LINC02086 inhibits ferroptosis and promotes malignant phenotypes of pancreatic cancer via miR-342-3p/CA9 axis.

Long noncoding RNAs (lncRNAs) play important roles in modulating the tumorigenesis and progression of malignant tumors. LINC02086 is a newly identified oncogene associated with tumorigenesis, but its role in pancreatic cancer (PC) has not been fully elucidated. In this study we examined the expression levels of LINC02086, miR-342-3p, and CA9 in PC. The relationship of ferroptosis with these factors was analyzed by detecting the expression levels of Fe2+, reactive oxygen species (ROS), and ferroptosis marker proteins. The expression of these genes was altered to observe their effects on cell proliferation, migration, and invasion ability. Bioinformatics was used to predict target genes, and the binding relationship was verified luciferase reporter assay. Finally, the function of LINC02086 was evaluated in vivo. The findings suggest that LINC02086 is highly expressed in PC tissues and cell lines and is correlated with a poor prognosis. In vitro experiments demonstrated that LINC02086 knockdown promoted ferroptosis in PC cells to suppress their malignant phenotype. LINC02086 acts as a competitive endogenous RNA that adsorbed miR-342-3p. miR-342-3p hinders the malignant progression of PC by promoting ferroptosis. In addition, miR-342-3p targets CA9 and affects its function. Further mechanistic studies revealed that LINC02086 inhibits ferroptosis and promotes PC progression by acting as a sponge for miR-342-3p to upregulate CA9 expression. In vivo experiments further confirmed this mechanism. Taken together, LINC02086 upregulates CA9 expression by competitively binding with miR-342-3p, thereby inhibiting ferroptosis in PC cells and promoting their malignant phenotype. The results of our study provide new insights into how LINC02086 contributes to the progression of PC.

Clinical significance of tumor suppressor genes methylation in circulating tumor DNA of patients with pancreatic cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a potential diagnostic and prognostic biomarker in various tumors. However, the role of tumor suppressor genes (TSGs) methylation in ctDNA of patients with pancreatic cancer (PC) remains largely unclear. METHODS: Patients with PC (n = 43), pancreatic benign diseases (n = 39), and healthy controls (n = 20) were enrolled in the study. Quantitative analysis of methylation pattern of five candidate TSGs including NPTX2, RASSF1A, EYA2, p16, and ppENK in ctDNA was performed by next generation sequencing (NGS). The diagnostic performances of these 5-TSGs methylation were assessed by the operating characteristic (ROC) curve and clinicopathological features correlation analysis. Meanwhile, the changes in methylation levels of these 5-TSGs on the 7th postoperative day were evaluated in 23 PC patients who underwent radical resection. RESULTS: The methylation levels of RASSF1A, EYA2, ppENK and p16 genes in patients with PC were significantly higher than those in healthy controls. EYA2, p16 and ppENK genes showed significantly hypermethylation in PC than those in pancreatic benign diseases. NPTX2, RASSF1A, EYA2, p16 and ppENK genes showed significantly hypermethylation in pancreatic benign diseases than those in healthy controls (P < 0.05). The methylation levels of these 5 candidate TSGs were not correlated with the tumor size, nerve invasion, lymph node metastasis and TNM stage of PC. The AUC of these biomarkers for diagnosis of PC ranged from 0.65 to 0.96. The AUC values of these methylated genes and CpG sites for differentiating malignant and benign pancreatic diseases were ranging from 0.68 to 0.92. Combined the hypermethylated genes improved the detective ability of PC than single gene. The methylation levels of NPTX2, EYA2 and ppENK genes were significantly decreased after radical resection of PC. CONCLUSION: Quantitative analysis of methylation pattern of NPTX2, RASSF1A, EYA2, p16 and ppENK in ctDNA by NGS could be a valuable non-invasive tool for detection and monitoring of PC.

The relationship between VEGF-460(T>C) polymorphism and cancer risk: A systematic review and meta-analysis based on 46 reports.

