ABSTRACT
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief and Authors. Following concerns raised in the public domain, the authors contacted the journal to request the retraction of the article. Sections of panels from various figures appear similar to each other, particularly panels from Figs. 3G, 5B and 3G and 5F, 3F, S4D, S5D, S5C and S10C, as well as S10E.
ABSTRACT
Perineural invasion (PNI) is a typical pathological feature of pancreatic ductal adenocarcinoma (PDAC). PNI is associated with poor prognosis of PDAC patients, however, the underlying molecular mechanisms in the development of PNI have not been fully revealed. In this study, we found that the expression of GM-CSF and HIF-1α were dramatically increased in PDAC cells. The overexpression of HIF-1α and GM-CSF closely correlated with increased occurrence of PNI and cancer-related pain and shortened overall survival in PDAC patients. GM-CSF expression in PDAC cells was mediated by HIF-1α through direct binding to the hypoxia response element in the GM-CSF promoter. The activated HIF-1α can up-regulate GM-CSF expression and secretion, which promoted the migration of Schwann cells in tumor microenvironment. Furthermore, GM-CSF overexpression could rescue the inhibition of Schwann cells migration by HIF-1α knockdown. Moreover, HIF-1α inhibition with PX478 drastically reduced the expression level of GM-CSF and decreased the PNI in a PDAC xenograft mouse model. Overall, our results demonstrated that the HIF-1α/GM-CSF pathway is involved in the tumor-nerve interactions and promotes the occurrence of PNI. The blockade of this signal might help to inhibit PDAC progression.
Subject(s)
Carcinoma, Pancreatic Ductal/pathology , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Pancreatic Neoplasms/pathology , Schwann Cells/pathology , Adult , Aged , Animals , Carcinoma, Pancreatic Ductal/metabolism , Cell Line, Tumor , Cell Movement/physiology , Female , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Male , Mice , Mice, Nude , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Pancreatic Neoplasms/metabolism , Peripheral Nerves/pathology , Schwann Cells/metabolism , Up-RegulationABSTRACT
The aim of the present study was to screen the potential osteosarcoma (OS)associated genes and to obtain additional insight into the pathogenesis of OS. Transcriptional profile (ID: GSE28256) and copy number variations (CNV) profile were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) between MET protooncogenetransformed human primary osteoblast (METHOB) samples and the control samples were identified using the Linear Models for Microarray Data package. Subsequently, CNV areas and CNVs were identified using cutoff criterion of >30%overlap within the cases using detect_cnv.pl in PennCNV. Genes shared in DEGs and CNVs were obtained and discussed. Additionally, the Database for Annotation, Visualization and Integrated Discovery was used to identify significant Gene Ontology (GO) functions and pathways in DEGs with P<0.05. A total of 1,601 DEGs were screened out in METHOBs and compared with control samples, including 784 upregulated genes, such as E2F transcription factor 1 (E2F1) and 2 (E2F2) and 817 downregulated genes, such as retinoblastoma 1 (RB1) and cyclin D1 (CCND1). DEGs were enriched in 344 GO terms, such as extracellular region part and extracellular matrix and 14 pathways, including pathways in cancer and extracellular matrixreceptor interaction. Additionally, 239 duplications and 439 deletions in 678 genes from 1,313 chromosome regions were detected. A total of 12 genes were identified to be CNVdriven genes, including cadherin 18, laminin subunit α 1, spectrin ß, erythrocytic, ciliary rootlet coiledcoil, rootletin pseudogene 2, ß1,4-N-acetyl-galactosaminyltransferase 1, G protein regulated inducer of neurite outgrowth 1, EH domain binding protein 1like 1, growth factor independent 1, cathepsin Z, WNK lysine deficient protein kinase 1, glutathione Stransferase mu 2 and microsomal glutathione Stransferase 1. Therefore, cell cycleassociated genes including E2F1, E2F2, RB1 and CCND1, and cell adhesionassociated genes, such as CDH18 and LAMA1 may be used as diagnosis and/or therapeutic markers for patients with OS.