Pathological significance of intracytoplasmic connexin proteins: Implication in tumor progression
Pathological significance of intracytoplasmic connexin proteins: Implication in tumor progression
复制标题
胞质内连接蛋白的病理意义：对肿瘤进展的影响
DOI：
10.1007/s00232-007-9048-6
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发表时间：
2007-08-01
影响因子：
2.4
通讯作者：
Enomoto, Katsuhiko
中科院分区：
文献类型：
--
作者：
Omori, Yasufumi;Li, Qingchang;Enomoto, Katsuhiko
大量证据表明间隙连接细胞间通讯（GJIC）通过阻止肿瘤进展阶段来抑制肿瘤发展。一致的是，GJIC 在肿瘤中下调。 GJIC 的下调不仅是由连接蛋白表达水平降低引起的，而且是由它们异常的细胞质定位引起的。尽管长期以来人们认为连接蛋白的胞质定位只是GJIC下调的机制之一，但对人类肿瘤样本的仔细研究表明，胞浆内连接蛋白的表达水平与肿瘤的恶性程度和进展阶段密切相关。假设胞质内连接蛋白应该具有其适当的功能，并且它们的增加应该促进肿瘤进展，如细胞迁移、侵袭和转移，我们检查了过表达的连接蛋白32 (Cx32)蛋白对人HuH7肝癌细胞表型的影响，该细胞仅在细胞质中表达基础水平的内源性Cx32。使用 Tet-off Cx32 构建体对细胞进行逆转录病毒转导，以便从培养基中去除多西环素可以诱导细胞质中 Cx32 蛋白的过度表达。即使过度表达，Cx32 蛋白仍保留在细胞质（即高尔基体）中，并且不会诱导 GJIC。然而，细胞质中Cx32蛋白的过度表达增强了HuH7细胞的运动性和侵袭性，并在将细胞异种移植到SCID小鼠体内时诱导转移。总而言之，连接蛋白的细胞质积累可能发挥有利于肿瘤进展的作用。
A considerable amount of evidence has established that gap junctional intercellular communication (GJIC) suppresses tumor development by halting the stage of tumor promotion. Consistently, GJIC is downregulated in tumors. The downregulation of GJIC is caused by not only the reduced expression level of connexin proteins but also their aberrant cytoplasmic localization. Although it has long been thought that cytoplasmic localization of connexin proteins is merely one of the mechanisms of the downregulation of GJIC, careful studies with human tumor samples have indicated that the expression level of intracytoplasmic connexin proteins correlates well with the grade of malignancy and the progression stage of tumors. Hypothesizing that intracytoplasmic connexin proteins should have their proper functions and that their increase should facilitate tumor progression such as cell migration, invasion and metastasis, we examined the effects of overexpressed connexin32 (Cx32) protein on the phenotype of human HuH7 hepatoma cells, which express a basal level of endogenous Cx32 only in cytoplasm. The cells were retrovirally transduced with the Tet-off Cx32 construct so that withdrawal of doxycycline from the culture medium could induce overexpression of Cx32 protein in cytoplasm. Even when overexpressed, Cx32 protein was retained in cytoplasm, i.e., Golgi apparatuses, and did not induce GJIC. However, overexpression of Cx32 protein in cytoplasm enhanced both the motility and the invasiveness of HuH7 cells and induced metastasis when the cells were xenografted into SCID mice. Taken together, cytoplasmic accumulation of connexin proteins may exert effects favorable for tumor progression.