Batra Sonny, Shi Yihui, Kuchenbecker Kristopher M, He Biao, Reguart Noemi, Mikami Iwao, You Liang, Xu Zhidong, Lin Yu-Ching, Clément Geneviève, Jablons David M
Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Biochem Biophys Res Commun. 2006 Apr 21;342(4):1228-32. doi: 10.1016/j.bbrc.2006.02.084. Epub 2006 Feb 24.
Wnt inhibitory factor-1 (WIF-1) is a secreted protein that antagonizes Wnt signaling. We recently demonstrated the importance of aberrant activation of the Wnt signaling pathway in various cancers including malignant pleural mesothelioma. In this study, we revealed downregulated WIF-1 expression in cell lines and primary tissue when compared to normal mesothelial cell lines and adjacent pleura, respectively. We observed hypermethylation in four of four mesothelioma cell lines, but not in two normal mesothelial cell lines. In primary tissue samples, we observed methylation in three paired tumor specimens compared to their adjacent normal pleura and methylation in eight of nine unpaired tumor tissue samples. Taken together, our studies suggest that WIF-1 silencing due to its promoter hypermethylation is an important mechanism underlying the constitutively activated Wnt signaling in mesothelioma. New therapies toward inhibition of the Wnt pathway through WIF-1 might be promising for the future treatment of malignant mesothelioma.
Wnt抑制因子-1（WIF-1）是一种可拮抗Wnt信号传导的分泌蛋白。我们最近证明了Wnt信号通路异常激活在包括恶性胸膜间皮瘤在内的各种癌症中的重要性。在本研究中，我们发现与正常间皮细胞系和相邻胸膜相比，细胞系和原发组织中WIF-1表达下调。我们在四个间皮瘤细胞系中均观察到高甲基化，而在两个正常间皮细胞系中未观察到。在原发组织样本中，与相邻正常胸膜相比，我们在三个配对肿瘤标本中观察到甲基化，在九个非配对肿瘤组织样本中的八个中观察到甲基化。综上所述，我们的研究表明，由于其启动子高甲基化导致的WIF-1沉默是间皮瘤中Wnt信号持续激活的重要机制。通过WIF-1抑制Wnt通路的新疗法可能对恶性间皮瘤的未来治疗具有前景。
