In mice bearing orthotopical xenografts with HCCLM6, OPN inhibition following therapeutic treatment with OPN ASO significantly decreased lung metastases although tumor weight did not appear to be reduced.
The Ht2 and -443TT genotype could significantly increase the promoter transcriptional activity and expression level of OPN compared with the Ht3 or -443CC genotype, and lead to an obvious increase in both in vitro invasion and in vivo tumor growth and lung metastasis of HCC cells (P<0.05).
Notably, inhibition of fibroblast osteopontin with low doses of a novel small molecule prevents lung metastasis in a mouse model of human breast cancer metastasis.
Intravenous injection of recombinant OPN restored the lung metastasis of OPN-deficient 4T1 cells, suggesting that OPN functioned in a paracrine manner.
Oppositely, tumor-originated intracellular osteopontin promoted tumor cell survival by preventing tumor-related protein 53-mediated apoptosis, while the secretory osteopontin functioned in a paracrine mode to accelerate lung metastasis by enhancing tumor-derived C-C-motif chemokine ligand 2 signaling to cognate host receptors.
Mechanically, CD44v, but not CD44s, responds to osteopontin (OPN) in the lung environment to enhance cancer cell invasiveness and promote lung metastasis.
Plumbagin reduces osteopontin-induced invasion through inhibiting the Rho-associated kinase signaling pathway in A549 cells and suppresses osteopontin-induced lung metastasis in BalB/c mice.
We show that JNK signaling enhances expression of the ECM and stem cell niche components osteopontin, also called secreted phosphoprotein 1 (SPP1), and tenascin C (TNC), that promote lung metastasis.