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.phospholipase C delta 1 | epithelial-to-mesenchymal transition | tumor suppressor C olorectal cancer (CRC) is one of the most common cancers and causes of cancer-related deaths worldwide. Although CRC patients with unresectable tumors and metastasis have been treated with chemotherapy, recent advances in molecular research about CRC have resulted in the development of molecular targeted therapies, such as cetuximab and panitumumab. Chemotherapy combined with these targeted therapies improves the prognosis of CRC patients with unresectable tumors to some extent (1, 2). However, some CRC patients with activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are unable to benefit from such drugs, because both cetuximab and panitumumab are epidermal growth factor (EGF) receptor-targeting agents and mutant KRAS constitutively activates the downstream signaling of EGF receptor (3). A more vigorous study using KRAS-mutant CRC is needed to identify novel molecular targets for drugs that will improve the prognosis of CRC patients with unresectable tumors, especially those with KRAS mutations.Mutations in KRAS are found in about 40% of CRC patients. Constitutively active KRAS mutations lead to the hyperactivation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) [mitogen-activated protein kinase (MAPK)] signaling and/or phosphatidylinositol-3 kinase (PI3K) pathways (4). Activation of MEK/ERK (MAPK) signaling results in increased phosphorylation...

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