the general data of the two groups of patients, the prevalence of emphysema in the elderly group was significantly higher than that in the non-elderly group (p = 0.001). However, there was no statistically significant difference between the two groups in surgery time, intraoperative blood loss, thoracic drainage tube retention time, postoperative hospital stay, incision satisfaction, or postoperative complications (p > 0.05). CONCLUSIONS: Uniportal video-assisted thoracoscopic segmental resection of the lung is feasible and safe in elderly patients with NSCLC aged over 65 years.

CDK14 expression is elevated in patients with non-small cell lung cancer and correlated with poor prognosis.

OBJECTIVE: To investigate the clinical significance of cyclin-dependent kinase 14 (CDK14) expression in patients with non-small cell lung cancer (NSCLC). METHODS: The present prospective observational study included 193 patients diagnosed with NSCLC between January 2010 and December 2014. NSCLC tumor tissues and paired paracancerous normal tissues were obtained from all patients. CDK14, thyroid transcription factor 1 (TTF-1), cytokeratin 5/6 (CK5/6), and Ki67 expression was measured via immunohistochemistry (IHC). RESULTS: CDK14 staining was strong (>3) in 129 patients (66.49%) and weak (≤3) in 64 patients (33.16%). The mean IHC scores were markedly higher in tumor tissues than in paracancerous tissues. Pearson's analysis demonstrated that the IHC scores of CDK14 expression were positively correlated with TTF-1, CK5/6, and Ki67 scores. Kaplan-Meier analysis illustrated that 5-year overall survival was markedly longer in patients with weak CDK14 staining. TNM stage, pleural invasion, lymph node metastasis, CDK14 expression, and Ki67 expression were risk factors for 5-year overall survival in patients with NSCLC. CONCLUSION: CDK14 overexpression portended poor outcomes in patients with NSCLC, and CDK14 expression was correlated with TTF-1, CK5/5, and Ki67 expression.

Diagnostic potential of extracellular vesicle-associated microRNA-10b and tumor markers for lung adenocarcinoma.

MicroRNAs (miRNAs/miRs) in extracellular vesicles (EVs) are potential diagnostic markers. The purpose of the present study was to investigate potential EV miRNA biomarkers for lung adenocarcinoma (LUAD). Potential miRNAs were identified by searching public databases and verified by examining clinical samples. The diagnostic value of EV-associated miR-10b, plasma miR-10b and tumor markers (TMs), including α-fetoprotein (AFP), neuron-specific enolase, carcinoembryonic antigen (CEA), cytokeratin 19 fragment 21-1 (CYFRA211), pro-gastrin-releasing-peptide, carbohydrate antigen (CA)125, CA153, CA199 and CA724, was evaluated via receiver operating characteristic curve analysis. By searching the Gene Expression Omnibus and The Cancer Genome Atlas databases, miR-10b was identified as a potential biomarker. The analysis of clinical samples suggested that EV-associated miR-10b from plasma was significantly differentially expressed between LUAD and control samples. EV-associated miR-10b could function as a diagnostic marker for LUAD, with an AUC of 0.998, which was higher than the AUCs for TMs such as AFP, CEA, CYFRA211, CA125, CA153, CA199, CA724, pro-gastrin-releasing-peptide and neuron-specific enolase. In conclusion, EV-associated miR-10b may be a potential diagnostic biomarker for LUAD that is superior to plasma miR-10b and TMs.

The Significance of Secreted Phosphoprotein 1 in Multiple Human Cancers.

Malignant tumor represents a major reason for death in the world and its incidence is growing rapidly. Developing the tools for early diagnosis is possibly a promising way to offer diverse therapeutic options and promote the survival chance. Secreted phosphoprotein 1 (SPP1), also called Osteopontin (OPN), has been demonstrated overexpressed in many cancers. However, the specific role of SPP1 in prognosis, gene mutations, and changes in gene and miRNA expression in human cancers is unclear. In this report, we found SPP1 expression was higher in most of the human cancers. Based on Kaplan-Meier plotter and the PrognoScan database, we found high SPP1 expression was significantly correlated with poor survival in various cancers. Using a large dataset of colon adenocarcinoma (COAD), head and neck cancer (HNSC), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC) patients from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, this study identified 22 common genes and 2 common miRNAs. GO, and KEGG paths analyses suggested that SPP1 correlated genes were mainly involved in positive regulation of immune cell activation and infiltration. SPP1-associated genes and miRNAs regulatory networks suggested that their interactions may play a role in the progression of four selected cancers. SPP1 showed significant positive correlation with the immunocyte and immune marker sets infiltrating degrees. All of these data provide strong evidence that SPP1 may promote tumor progress through interacting with carcinogenic genes and facilitating immune cells' infiltration in COAD, HNSC, LUAD, and LUSC.

Circadian clock associates with tumor microenvironment in thoracic cancers.