BACKGROUND: Extensive studies on the link between single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) and various malignancy risks produced conflicting results, notably for VEGF-460(T/C). To evaluate this correlation more comprehensively and accurately, we perform a meta-analysis. METHODS: Through retrieving 5 databases (Web of Science (WoS), Embase, Pubmed, Wanfang database (Wangfang), and China National Knowledge Infrastructure (CNKI)) and applying hand search, citation search, and gray literature search, 44 papers included 46 reports were enrolled. To evaluate the relationship between VEGF-460 and cancer risk, we pooled odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Our results indicated that the VEGF-460 polymorphism is not related to malignancy susceptibility (dominant model, OR = 0.98, 95% CI = 0.87-1.09; recessive model, OR = 0.95, 95% CI = 0.82-1.10; heterozygous model, OR = 0.99, 95% CI = 0.90-1.10; homozygous model, OR = 0.92, 95% CI = 0.76-1.10; additive model, OR = 0.98, 95% CI = 0.90-1.07). While, in subgroup analysis, this SNP may reduce the risk of hepatocellular carcinoma. CONCLUSION: this meta-analysis indicated that VEGF-460 was irrelevant to overall malignancy risk, but it might be a protective factor for hepatocellular carcinoma.

Distribution characteristics and clinical significance of infiltrating T cells in the tumor microenvironment of pancreatic cancer.

Tumor-infiltrating lymphocytes (TILs) are important components of the tumor microenvironment (TME). However, the distribution characteristics of TILs and their significance in pancreatic cancer (PC) remain largely unexplored. The levels of TILs, including the total number of T cells, cluster of differentiation (CD)4+ T cells, CD8+ cytotoxic T lymphocytes (CTLs), regulatory T-cells (Tregs), programmed cell death protein 1+ T cells and programmed cell death ligand 1 (PD-L1)+ T cells, in the TME of patients with PC were detected using multiple fluorescence immunohistochemistry. The associations between the number of TILs and the clinicopathological characteristics were investigated using χ2 tests. In addition, Kaplan-Meier survival and Cox regression analyses were used to assess the prognostic value of these TIL types. Compared with paracancerous tissues, in PC tissues, the proportions of total T cells, CD4+ T cells and CD8+ CTLs were markedly decreased, while those of Tregs and PD-L1+ T cells were significantly increased. The levels of CD4+ T cell and CD8+ CTL infiltrates were inversely associated with tumor differentiation. Higher infiltrates of Tregs and PD-L1+ T cells were closely associated with advanced N and TNM stages. It is important to note that the infiltrates of total T cells, CD4+ T cells, Tregs and PD-L1+ T cells in the TME were independent risk factors for the prognosis of PC. PC was characterized by an immunosuppressive TME with a decrease in the number of CD4+ T cells and CD8+ CTLs, and an increase in the number of Tregs and PD-L1+ T cells. Overall, the number of total T cells, CD4+ T cells, Tregs and PD-L1+ T cells in the TME was a potential predictive marker for the prognosis of PC.

Organ-Sparing Pancreatectomy for Benign or Low-Grade Malignant Pancreatic Tumors: A Single-Center Experience with 101 Consecutive Patients.

BACKGROUND Pancreaticoduodenectomy (PD) and distal pancreatectomy with splenectomy (DPS) are considered the standard procedures for pancreatic lesions. However, long-term metabolic consequences of PD and DPS applied for benign or low-grade malignant tumors need to be addressed. This study aimed to investigate the short- and long-term outcomes of organ-sparing pancreatectomy for benign or low-grade malignant pancreatic tumors in our institution. MATERIAL AND METHODS The clinical data of 101 patients with benign or low-grade malignant pancreatic tumors who underwent organ-sparing pancreatectomy from January 2009 to September 2021 were retrospectively analyzed, including 40 tumor enucleations (EN), 22 central pancreatectomies (CP), 25 spleen-preserving distal pancreatectomies (SPDP), 7 pylorus-preserving pancreaticoduodenectomies (PPPD) and 7 duodenum-preserving pancreatic head resections (DPPHR). RESULTS The mean operative time, intraoperative blood loss, and length of hospital stay were 182.9±74.6 min, 191.9±127.8 mL, and 11.6±8.1 days, respectively. EN had the shortest operative time, while DPPHR had the longest operative time. The mean intraoperative blood loss of DPPHR and PPPD was significantly greater than the others (all P<0.05). The length of hospital stay of PPPD was longest. The overall morbidity was 33.6%. The reoperation rate was 1.0% and there was no mortality. The incidence of pancreatic endocrine insufficiency and exocrine insufficiency were 5.9% and 6.9%, respectively. None patients had tumor recurrence during the follow-up period. CONCLUSIONS Organ-sparing pancreatectomy is associated with acceptable perioperative risk and postoperative complications and better long-term outcomes in the aspects of preservation of function and curability in benign or low-grade malignant pancreatic tumors.