JAG1, Regulated by microRNA-424-3p, Involved in Tumorigenesis and Epithelial-Mesenchymal Transition of High Proliferative Potential-Pituitary Adenomas.

Yiyuan Chen,Sen Cheng,Weiyan Xie,Hua Gao,Bin Li,Qiuyue Fang,Chuzhong Li,Jie Feng,Jianhua Cheng,Yazhuo Zhang

doi:10.3389/fonc.2020.567021

Abstract

Pituitary adenomas (PAs) are a neoplastic proliferation of anterior pituitary. Signature of Notch pathway relies upon the histopathological type of PAs. The details of Notch pathway that are involved in the migration and invasion of Pas are still unclear. This paper filters and testifies the relation between Notch signaling pathway and the migration/invasion in subtypes of PAs. The diversity of genes and pathways is investigated based on transcriptome data of 60 patients by KEGG pathway analysis and GSEA. A series of functional experiments demonstrate the role of candidate genes by overexpression and antibody blocking in GH3 cell line. Volcano map and GSEA results exhibit the differential and the priority of Jagged1 canonical Notch Ligand (JAG1) in the Notch pathway combined with clinical features. JAG1 is involved in epithelial–mesenchymal transition (EMT) in PAs by correlation analysis of RNA-seq data. Progression-free survival (PFS) of patients with high JAG1 was shorter than patients with low JAG1 according to follow-up data (P = 0.006). Furthermore, overexpression and antibody blocking experiments in GH3 cell line indicate that JAG1 could promote cell proliferation, migration, and G1/S transition. Double luciferase reporter assay gives manifests that JAG1 is the target gene of miR-424-3p, and mimics or inhibitor of miR-424-3p can regulate the level of JAG1 which, in turn, affects cell proliferation and the levels of MMP2 and VIM in GH3 cell line, respectively. Our study delves into the relation between the Notch signaling pathway and cell proliferation and EMT in PAs, providing a potential treatment through targeting JAG1.

Highlights

Pituitary adenoma is a neoplastic proliferation of anterior pituitary and accounts for 10–15% of intracranial tumors (1)
This paper examines the priority of JAG1 in Notch signaling pathway and verifies its functions that provide potential molecular therapeutics for future therapy
According to Five-Tiered prognostic classification of PitNETs, patients were identified into two phenotypes: 30 non-proliferative (1/2a) and 30 proliferative (1/ 2b); 32 non-invasive (1a/b) and 28 invasive (2a/b)

Summary

Introduction

Pituitary adenoma is a neoplastic proliferation of anterior pituitary and accounts for 10–15% of intracranial tumors (1). Except for lactotroph adenomas, the initial therapy for patients with PAs is generally transsphenoidal surgery, while medical therapy is being reserved for those with unfavorable surgical outcome (2). The diagnosis of invasion is mainly based on adenomas extent and invasion of adjacent anatomic structures, especially Knosp staging. In 2013, Trouillas et al depicted the Five-Tiered prognostic classification of PitNETs including tumor diameter, tumor type, and grading that was based on invasion and proliferation (5, 6). Most commonly utilized molecular markers of proliferation categories (PitNETs: 1/2a, 1/2b) are: 1) Ki67 index: >3%; 2) mitoses count: n >2/10 high power field (HPF), 3) p53 detection positive (10 strongly positive nuclei/10HPF) (7). Pituitary tumor-transforming gene 1 (PTTG1) and c-Myc play important roles in early pituitary tumorigenesis (8). The mechanism of different proliferation categories is still unclear

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Conclusion