Mesothelin enhances invasion of ovarian cancer by inducing MMP-7 through MAPK/ERK and JNK pathways

Abstract

Ovarian cancer has one of the highest mortalities in malignancies in women, but little is known of its tumour progression properties and there is still no effective molecule that can monitor its growth or therapeutic responses. MSLN (mesothelin), a secreted protein that is overexpressed in ovarian cancer tissues with a poor clinical outcome, has been previously identified to activate PI3K (phosphoinositide 3-kinase)/Akt signalling and inhibit paclitaxel-induced apoptosis. The present study investigates the correlation between MSLN and MMP (matrix metalloproteinase)-7 in the progression of ovarian cancer, and the mechanism of MSLN in enhancing ovarian cancer invasion. The expression of MSLN correlated well with MMP-7 expression in human ovarian cancer tissues. Overexpressing MSLN or ovarian cancer cells treated with MSLN showed enhanced migration and invasion of cancer cells through the induction of MMP-7. MSLN regulated the expression of MMP-7 through the ERK (extracellular-signal-regulated kinase) 1/2, Akt and JNK (c-Jun N-terminal kinase) pathways. The expression of MMP-7 and the migrating ability of MSLN-treated ovarian cancer cells were suppressed by ERK1/2- or JNK-specific inhibitors, or a decoy AP-1 (activator protein 1) oligonucleotide in in vitro experiments, whereas in vivo animal experiments also demonstrated that mice treated with MAPK (mitogen-activated protein kinase)/ERK- or JNK-specific inhibitors could decrease intratumour MMP-7 expression, delay tumour growth and extend the survival of the mice. In conclusion, MSLN enhances ovarian cancer invasion by MMP-7 expression through the MAPK/ERK and JNK signal transduction pathways. Blocking the MSLN-related pathway could be a potential strategy for inhibiting the growth of ovarian cancer.

Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis

“…Despite extensive studies of human cancer cells, the functional properties of the MSLN/MUC16 signaling pathway remain poorly understood. MUC16 was identified as an MSLN ligand, and MSLN/MUC16 signaling was linked to AKT and ERK1/2 activation and was implicated in the metastatic growth and dissemination of cancer cells (46)(47)(48)(49). Like other GPI-anchored proteins, MSLN requires MUC16 and/or utilizes other receptors for intracellular signaling.…”

Mesothelin Promotes Invasion and Metastasis in Breast Cancer Cells

“…16 Additionally, mesothelin can regulate cancer cell invasion via the ERK1/2 signalling pathway, 14 and MMP-9 is regulated by ERK1/2 in human breast cancer cells. 17 Mesothelin may, therefore, enhance invasion of breast cancer cells through ERK/MMP-9 pathways.…”

Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody–Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect

“…Mesothelin is known to bind to CA125 (cancer antigen 125, also known as MUC16), and this interaction may be involved in the metastatic spread of CA125-expressing ovarian cancer cells that bind to mesothelinexpressing cells lining the peritoneal cavity (11,12). Mesothelin may further contribute to metastasis by inducing the expression of matrix metalloproteinases 7 and 9 (13,14). In pancreatic cancer cells, mesothelin has been shown to contribute to tumorigenesis by inducing interleukin-6 expression and cell proliferation and by promoting resistance to TNF-a (15,16).…”