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Abstract
BackgroundOsteopontin (OPN) is a secreted phosphoprotein expressed by neoplastic cells involved in the malignant potential and aggressive phenotypes of human malignancies, including gastrointestinal stromal tumors (GISTs). Our previous study showed that OPN can promote tumor cell proliferation in GISTs. In this series, we further aim to investigate the effect of OPN on apoptosis in GISTs.MethodsThe expression of apoptotic and anti-apoptotic proteins in response to OPN was evaluated. In vitro effects of OPN against apoptosis in GIST were also assessed. GIST specimens were also used for analyzing protein expression of specific apoptosis-related molecules and their clinicopathologic significance.ResultsUp-regulation of β-catenin and anti-apoptotic proteins Mcl-1 with concomitant suppression of apoptotic proteins in response to OPN was noted. A significant anti-apoptotic effect of OPN on imatinib-induced apoptosis was identified. Furthermore, Mcl-1 overexpression was significantly associated with OPN and β-catenin expression in tumor tissues, as well as worse survival clinically.ConclusionsOur study identifies anti-apoptotic effects of OPN that, through β-catenin-mediated Mcl-1 up-regulation, significantly antagonized imatinib-induced apoptosis in GISTs. These results provide a potential rationale for therapeutic strategies targeting both OPN and Mcl-1 of the same anti-apoptotic signaling pathway, which may account for resistance to imatinib in GISTs.
Highlights
Osteopontin (OPN) is a secreted phosphoprotein expressed by neoplastic cells involved in the malignant potential and aggressive phenotypes of human malignancies, including gastrointestinal stromal tumors (GISTs)
Since tumor cell proliferation and apoptosis are closely related and usually coexisting hallmark features characteristic of cancer cells, including GIST, and since we have identified the effect of OPN on promoting tumor proliferation in GIST, we further hypothesize that OPN may play a role in the regulation of apoptosis in GIST
Similar effects of OPN in promoting the expression of β-catenin and Mcl-1 were noted in imatinib-resistant GIST48B and GIST62
Summary
Osteopontin (OPN) is a secreted phosphoprotein expressed by neoplastic cells involved in the malignant potential and aggressive phenotypes of human malignancies, including gastrointestinal stromal tumors (GISTs). It is important to identify the mechanisms underlying imatinib-resistance so that therapeutic interventions can be developed and applied to this particular GIST patient group. Osteopontin (OPN), initially termed Eta-1, standing for early T cell activation gene 1, or spp, abbreviated from secreted phosphoprotein 1, was originally identified as a secreted protein from transformed mammalian cells [8,9]. OPN, being frequently overexpressed in miscellaneous tumor cell types, plays important roles in their malignant potential and aggressiveness, including tumor growth, invasion, metastasis, survival, angiogenesis, and tumorigenesis [12,13,14]
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