Increased tight junction permeability can result from protein kinase C activation/translocation and act as a tumor promotional event in epithelial cancers
Increased tight junction permeability can result from protein kinase C activation/translocation and act as a tumor promotional event in epithelial cancers
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DOI：
10.1111/j.1749-6632.2000.tb05246.x
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发表时间：
2000-01-01
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影响因子：
--
通讯作者：
Soler, AP
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文献类型：
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作者：
Mullin, JM;Laughlin, KV;Soler, AP
LLC-PK 1上皮细胞培养物暴露于佛波酯肿瘤促进剂导致蛋白激酶C-α（PKC-α）从胞质立即易位到膜相关区室。在非常相似的时间过程中，紧密连接（细胞旁）渗透性发生显著和持续的增加。这种增加的渗透性不仅延伸到盐和糖，而且还延伸到大分子。40倍增加的跨上皮流量的生物活性的EGF和胰岛素发生。紧密连接屏障功能的恢复与PKC-α的蛋白酶体下调一致。下调活化的膜相关PKC-α的失败与多层细胞生长的出现和紧密连接的持续渗漏相关。PKC-α的加速下调仅导致紧密连接通透性的部分和短暂增加。显性/阴性PKC-α的转染导致紧密连接通透性响应佛波醇酯的较慢增加。在使用大鼠结肠的单独研究中，二甲肼（DMH）诱导的结肠癌发生之前，异常隐窝和跨上皮渗透性的数量呈线性增加，作为DMH治疗周数的函数。已经发现大鼠和人结肠腺癌都具有均匀的紧密连接渗漏。而大多数人结肠增生性和腺瘤性息肉含有非泄漏的紧密连接，腺瘤性息肉与异型增生的变化，具有泄漏的紧密连接。我们的总体假设是，紧密连接泄漏是上皮癌变的晚期事件，但将允许腔液室中的生长因子第一次进入细胞间和间质液空间，与仅位于基底侧细胞表面的受体结合，并引起上皮细胞动力学的变化。因此，紧密连接渗漏是上皮癌特有的促进事件。
Exposure of LLC-PK1 epithelial cell cultures to phorbol ester tumor promoters causes immediate translocation of protein kinase C-alpha (PKC-alpha) from cytosolic to membrane-associated compartments. With a very similar time course, a dramatic and sustained increase in tight junctional (paracellular) permeability occurs. This increased permeability extends not only to salts and sugars but macromolecules as well. Fortyfold increases of transepithelial fluxes of biologically active EGF and insulin occur. Recovery of tight junction barrier function coincides with proteasomal downregulation of PKC-alpha. The failure to downregulate activated membrane-associated PKC-alpha has correlated with the appearance of multilayered cell growth and persistent leakiness of tight junctions. Accelerated downregulation of PKC-alpha results in only a partial and transient increase in tight junction permeability. Transfection of a dominant/ negative PKC-oc results in a slower increase in tight junction permeability in response to phorbol esters. In a separate study using rat colon, dimethylhydrazine (DMH)-induced colon carcinogenesis has been preceded by linear increases in both the number of aberrant crypts and transepithelial permeability, as a function of weeks of DMH treatment. Adenocarcinomas of both rat and human colon have been found to have uniformly leaky tight junctions. Whereas most human colon hyperplastic and adenomatous polyps contain nonleaky tight junctions, adenomatous polyps with dysplastic changes did possess leaky tight junctions. Our overall hypothesis is that tight junctional leakiness is a late event in epithelial carcinogenesis but will allow for growth factors in luminal fluid compartments to enter the intercellular and interstitial fluid spaces for the first time, binding to receptors that are located on only the basal-lateral cell surface, and causing changes in epithelial cell kinetics. Tight junctional leakiness is therefore a promotional event that would be unique to epithelial cancers.