Hsa_circ_0084003 modulates glycolysis and epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma through targeting hsa-miR-143-3p/DNMT3A axis.

Pancreatic ductal adenocarcinoma, one of the deadliest tumors of the digestive tract, is a difficult and invasive malignancy. Current treatment for pancreatic ductal adenocarcinoma mainly depends on surgery combined with radiotherapy and chemotherapy, which, however, often resulting in questionable curative effect. Therefore, new targeted therapies are needed in future treatment. We first interfered with hsa_circ_0084003 expression in pancreatic ductal adenocarcinoma cells, and further studied how hsa_circ_0084003 functioned in regulating pancreatic ductal adenocarcinoma cell aerobic glycolysis and epithelial-mesenchymal transition, and also evaluated the regulatingeffect of hsa_circ_0084003 on hsa-miR-143-3p and its target DNA methyltransferase 3A. Hsa_circ_0084003 knockdown could notably inhibit the aerobic glycolysis and epithelial-mesenchymal transition of pancreatic ductal adenocarcinoma cells. Mechanistically, hsa_circ_0084003 could regulate its downstream target DNA methyltransferase 3A by binding to hsa-miR-143-3p, and overexpression of hsa_circ_0084003 could reverse the anticarcinogenic effect of hsa-miR-143-3p on aerobic glycolysis and epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma cells. Hsa_circ_0084003, as a carcinogenic circular RNA, regulated its downstream target DNA methyltransferase 3A to promote pancreatic ductal adenocarcinoma cell aerobic glycolysis and epithelial-mesenchymal transition through sponging hsa-miR-143-3p. Therefore, hsa_circ_0084003 could be studied as a possible therapeutic target regarding pancreatic ductal adenocarcinoma.

LncRNA NORAD regulates the mechanism of the miR-532-3p/Nectin-4 axis in pancreatic cancer cell proliferation and angiogenesis.

Backgound: Pancreatic cancer (PC) is one of the deadliest cancers worldwide, and cell proliferation and angiogenesis play an important role in its occurrence and development. High levels of lncRNANORAD have been detected in many tumors, including PC, yet the effect and mechanism of lncRNA NORAD on PC cell angiogenesis are unexplored. Methods: qRT.PCR was applied to quantify lncRNA NORAD and miR-532-3p expression in PC cells, and a dual luciferase reporter gene was used to verify the targeting effects of NORAD, miR-532-3p and Nectin-4. Then, we regulated NORAD and miR-532-3p expression in PC cells and detected their effects on PC cell proliferation and angiogenesis using cloning experiments and HUVEC tube formation experiments. Results: LncRNA NORAD was upregulated and miR-532-3p was downregulated in PC cells compared with normal cells. Knockdown of NORAD inhibited PC cell proliferation and angiogenesis. LncRNA NORAD and miR-532-3p competitively bound to promote the expression of the miR-532-3p target gene Nectin-4, thereby promoting proliferation and angiogenesis of PC cells in vitro. Conclusion: LncRNA NORAD promotes the proliferation and angiogenesis of PC cells by regulating the miR-532-3p/Nectin-4 axis, which may be a potential biological target in the diagnosis and treatment of clinical PC.

Effects of genetic polymorphisms of LINC-PINT gene on liver cancer susceptibility in the Chinese Han population.

Objective: Liver cancer (LC) is the most common cause of cancer mortality. This study aimed to explore the impact of LINC-PINT polymorphisms on LC. Materials & methods: The authors recruited 591 LC patients and 592 healthy controls. The association between LINC-PINT polymorphisms and susceptibility to LC was determined by logistic regression analysis. Results: The authors found that rs157916 and rs16873842 reduced susceptibility to LC. rs157916 decreased LC risk in patients aged <55 years, nondrinkers and those with BMI <24. rs16873842 had a protective role against LC in patients aged ≥55 years, women, nonsmokers and those with BMI ≥24. rs7801029 decreased LC risk in patients with BMI <24. rs28662387 increased LC risk in women. Conclusion: LINC-PINT polymorphisms exert a protective effect against LC.

MiR-532-3p inhibited the methylation of SOCS2 to suppress the progression of PC by targeting DNMT3A.

Pancreatic cancer (PC) is one of the deadliest malignancies, with poor diagnosis and prognosis. miR-532-3p has been reported to be a tumor suppressor in various cancers, whereas the mechanism of miR-532-3p in the progression of PC remains poorly understood. In this study, it was found that miR-532-3p and SOCS2 were down-regulated, whereas DNMT3A was up-regulated in PC. Knockdown of DNMT3A or overexpression of miR-532-3p suppressed PC cell proliferation, invasion, and migration, as well as tumor formation in nude mice. DNMT3A induced the methylation of SOCS2 promoter. SOCS2 knockdown reversed the inhibiting effect of DNMT3A silencing on PC cell growth. miR-532-3p directly bound to DNMT3A and negatively regulated its expression while up-regulating SOCS2 levels. DNMT3A overexpression reversed the inhibiting effect of miR-532-3p overexpression on PC cell growth. In conclusion, the overexpression of miR-532-3p could suppress proliferation, invasion, and migration of PC cells, as well as tumor formation in nude mice through inhibiting the methylation of SOCS2 by targeting DNMT3A.

Contribution of PNPLA3 gene polymorphisms to hepatocellular carcinoma susceptibility in the Chinese Han population.

