The VHL tumor suppressor gene is frequently inactivated in several human tumors, including bone sarcomas. We previously identified that reduced expression of VHL protein is implicated in sarcomagenesis. However, the underlying biological functions of restored VHL protein expression have not been clearly elucidated in bone sarcomas. Here we initially constructed a recombinant adenovirus 5-VHL vector (Ad5-VHL) and evaluated its expression in bone sarcomas, and antitumor activity in vitro and in vivo. We found that the adenovirus-mediated increase of VHL significantly suppresses bone sarcoma cell growth, attributed to induction of apoptosis mediated by increased caspase-3 activity and modulated Bcl-2 protein family. This suppression effect involves inhibition of Wnt/β-catenin signaling and upregulation of GSK-3β. Moreover, Ad5-VHL showed a dramatic antitumor effect on a chondrosarcoma xenograft model. These findings establish that Ad5-VHL suppresses bone sarcoma cell growth by inhibiting Wnt/β-catenin signaling, and may be a novel target for gene-based therapy of bone sarcomas.

中文翻译：

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VHL的腺病毒传递通过抑制Wnt /β-catenin信号传导来抑制骨肉瘤细胞的生长。

VHL抑癌基因经常在几种人类肿瘤（包括骨肉瘤）中失活。我们先前确定，VHL蛋白的表达降低与肉瘤的发生有关。然而，尚未在骨肉瘤中清楚地阐明了恢​​复的VHL蛋白表达的潜在生物学功能。在这里，我们最初构建了重组腺病毒5-VHL载体（Ad5-VHL），并评估了其在骨肉瘤中的表达以及在体内外的抗肿瘤活性。我们发现，腺病毒介导的VHL的增加显着抑制了骨肉瘤细胞的生长，这归因于caspase-3活性增加和Bcl-2蛋白家族调节介导的凋亡诱导。该抑制作用涉及抑制Wnt /β-连环蛋白信号传导和上调GSK-3β。而且，Ad5-VHL对软骨肉瘤异种移植模型显示出显着的抗肿瘤作用。这些发现证实，Ad5-VHL通过抑制Wnt /β-catenin信号传导抑制骨肉瘤细胞的生长，并且可能成为基于基因治疗骨肉瘤的新靶标。