TIPE1 induces apoptosis by negatively regulating Rac1 activation in hepatocellular carcinoma cells
TIPE1 induces apoptosis by negatively regulating Rac1 activation in hepatocellular carcinoma cells
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TIPE1通过负调控Rac1激活诱导肝癌细胞凋亡
DOI：
10.1038/onc.2014.208
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发表时间：
2015-05-14
期刊：
影响因子：
8
通讯作者：
Ma, C.
中科院分区：
文献类型：
--
作者：
Zhang, Z.;Liang, X.;Ma, C.
TIPE1 （tumor necrosis factor- α -induced protein 8-like 1或TNFAIP8L1）是新发现的TIPE （TNFAIP8）家族成员，在调节细胞死亡中发挥作用。然而，TIPE1在生理和病理条件下的生物学功能在很大程度上是未知的。在这里，我们报道了TIPE1在肝细胞癌（HCC）中的作用。免疫组化染色结果显示，HCC组织中TIPE1表达水平较癌旁非肿瘤组织明显下调，与肿瘤病理分级及患者生存呈正相关。通过Balb/c小鼠同种移植物肿瘤模型，我们发现TIPE1显著降低小鼠肝癌同种移植物的生长和肿瘤重量。与此一致的是，TIPE1抑制培养的HCC细胞系的细胞生长和集落形成能力，进一步确定这是由于TIPE1以caspase不依赖的、坏死他汀-1 （nec1）不敏感的方式诱导凋亡。此外，机制研究表明，TIPE1与Rac1相互作用，抑制Rac1及其下游p65和c-Jun n -末端激酶途径的激活。此外，组成型活性Rac1的过表达部分挽救了TIPE1诱导的细胞凋亡，而敲低Rac1可显著恢复TIPE1小干扰RNA诱导的细胞生长失调。我们的研究结果表明，TIPE1通过负调控Rac1通路诱导HCC细胞凋亡，TIPE1的缺失可能是HCC患者预后的新指标。
TIPE1 (tumor necrosis factor-alpha-induced protein 8-like 1 or TNFAIP8L1) is a newly identified member of the TIPE (TNFAIP8) family, which play roles in regulating cell death. However, the biologic functions of TIPE1 in physiologic and pathologic conditions are largely unknown. Here, we report the roles of TIPE1 in hepatocellular carcinoma (HCC). Evaluated by immunohistochemical staining, HCC tissues showed significantly downregulated TIPE1 expression compared with adjacent non-tumor tissues, which positively correlated with tumor pathologic grades and patient survival. Using a homograft tumor model in Balb/c mice, we discovered that TIPE1 significantly diminished the growth and tumor weight of murine liver cancer homografts. Consistently, TIPE1 inhibited both cell growth and colony formation ability of cultured HCC cell lines, which was further identified to be due to TIPE1-inducing apoptosis in a caspase-independent, necrostatin-1 (Nec-1)-insensitive manner. Furthermore, mechanistic investigations revealed that TIPE1 interacted with Rac1, and inhibited the activation of Rac1 and its downstream p65 and c-Jun N-terminal kinase pathway. Moreover, overexpression of constitutively active Rac1 partially rescued the apoptosis induced by TIPE1, and Rac1 knockdown significantly restored the deregulated cell growth induced by TIPE1 small interfering RNA. Our findings revealed that TIPE1 induced apoptosis in HCC cells by negatively regulating Rac1 pathway, and loss of TIPE1 might be a new prognostic indicator for HCC patients.