OBJECTIVES: The purpose of this study was to investigate the association of PNPLA3 single nucleotide polymorphisms (SNPs) (rs738409 C > G, rs3747207 G > A, rs4823173 G > A, and rs2896019 T > G) with hepatocellular carcinoma (HCC) susceptibility. METHODS: This case-control study included 484 HCC patients and 487 controls. Logistic regression analysis was performed to study the associations of PNPLA3 gene polymorphisms with HCC susceptibility, and odds ratios with their corresponding 95% confidence intervals were calculated to evaluate these correlations. RESULTS: In the overall analysis, we found that the G allele (OR = 1.25, 95% CI = 1.04-1.50, p = 0.018, false discovery rate (FDR)-p = 0.035) and GG genotype (OR = 1.59, 95% CI = 1.06-2.39, p = 0.024, FDR-p = 0.048) of rs2896019 were significantly associated with increased HCC susceptibility. In stratified analysis, we found that all four SNPs were related to increased HCC susceptibility in subjects aged > 55 years. In haplotype analysis, the GAAG haplotype was significantly associated with increased HCC susceptibility (OR = 1.25, 95% CI = 1.03-1.53, p = 0.023, FDR-p = 0.046). Besides, we noticed that rs738409 was significantly correlated with alpha-fetoprotein (AFP) (p = 0.007), and HCC patients with the GG genotype had a higher level of AFP. CONCLUSIONS: Our study suggested that PNPLA3-rs2896019 was significantly associated with an increased susceptibility to HCC.

Circular RNA Fibroblast Growth Factor Receptor 1 Promotes Pancreatic Cancer Progression by Targeting MicroRNA-532-3p/PIK3CB Axis.

OBJECTIVE: The aim of the study is to explore the contribution and mechanism of circular RNA fibroblast growth factor receptor 1 (circFGFR1) in pancreatic ductal adenocarcinoma (PDAC) progression. METHODS: Expressions of circFGFR1, microRNA (miR)-532-3p, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB) were assessed by quantitative real-time polymerase chain reaction or in situ hybridization. Fluorescence in situ hybridization determined the subcellular localization of circFGFR1. Immunohistochemistry was used to detect PIK3CB expression in PDAC tissues. Cell growth was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. Wound healing, transwell, and flow cytometry assays examined the migration, invasion, and apoptosis. Dual-luciferase and RNA pull-down assay verified the interactions between circFGFR1/PIK3CB and miR-532-3p. In vivo xenograft tumor growth and lung metastasis were assessed in nude mice. RESULTS: Functionally, knockdown of circFGFR1 restrained in vitro PDAC cell growth, migration, invasion, and in vivo xenograft tumor growth and lung metastasis. In addition, circFGFR1 could sponge miR-532-3p to upregulate PIK3CB level. Rescue experiments revealed that the tumor-suppressive effects caused by miR-532-3p mimics could be reversed by circFGFR1 or PIK3CB overexpression. CONCLUSIONS: Our data revealed that circFGFR1 driven the malignant progression of PDAC by targeting miR-532-3p/PIK3CB axis, suggesting that inhibition of circFGFR1 might be considered as a therapeutic target for PDAC.

Circular RNA Circ-STIL Contributes to Cell Growth and Metastasis in Hepatocellular Carcinoma via Regulating miR-345-5p/AQP3 Axis.

BACKGROUND: Circular RNAs (circRNAs) are implicated in the pathogenesis and development of hepatocellular carcinoma (HCC). However, the function and latent mechanism of circ-STIL in HCC have not been elucidated. AIMS: This study was designed to explore the precise role and underlying molecular mechanism of circ-STIL in HCC advancement. METHODS: The expression levels of circ-STIL, SCL/TAL1 interrupting locus (STIL), miR-345-5p and aquaporin-3 (AQP3) were measured by quantitative real-time polymerase chain reaction or western blot. Cell proliferation was assessed by 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide assay and colony formation assay. Cell apoptosis was analyzed by flow cytometry. Transwell assay was conducted to analyze cell migratory and invasive capacities. The interactions among circ-STIL, miR-345-5p and AQP3 were confirmed by dual-luciferase reporter and RNA immunoprecipitation assays. Xenograft tumor model was established to analyze the role of circ-STIL in HCC in vivo. RESULTS: Circ-STIL was upregulated in HCC tissues and cells. Circ-STIL knockdown inhibited HCC cell progression by reducing cell proliferation, migration and invasion and promoting cell apoptosis. MiR-345-5p was a direct target of circ-STIL, and AQP3 was targeted by miR-345-5p in HCC. Circ-STIL knockdown or miR-345-5p overexpression impeded cell malignant behaviors in HCC cells, and the effects could be reversed by miR-345-5p silence or AQP3 enhancement, respectively. Meanwhile, circ-STIL regulated AQP3 expression by sponging miR-345-5p. Besides, circ-STIL downregulation retarded HCC tumor growth in vivo. CONCLUSION: Circ-STIL knockdown suppressed HCC development by regulating miR-345-5p/AQP3 pathway, which might provide a promising target for HCC therapy.

Application of the Preoperative Assistant System Based on Machine Learning in Hepatocellular Carcinoma Resection.

To conduct better research in hepatocellular carcinoma resection, this paper used 3D machine learning and logistic regression algorithm to study the preoperative assistance of patients undergoing hepatectomy. In this study, the logistic regression model was analyzed to find the influencing factors for the survival and recurrence of patients. The clinical data of 50 HCC patients who underwent extensive hepatectomy (≥4 segments of the liver) admitted to our hospital from June 2020 to December 2020 were selected to calculate the liver volume, simulated surgical resection volume, residual liver volume, surgical margin, etc. The results showed that the simulated liver volume of 50 patients was 845.2 + 285.5 mL, and the actual liver volume of 50 patients was 826.3 ± 268.1 mL, and there was no significant difference between the two groups (t = 0.425; P > 0.05). Compared with the logistic regression model, the machine learning method has a better prediction effect, but the logistic regression model has better interpretability. The analysis of the relationship between the liver tumour and hepatic vessels in practical problems has specific clinical application value for accurately evaluating the volume of liver resection and surgical margin.