Hsu Kai-Hsi, Tsai Hung-Wen, Lin Pin-Wen, Hsu Yun-Shang, Lu Pei-Jung, Shan Yan-Shen
Department of Surgery, National Cheng Kung University, College of Medicine, Tainan 70428, Taiwan.
World J Surg Oncol. 2014 Jun 20;12:189. doi: 10.1186/1477-7819-12-189.
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). 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.
The 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.
Up-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.
Our 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.
骨桥蛋白（OPN）是一种分泌型磷蛋白，由参与人类恶性肿瘤（包括胃肠道间质瘤，GISTs）恶性潜能和侵袭性表型的肿瘤细胞表达。我们之前的研究表明，OPN可促进GISTs中的肿瘤细胞增殖。在本系列研究中，我们进一步旨在探究OPN对GISTs细胞凋亡的影响。
评估了响应OPN时凋亡蛋白和抗凋亡蛋白的表达。还评估了OPN对GISTs细胞凋亡的体外作用。GISTs标本也用于分析特定凋亡相关分子的蛋白表达及其临床病理意义。
发现响应OPN时，β-连环蛋白和抗凋亡蛋白Mcl-1上调，同时凋亡蛋白受到抑制。确定了OPN对伊马替尼诱导的凋亡具有显著的抗凋亡作用。此外，Mcl-1过表达与肿瘤组织中OPN和β-连环蛋白的表达显著相关，且临床生存率较差。
我们的研究确定了OPN的抗凋亡作用，即通过β-连环蛋白介导的Mcl-1上调，显著拮抗伊马替尼诱导的GISTs细胞凋亡。这些结果为针对同一抗凋亡信号通路中的OPN和Mcl-1的治疗策略提供了潜在的理论依据，这可能是GISTs对伊马替尼耐药的原因。
