The cytomegalovirus protein UL138 induces apoptosis of gastric cancer cells by binding to heat shock protein 70.
The cytomegalovirus protein UL138 induces apoptosis of gastric cancer cells by binding to heat shock protein 70.
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巨细胞病毒蛋白UL138通过与热休克蛋白70结合诱导胃癌细胞凋亡
DOI：
10.18632/oncotarget.6800
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发表时间：
2016-02-02
期刊：
影响因子：
--
通讯作者：
Xue X
中科院分区：
文献类型：
--
作者：
Chen W;Lin K;Zhang L;Guo G;Sun X;Chen J;Ye L;Ye S;Mao C;Xu J;Zhang L;Jiang L;Shen X;Xue X
人巨细胞病毒（HCMV）可能作为一种肿瘤促进因子，在多种人类恶性肿瘤的发生发展过程中发挥“肿瘤调节”作用。然而，我们首次证明了HCMV潜伏相关基因UL 138可以作为胃癌（GC）的肿瘤抑制剂。在HCMV阳性的胃腺癌组织中，UL 138的表达下调，尤其是在低分化或无分化的肿瘤中。UL 138在几种人GC细胞系中的过表达抑制细胞活力并诱导细胞凋亡，与抗细胞凋亡Bcl-2蛋白的减少和裂解的半胱天冬酶-3和半胱天冬酶-9的诱导相关。此外，蛋白质阵列分析显示，UL 138与伴侣蛋白，热休克蛋白70（HSP 70）相互作用。这种相互作用通过GC细胞系中的原位免疫沉淀和免疫染色来证实。此外，这种UL 138介导的癌细胞死亡可以有效地抑制GC异种移植动物模型中的人肿瘤生长。总之，这些结果揭示了巨细胞病毒蛋白UL 138在诱导GC细胞凋亡中的一个先前未知的作用，这可能意味着病毒蛋白在与伴侣蛋白和凋亡相关蛋白的相互作用中抑制癌症生长的一般机制。我们的研究结果可能为GC治疗的新治疗策略提供潜在目标。
It has been hypothesized that human cytomegalovirus (HCMV) could act as a tumor promoter and play an “oncomodulatory” role in the neoplastic process of several human malignancies. However, we demonstrate for the first time that UL138, a HCMV latency-associated gene, could act as a tumor inhibitor in gastric cancer (GC). The expression of UL138 is down-regulated in HCMV positive gastric adenocarcinoma tissues, especially in poorly or none differentiated tumors. Overexpression of UL138 in several human GC cell lines inhibits cell viability and induces apoptosis, in association with the reduction of an anti-apoptotic Bcl-2 protein and the induction of cleaved caspase-3 and caspase-9. Moreover, protein array analysis reveals that UL138 interacts with a chaperone protein, heat shock protein 70 (HSP70). This interaction is confirmed by immunoprecipitation and immunostaining in situ in GC cell lines. In addition, this UL138-mediated cancer cell death could efficiently lead to suppression of human tumor growth in a xenograft animal model of GC. In conclusion, these results uncover a previously unknown role of the cytomegalovirus protein UL138 in inducing GC cells apoptosis, which might imply a general mechanism that viral proteins inhibit cancer growth in interactions with both chaperones and apoptosis-related proteins. Our findings might provide a potential target for new therapeutic strategies of GC treatment.