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Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):13505-10. doi: 10.1073/pnas.1405374111. Epub 2014 Sep 2.

Phospholipase Cδ1 induces E-cadherin expression and suppresses malignancy in colorectal cancer cells.

Author information

1
Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan; and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 192-0392, Japan.
2
Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan; and.
3
Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan; and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 192-0392, Japan kfukami@toyaku.ac.jp.

Abstract

Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in CRC predict the ineffectiveness of EGF receptor-targeted therapy. Previous transcriptional microarray analysis suggests the association between phospholipase Cδ1 (PLCδ1) expression and KRAS mutation status in CRC. However, both the roles and the regulatory mechanisms of PLCδ1 in CRC are not known. Here, we found that the expression of PLCδ1, one of the most basal PLCs, is down-regulated in CRC specimens compared with normal colon epithelium by immunohistochemistry. Furthermore, we examined the roles of PLCδ1 in CRC cell lines that harbor an activating KRAS mutation. Ectopic expression of PLCδ1 in CRC cells induced the expression of E-cadherin, whereas knockdown of PLCδ1 repressed the expression of E-cadherin. Moreover, the overexpression of PLCδ1 suppressed the expression of several mesenchymal genes and reduced cell motility, invasiveness, and in vivo tumorigenicity of SW620 CRC cells. We also showed that PLCδ1 expression is repressed by the KRAS/mitogen-activated protein kinase kinase (MEK) pathway. Furthermore, PLCδ1 suppressed the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 through E-cadherin induction in CRC cells, suggesting the presence of a negative regulatory loop between KRAS/MEK/ERK signaling and PLCδ1. These data indicate that PLCδ1 has tumor-suppressive functions in CRC through E-cadherin induction and KRAS/MEK/ERK signal attenuation.

KEYWORDS:

epithelial-to-mesenchymal transition; phospholipase C delta 1; tumor suppressor

PMID:
25197077
PMCID:
PMC4169964
DOI:
10.1073/pnas.1405374111
[Indexed for MEDLINE]
Free PMC Article

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