3993

LLGL2

lethal giant larvae homolog 2 (Drosophila);LLGL2;lethal giant larvae homolog 2 (Drosophila)

human giant larvae homolog|lethal(2) giant larvae protein homolog 2

17q25.1

protein-coding

Atypical protein kinase C lambda/iota (aPKC lambda/iota) is expressed in several human cancers; however, the correlation between aPKC lambda/iota localization and cancer progression in human lung adenocarcinoma (LAC) remains to be clarified. We found that patients with a high level of aPKC lambda/iota expression in LAC had significantly shorter overall survival than those with a low level of aPKC lambda/iota expression. In addition, localization of aPKC lambda/iota in the apical membrane or at the cell-cell contact was associated with both lymphatic invasion and metastasis. The intercellular adhesion molecule, E-cadherin, was decreased in LACs with highly expressed aPKC lambda/iota at the invasion site of tumor cells. This result suggested that the expression levels of aPKC lambda/iota and E-cadherin reflect the progression of LAC. On double-immunohistochemical analysis, aPKC lambda/iota and Lgl2, a protein that interacts with aPKC lambda/iota, were co-localized within LACs. Furthermore, we found that Lgl2 bound the aPKC lambda/iota-Par6 complex in tumor tissue by immune-cosedimentation analysis. Apical membrane localization of Lgl2 was correlated with lymphatic invasion and lymph node metastasis. These results thus indicate that aPKC lambda/iota expression is altered upon the progression of LAC. This is also the first evidence to show aPKC lambda/iota overexpression in LAC and demonstrates that aPKC lambda/iota localization at the apical membrane or cell-cell contact is associated with lymphatic invasion and metastasis of the tumor.

Invasion and metastasis are the hallmarks of malignant tumor progression and the main cause of death in cancer. The embryonic program "epithelial-mesenchymal transition" (EMT) is thought to trigger invasion by allowing tumor cell dissemination. Here, we describe that the EMT-inducing transcriptional repressor ZEB1 promotes colorectal cancer cell metastasis and loss of cell polarity. Thereby, ZEB1 suppresses the expression of cell polarity factors, in particular of Lgl2, which we found reduced in colorectal and breast cancers. We further show that retention of Lgl2 expression is critical for the epithelial phenotype and that its loss might be involved in metastasis. Thus, by linking EMT, loss of polarity, and metastasis, ZEB1 is a crucial promoter of malignant tumor progression.