The application of cancer chronotherapy is to treat cancers based on at specific times during circadian rhythms. Previous studies have characterized the impact of circadian clock on tumorigenesis and specific immune cells. Here, by using multi-omics computation techniques, we systematically characterized the distinct roles of core circadian clock genes in thoracic cancers including lung adenocarcinoma, lung squamous cell carcinoma, and esophageal carcinoma. Strikingly, a wide range of core clock genes are epigenetically altered in lung adenocarcinomas and lung squamous cell carcinomas but not esophageal carcinomas. Further cancer hallmark analysis reveals that several core clock genes highly correlate with apoptosis and cell cycle such as RORA and PER2. Interestingly, our results reveal that CD4 and CD8 T cells are correlated with core clock molecules especially in lung adenocarcinomas and lung squamous cell carcinomas, indicating that chrono-immunotherapy may serve as a candidate option for future cancer management.

Benefits of surgery in the multimodality treatment of stage IIB-IIIC small cell lung cancer.

Surgery combined with chemotherapy/radiotherapy is recommended for early stage small cell lung cancer (SCLC); however, the role of surgery in the multimodality treatment of advanced disease remains controversial. The clinical data of patients between 2000 and 2015 were obtained from the Surveillance, Epidemiology, and End Results database. The surgery group included 998 patients with stage IIB-IIIC. A matched non-surgery group (n = 2994) was generated by propensity score matching. The Kaplan-Meier method and log-rank tests were used for survival analyses. Univariate and multivariate analyses were used to identify significant prognostic factors. After matching, there were no significant differences between the two groups in race, age, sex, T classification, N classification, TNM stage, marital status, primary sites, and origin record NAACCR Hispanic Identification Algorithm (NHIA). The surgery group showed better overall survival and cancer-specific survival than the non-surgery group. Univariate and multivariate analyses showed that therapy methods, age, sex, T classification, and N classification were independent prognostic predictors for stage IIB-IIIC SCLC (all P < 0.05). Stratified analyses showed that survival outcomes favored surgery in any age groups, men and women, any T classification except T3, and N0-2 but not N3 compared with non-surgical treatment. The survival differences favored surgery in stage IIB and IIIA SCLC, although they were not significant in stage IIB and IIIC SCLC. Therefore, surgery was associated with improved survival in stage IIB and IIIA SCLC, but not in stage IIIB and IIIC SCLC.

The application of nano-enrichment in CTC detection and the clinical significance of CTCs in non-small cell lung cancer (NSCLC) treatment.

Circulating tumor cells (CTCs) are an independent prognostic marker in non-small cell lung cancer (NSCLC). CTC numbers are closely related to early diagnosis, clinical stage, therapy surveillance, and prognosis of NSCLC. We used a more efficient nano-enrichment method to detect CTCs in NSCLC patients and explored the clinical value of CTCs. The results showed that CTC numbers in stage IV cases were significantly higher than those in stage I, II or III cases. The number of CTCs in poorly-differentiated cases was significantly higher than that in well-differentiated cases. During six chemotherapy cycles, the average CTC number decreased from 5.8/7.5 ml in cycle #1 to 2.4/7.5 ml in cycle #4 and remained at almost the same level from 4 to 6 cycles. CTC numbers in patients with EGFR mutations was significantly higher than those in patients with no mutations. The average progression free survival (PFS) in the favorable group (CTC ≤ 5/7.5 ml) was 11.3 months, which was longer than that in the unfavorable group (CTC > 5/7.5 ml, 7.2 months). In conclusion, the assessment of NSCLC cannot be performed using a single CTC analysis. The clinical value is more significant in the continuous analysis of CTC data, as well as the cross-validation of other indexes and imaging results.

Clinical characteristics and prognosis of basaloid squamous cell carcinoma of the lung: a population-based analysis.

BACKGROUND: This study analyzed the clinical features and prognosis of basaloid squamous cell carcinoma of the lung (BSC), and constructed a nomogram to predict the prognoses of patients. METHODS: The information of pure BSC patients was obtained in the Surveillance, Epidemiology, and End Results database between 2004 and 2015. Then, it was evaluated, and compared with the data of lung squamous cell carcinoma (SCC), lung large cell carcinoma (LCC) and lung adenocarcinoma (LAC) patients. Subsequently, we used univariate and multivariate analyses to investigate the independent factors related to the prognoses of patients with BSC and constructed a nomogram to verify the prognoses. RESULTS: A total of 425 patients diagnosed with BSC were enrolled. Compared with patients with SCC, LCC and LAC, the mean survival time of BSC patients was better than all of them. Compared with SCC, there were significant differences between the characteristics of grade (P < 0.001), total stage (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), M stage (P < 0.001), surgery (P < 0.001), radiotherapy (P < 0.001), and chemotherapy (P < 0.001), while BSC also had significantly different clinical characteristics from LCC and LAC. Univariate and multivariate survival analyses showed that age (P < 0.001), T stage (P < 0.001), N stage (P = 0.009), M stage (P < 0.001), and surgery (P < 0.001) were independent prognostic factors of BSC. The survival of patients undergoing lobectomy was significantly better than sublobar resection, with an OR of 0.389 (0.263-0.578). We constructed a nomogram with a C-index of 0.750 (95% confidence interval) based on the results of multivariate analysis. The calibration curves based on nomogram scores indicated that the nomogram could accurately predict the prognosis of patients. CONCLUSIONS: BSC had unique clinical and prognostic features. T stage, N stage, M stage, age, and surgery were independently associated with overall survival (OS). Lobectomy was a relative ideal choice for patients with BSC. The nomogram effectively predicted the OS at 1-, 3-, and 5-years.

