Background: Gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) is a rare heterogeneous tumor. Liver metastasis seriously affects the prognosis of GEP-NEN. However, few tools are existed to predict GEP-NEN complicated with synchronous liver metastasis. Aims: To analyze the risk factors of synchronous liver metastasis in patients with GEP-NEN and establish a nomogram to predict synchronous liver metastasis in patients with GEP-NEN. Methods: A total of 10 973 pathologically confirmed patients with GEP-NEN from Jan. 2010 to Dec. 2017 were collected from SEER database and divided randomly into training set (n=7 511) and test set (n=3 462). Both groups were divided into liver metastasis group and non-liver metastasis group according to the occurrence of liver metastasis. Multifactorical logistic regression analysis was used to identify the risk factors of liver metastasis in patients with GEP-NEN. R software was used to establish and verify the nomogram of liver metastasis in GEP-NEN patients. Results: Liver metastasis was associated with gender, age, race, primary tumor site, degree of differentiation, tumor diameter, T3/4 stage, and lymph node metastasis in patients with GEP-NEN. The results of multivariate logistic regression analysis showed that primary tumor site (small intestine and pancreas), differentiation degree (poorly differentiated and undifferentiated), diameter of tumor ≥ 5 cm, T3/4 stage and lymph node metastasis were independent risk factors affecting liver metastasis in patients with GEP-NEN (P< 0.001). The concordance index of internal validation for nomogram was 0.838 (95% CI: 0.826-0.849), and the concordance index of external validation was 0.847 (95% CI: 0.829-0.864). Conclusions: GEP-NEN patients with primary tumor site in small intestine or pancreas, poor differentiation and undifferentiation, diameter of tumor ≥5 cm, T3/4 stage and lymph node metastasis are more likely to develop liver metastasis which suggested that such patients need to be alert for the occurrence of liver metastasis and need more aggressive treatment. The calibration curves fits are good for both the training and test sets, and can help clinicians to make individualized prediction for whether the GEP-NEN patient has synchronous liver metastasis at the initial diagnosis.

BACKGROUND: Angiogenesis is described as a complex process in which new microvessels sprout from endothelial cells of existing vasculature. This study aimed to determine whether long non-coding RNA (lncRNA) H19 induced the angiogenesis of gastric cancer (GC) and its possible mechanism. METHODS: Gene expression level was determined by quantitative real-time polymerase chain reaction and western blotting. Cell counting kit-8, transwell, 5-Ethynyl-2'-deoxyuridine (EdU), colony formation assay, and human umbilical vein endothelial cells (HUVECs) angiogenesis assay as well as Matrigel plug assay were conducted to study the proliferation, migration, and angiogenesis of GC in vitro and in vivo . The binding protein of H19 was found by RNA pull-down and RNA Immunoprecipitation (RIP). High-throughput sequencing was performed and next Gene Ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to analyze the genes that are under H19 regulation. Methylated RIP (me-RIP) assay was used to investigate the sites and abundance among target mRNA. The transcription factor acted as upstream of H19 was determined through chromatin immunoprecipitation (ChIP) and luciferase assay. RESULTS: In this study, we found that hypoxia-induced factor (HIF)-1α could bind to the promoter region of H19, leading to H19 overexpression. High expression of H19 was correlated with angiogenesis in GC, and H19 knocking down could inhibit cell proliferation, migration and angiogenesis. Mechanistically, the oncogenic role of H19 was achieved by binding with the N 6 -methyladenosine (m 6 A) reader YTH domain-containing family protein 1 (YTHDF1), which could recognize the m 6 A site on the 3'-untransated regions (3'-UTR) of scavenger receptor class B member 1 (SCARB1) mRNA, resulting in over-translation of SCARB1 and thus promoting the proliferation, migration, and angiogenesis of GC cells. CONCLUSION HIF-1α induced overexpression of H19 via binding with the promoter of H19, and H19 promoted GC cells proliferation, migration and angiogenesis through YTHDF1/SCARB1, which might be a beneficial target for antiangiogenic therapy for GC.
Humans ; Cell Line, Tumor ; Cell Proliferation/genetics* ; Endothelial Cells/metabolism* ; Gene Expression Regulation ; Gene Expression Regulation, Neoplastic/genetics* ; Hypoxia ; MicroRNAs/genetics* ; RNA ; RNA, Long Noncoding/metabolism* ; RNA-Binding Proteins/metabolism* ; Scavenger Receptors, Class B/metabolism* ; Stomach Neoplasms/genetics*