The Notch ligand Jagged2 promotes lung adenocarcinoma metastasis through a miR-200–dependent pathway in mice

Abstract

Epithelial tumor cells transit to a mesenchymal state in response to extracellular cues, in a process known as epithelial-to-mesenchymal transition (EMT). The precise nature of these cues has not been fully defined, an important issue given that EMT is an early event in tumor metastasis. Here, we have found that a population of metastasis-prone mouse lung adenocarcinoma cells expresses Notch and Notch ligands and that the Notch ligand Jagged2 promotes metastasis. Mechanistically, Jagged2 was found to promote metastasis by increasing the expression of GATA-binding ( IntroductionLung cancer is the foremost cause of cancer-related death in Western countries, and metastasis is the leading cause of death in patients with lung cancer. Improving clinical outcomes will require a better understanding of the biological processes that initiate metastasis. Toward that goal, mouse models have been generated that develop lung adenocarcinomas with high or low propensities for invasion and metastasis. Mice that express K-ras G12D alleles inducibly, conditionally, or somatically develop lung adenocarcinomas with low invasive and metastatic potential (1-5), whereas mice that express K-ras G12D and p53 R172H alleles develop lung adenocarcinomas that metastasize widely (6-9). Thus, K-ras-driven mouse models of lung cancer acquire metastatic potential with the addition of a second mutation commonly found in lung cancer.Investigators have used mouse models of cancer to study the biological basis of metastasis. In one working hypothesis, epithelial tumor cells acquire the ability to invade and disseminate by undergoing epithelial-to-mesenchymal transition (EMT), which is characterized by a loss of cell-cell attachments and apical-basal polarization and gain of mesenchymal and invasive properties (10-19). The process of EMT is regulated by several transcriptional suppressor families, including the zinc-finger proteins Snail1 and Snail2, the 2-handed zinc-finger δEF1 family factors

Jagged 2 silencing inhibits motility and invasiveness of colorectal cancer cell lines

“…In breast cancer, JAG2 A B expression was found to promote metastasis and was significantly associated with overall and metastasis-free survival of breast cancer patients (11,19). Likewise, JAG2 was found to be capable of inducing the metastasis of lung adenocarcinoma cells in mice (20). These findings provide support to the hypothesis that JAG2 functions to promote metastasis in multiple cancer types.…”

MicroRNA-19 triggers epithelial–mesenchymal transition of lung cancer cells accompanied by growth inhibition

“…[37][38][39][40][41] For e.g., let-7, miR-30a, miR-125a-5p, miR-126, miR-183, miR-200, miR-21, miR-221, miR-222, and miR-328 have important roles in EMT, invasion, and metastasis of lung cancer. [42][43][44][45][46][47] In this study, we found that enforced expression of miR-19 (i.e., miR-19a and miR-19b-1) in lung cancer cells A549 and HCC827 cells triggered EMT, as shown by mesenchymal-like morphological changes, downregulation of epithelial proteins (e.g., E-cadherin, ZO-1, and α-catenin), upregulation of mesenchymal proteins (e.g., vimentin, FN1, N-cadherin, or snail1), formation of stress fibers, reduced cell adhesion, and enhanced cell migration and invasion. In addition, DNA microarray results also highlighted the expression of genes involved in EMT, migration, and metastasis in miR-19-expressing A549 cells.…”

The NOTCH Ligand JAGGED2 Promotes Pancreatic Cancer Metastasis Independent of NOTCH Signaling Activation

“…JAGGED2, highly expressed in PDAC cells (3,4), has been linked to metastasis of epithelial-derived tumors such as lung cancer (5), breast cancer (6), colon cancer (7), and urothelial carcinoma of bladder (8). Although the precise mechanism is not fully determined, it is generally believed through NOTCH signaling activation.…”