Circular RNA ADAM9 facilitates the malignant behaviours of pancreatic cancer by sponging miR-217 and upregulating PRSS3 expression

Abstract

Pancreatic cancer (PC) is a highly lethal human cancer. We previously found that Serine protease 3 (PRSS3), as an oncogene, is significantly upregulated in PC. In this study, we aimed to investigate the potential mechanism of PRSS3 dysregulation in PC. In this research, low miR-217 and high circ-ADAM9 expression were found in PC tissues and cell lines, which was closely associated with advanced clinical stage and lymph node metastasis. Patients with low miR-217 or high circ-ADAM9 expression had shorter survival time than those with high miR-217 or low circ-ADAM9 expression. Functionally, manipulation of miR-217 and circ-ADAM9 expression showed opposite effects on cell proliferation, migration and invasion. Stepwise mechanism studies indicated that circ-ADAM9 alleviated the inhibitory effect of miR-217 on PRSS3 by directly sponging miR-217 to increase the expression level of PRSS3, resulting in the activation of ERK/VEGF signalling pathway. In vivo, circ-ADAM9 silencing or miR-217 overexpression evidently retarded the growth of tumour, and the combination of them exhibited an additive inhibitory effect on tumourigenicity. Briefly, the ceRNA regulatory network of circ-ADAM9/ miR-217/PRSS3 plays a pivotal role in PC progression by the regulation of ERK/VEGF signalling pathway.

Current State of “Omics” Biomarkers in Pancreatic Cancer

“…Successfully accomplishing multi-omics data integration by systems biology approaches will fulfill future expectations and the need for robust, accurate, and feasible biomarker panels for pancreatic cancer. [166] Tumor tissue hsa_circ_0006215 Upregulated circRNA overexpression [167] Tumor tissue, plasma exosome circ-IARS Upregulated circRNA overexpression [168] Tumor tissue circ-PDE8A Upregulated circRNA overexpression [169] Tumor tissue/cell hsa_circ_0001649 Downregulated Microarray/qRT-PCR [170] Tumor tissue/cell hsa_circ_0005397 (circ-RHOT1) Upregulated Microarray/qRT-PCR [171] Tumor tissue/cell lines hsa_circ_0030235 Upregulated circRNA overexpression [172] Tumor tissue/cell lines hsa_circ_0007534 Upregulated circRNA overexpression [173] Tumor tissue/cell lines ciRS-7 (Cdr1as) Upregulated qRT-PCR [174] Tumor tissue hsa_circ_0007334 Upregulated Microarray/qRT-PCR [175] Tumor tissue circLDLRAD3 Upregulated circRNA knockdown [176] Tumor tissue/cell circASH2L Upregulated Microarray/qRT-PCR [177] Tumor tissue/cell lines circADAM9 Upregulated circRNA knockdown [178] Tumor tissue/cell hsa_circ_001653 Upregulated circRNA knockdown [179] Tumor tissue/cell circHIPK3 Upregulated circRNA knockdown [180] Tumor tissue/cell circFOXK2 Upregulated circRNA knockdown [181] Tumor tissue hsa_circ_0009065 (circBFAR) Upregulated circRNA overexpression [70] Tumor tissue hsa_circ_0086375 (circNFIB1) Downregulated circRNA knockdown [182] Tumor tissue/cell hsa_circ_0013912 Upregulated circRNA overexpression [183] Tumor tissue/cell lines hsa_circ_001587 Downregulated circRNA knockdown [184] Tumor [194] Tumor tissue BC008363 Upregulated Microarray/qRT-PCR [195] Tumor tissue HSATII Upregulated RNA-seq [196] Serum/plasma U2snRNA Upregulated Microarray/qRT-PCR [197] Pancreatic * CZE: capillary zone electrophoresis, ELISA: enzyme-linked immunosorbent assay, ELLA: Enzyme-linked lectin assay, FISH: fluorescence in situ hybridization, GC: gas chromatography, HILIC: Hydrophilic interaction chromatography, HRMAS: high-resolution magic angle spinning, LC: liquid chromatography, MS: mass spectrometry, NMR: nuclear magnetic resonance, qRT-PCR: quantitative reverse transcription polymerase chain reaction, TOF: time of flight, WB: Western blot, WES: Whole exome sequencing, WGS: whole genome ...…”

An Overview of ADAM9: Structure, Activation, and Regulation in Human Diseases

“…Circ-ADAM9 absorbs and inhibits miR-127, which is a tumor suppressor. Overexpressing circ-ADAM9 increases ERK signaling to promote cell proliferation and migration in vitro, and silencing circ-ADAM9 delays pancreatic tumor growth in vivo [ 88 ].…”

Circ_0075829 facilitates the progression of pancreatic carcinoma by sponging miR‐1287‐5p and activating LAMTOR3 signalling

“…8 In recent years, emerging evidence shows that dysregulated circRNAs could disturb the balance of ceRNA network, and further promote the tumorigenesis of different cancers, including PC. 9 For example, circ_0061825 facilitates breast cancer progression through targeting miR-326 and the signal path of its host gene TFF1. 10 And, circ-ASH2L is proved to facilitate tumour progression by sponging miR-34a and affecting the expression of Notch1 in PC.…”

“…Initially considered as the by‐products of splicing, 7 circRNAs have been found to play a series of important biological roles such as competing endogenous RNAs (ceRNAs) via sponging microRNAs (miRNAs), protein/peptide transcripts, gene transcription and RNA splicing factors 8 . In recent years, emerging evidence shows that dysregulated circRNAs could disturb the balance of ceRNA network, and further promote the tumorigenesis of different cancers, including PC 9 . For example, circ_0061825 facilitates breast cancer progression through targeting miR‐326 and the signal path of its host gene TFF1 10 .…”