Downregulation of PKCζ/Pard3/Pard6b is responsible for lung adenocarcinoma cell EMT and invasion

Abstract

Atypical protein kinase C ζ (PKCζ) 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 PKCζ/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 PKCζ/Pard3/Pard6 complex plays a role in the progression of non-small-cell lung cancer (NSCLC). We found that hypoxia downregulated the PKCζ/Pard3/Pard6 complex, correlating with induction of lung cancer cell migration and invasion. Silencing of the PKCζ/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 PKCζ than the adjacent normal tissues and in experimental mouse lung adenocarcinoma, the levels of Pard3 and PKCζ 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 PKCζ/Pard3/Pard6 contributes to NSCLC EMT, invasion, and chemoresistance.

Comprehensive mapping of the cell response to E. coli infection in porcine intestinal epithelial cells pretreated with exopolysaccharide derived from Lactobacillus reuteri

“…We also observed the upregulation of the PARD6B gene in the nontreated as well as pretreated cells infected with ETEC ( Figure 3). This gene (a member of the PAR6 family) encodes a protein involved in the cell polarization process [45]. JAMs are among other induced molecules that participate in the generation of the cell junctional system and TJ assembly [41].…”

FOXA2 promotes the proliferation, migration and invasion, and epithelial mesenchymal transition in colon cancer

“…EMT refers to a transformation process in which epithelial cells, under the influence by certain factors, lose the polarity of epithelial cells and acquire the characteristics of mesenchymal cells ( 20 ). This process is accompanied by changes in cell morphology, function, and gene expression profiles ( 21 ). EMT is a key step for tumor cells to break away from their original sites and gain the ability of invasion and metastasis, and alleviation of EMT suppresses invasion and metastasis of tumor cells ( 22 ).…”

Selection of microRNAs in extracellular vesicles for diagnosis of malignant pleural mesothelioma by in�vitro analysis

“…Therefore, decreasing the expression of proteins associated with tight junctions, adherens junctions, and focal adhesion may contribute to successful invasion of MPM cells. Zhou et al ( 32 ) reported that PARD3 contributes to the epithelial-mesenchymal transition (EMT) and invasion of non-small-cell lung cancer (NSCLC). PARD3 is associated with tight junctions and adherens junctions, and our results showed that PARD3 mRNA could be repressed by both hsa-miR-193a-5p and hsa-miR-551b-5p.…”