Pulmonary metastasis in newly diagnosed colon-rectal cancer: a population-based nomogram study.

BACKGROUND: Colorectal cancer (CRC) has a high worldwide incidence with a tendency to metastasize to the lungs. We aimed to identify clinical factors related to lung metastasis (LM) and analyze the prognosis of patients after LM. METHODS: Multivariate logistic regression analysis was used to identify risk factors for LM from CRC. Univariate and multivariate Cox proportional hazard models were performed to identify potentially important prognostic factors for patients with LM. RESULTS: Age (p = 0.010), tumor size (p < 0.001), T stage (p < 0.001), N stage (p < 0.001), race (p < 0.001), tumor site (p < 0.001), liver metastasis (p < 0.001), brain metastasis (p < 0.001), bone metastasis (p < 0.001), serum levels of carcinoembryonic antigen (CEA) (p < 0.001), and circumferential resection margin (CRM) (p < 0.001) were associated with a risk of LM from CRC. All factors (all, p < 0.001) except tumor size (p = 0.095) and race (p = 0.650) were related to the overall survival of patients. Two nomograms were formulated to visually predict lung metastasis risk and 1-, 3-, and 5- year overall survivals for patients with LM. The concordance indices were 0.754 and 0.749, respectively. CONCLUSIONS: Age, tumor size, histological grade, serum levels of CEA, tumor site, surgery modalities of CRC, CRM, number of positive lymph nodes, and chemotherapy were independent risk factors for LM from CRC. The nomograms we developed can be effectively used to forecast the risk of LM and predict the survival for LM from CRC.

Population-based analysis of esophageal large cell neuroendocrine carcinoma between 2004 and 2015.

BACKGROUND: Esophageal large cell neuroendocrine carcinoma (ELCNC) seems a rarely gastrointestinal malignancy. By far, its clinicopathological characteristics and prognosis have not been deeply studied. METHODS: The data of patients having ELCNC was extracted from the Surveillance, Epidemiology, and End Results (SEER) database, then assessed and compared with information from patients with esophageal small cell neuroendocrine carcinoma (ESCNC) or esophageal squamous cell carcinoma (ESCC). We used univariate and multivariate analyses to accurately detect independent prognostic factors. RESULTS: The data of 36 patients for ELCNC were obtained between 2004 and 2015. Compared with patients with ESCNC and ESCC, the mean survival time of ECLNC patients was worse than those with ESCC, while similar to ESCNC. Thus, ELCNC had significantly different clinicopathological characteristics compared to ESCNC and ESCC. Univariate and multivariate analyses revealed that age (P=0.001) and M stage (P=0.004) were independent prognostic factors. CONCLUSIONS: ELCNC is a rare subtype of esophageal neuroendocrine carcinoma. The clinicopathological features differ from those of other esophageal carcinomas. Prognosis may be closely related to age and M stage.

PEDF and PEDF-derived peptide 44mer protect cardiomyocytes against hypoxia-induced apoptosis and necroptosis via anti-oxidative effect.

Pigment epithelium-derived factor (PEDF) has many biological activities. But it's not known whether PEDF and its functional peptides could protect against hypoxia-induced cell death and the mechanisms are still unclear. We used cultured H9c2 cells and primary cardiomyocytes to show that apoptosis and necroptosis were significantly increased after hypoxia. Both PEDF and its fuctional peptides 44mer reduced apoptosis and necroptosis rates and inhibited the expression of cleaved caspase 3 and receptor-interacting protein 3 (RIP3). Furthermore, PEDF and 44mer could up-regulate super oxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) levels, promote clearing of reactive oxygen species (ROS) and malondialdehyde (MDA). While, 34mer, another functional peptides had no effect on cell apoptosis and necroptosis. Hereby this is the first evidence that PEDF and its functional peptide 44mer protect cultured H9c2 cells and primary cardiomyocytes against apoptosis and necroptosis under hypoxic condition via the anti-oxidative mechanism.