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首页> 外文期刊>Cellular Signalling >Downregulation of PKC zeta/Pard3/Pard6b is responsible for lung adenocarcinoma cell EMT and invasion
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Downregulation of PKC zeta/Pard3/Pard6b is responsible for lung adenocarcinoma cell EMT and invasion

机译：PKC Zeta / Pard3 / Pard6b的下调负责肺腺癌细胞EMT和侵袭

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摘要

Atypical protein kinase C zeta (PKC zeta forms an apico-basal polarity complex with Partitioning Defective (Pard) 3 and Pard6 to regulate normal epithelial cell apico-basolateral polarization. The dissociation of the PKC zeta/Pard3/ Pard6 complex is essential for the disassembly of the tight/adherens junction and epithelial-mesenchymal transition (EMT) that is critical for tumor spreading. Loss of cell polarity and epithelial organization is strongly correlated with malignancy and tumor progression in some other cancer types. However, it is unclear whether the PKC zeta/Pard3/Pard6 complex plays a role in the progression of non-small-cell lung cancer (NSCLC). We found that hypoxia downregulated the PKC zeta/Pard3/Pard6 complex, correlating with induction of lung cancer cell migration and invasion. Silencing of the PKC zeta/Pard3/Pard6 polarity complex components induced lung cancer cell EMT, invasion, and colonization in vivo. Suppression of Pard3 was associated with altered expression of genes regulating wound healing, cell apoptosis/death and cell motility, and particularly upregulation of MAP3K1 and fibronectin which are known to contribute to lung cancer progression. Human lung adenocarcinoma tissues expressed less Pard6b and PKC zeta than the adjacent normal tissues and in experimental mouse lung adenocarcinona, the levels of Pard3 and PKC zeta were also decreased. In addition, we showed that a methylation locus in the gene body of Pard3 is positively associated with the expression of Pard3 and that methylation of the Pard3 gene increased cellular sensitivity to carboplatin, a common chemotherapy drug. Suppression of Pard3 increased chemoresistance in lung cancer cells. Together, these results suggest that reduced expression of PKC zeta/ Pard3/Pard6 contributes to NSCLC EMT, invasion, and chemoresistance.
机译：非典型蛋白激酶C Zeta（PKC Zeta形成具有分配缺陷（PARD）3和PARD6的APICO基础极性复合物，以调节正常上皮细胞APICO-基石外侧极化。PKC ZETA / PARD3 / PARD6复合物的解离对拆卸至关重要紧密/粘附结和上皮 - 间充质转换（EMT）对肿瘤扩散至关重要。细胞极性和上皮组织的丧失与一些其他癌症类型的恶性肿瘤和肿瘤进展强烈相关。但是，目前尚不清楚PKC是否Zeta / Pard3 / Pard6复合体在非小细胞肺癌（NSCLC）的进展中起作用。我们发现缺氧下调PKC Zeta / Pard3 / Pard6复合物，与肺癌细胞迁移和侵袭的诱导相关。沉默PKC Zeta / PARD3 / PARD6极性复合组分诱导肺癌细胞EMT，侵袭和殖民化体内。抑制PARD3与表达改变有关调节伤口愈合的基因，细胞凋亡/死亡和细胞运动，以及众所周知的MAP3K1和纤连蛋白的较上调，这些蛋白是有助于肺癌进展。人肺腺癌组织表达较少的PARD6B和PKC ZETA比相邻的正常组织和实验小鼠肺腺癌，PARD3和PKC ZETA的水平也降低。此外，我们表明PARD3的基因体中的甲基化基因座与PARD3的表达呈正相关，并且PARD3基因的甲基化增加了对Carboplatin的细胞敏感性，是一种常见的化疗药物。抑制PARD3增加了肺癌细胞中的化学抑制。这些结果表明，PKC Zeta / Pard3 / Pard6的表达减少有助于NSCLC EMT，侵袭和化学抑制。

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