Phospholipase Cδ1 suppresses cell migration and invasion of breast cancer cells by modulating KIF3A-mediated ERK1/2/β- catenin/MMP7 signalling

Abstract

Phospholipase C δ1 (PLCD1) encodes an enzyme involved in energy metabolism, calcium homeostasis and intracellular movement. It is located at 3p22 in a region that is frequently deleted in multiple cancers, and the PLCD1 enzyme is a potential tumour suppressor in breast cancer that inhibits matrix metalloprotease (MMP) 7, but the detailed mechanism remains elusive. In this study, we found that PLCD1 was downregulated in breast cancers, and the gain-or-loss functional assay revealed that PLCD1 inhibited cell migration and invasion in vitro via the ERK1/2/β-catenin/MMP7 signalling pathway. Furthermore, KIF3A was identified as a downstream mediator of PLCD1, and there was an inverse correlation between the expression of PLCD1 and KIF3A. Knockdown of KIF3A expression alone suppressed cell migration and invasion, and attenuated ERK1/2/β-catenin/MMP7 signalling that was reactivated by knocking down PLCD1 in vitro. Collectively, our findings suggest that PLCD1 acts as a tumour suppressor, by KIF3A-mediated suppression of ERK1/2/β-catenin/MMP7 signalling, at least in part, in breast cancer.

Estrogen receptor beta as epigenetic mediator of miR-10b and miR-145 in mammary cancer

“…Moreover, the induction of miR-10b expression resulted in important changes in cell morphology, EMT markers, as well as expression of cell surface receptors, ECM components, including syndecan-1, which is a target of miR-10b [44], and proteolytic enzymes such as MMP2, MMP7 and MMP9. These alterations were accompanied by the strong increase in the phosphorylated levels of Erk1/2 kinase, which has been correlated with breast cancer proliferation and motility [70], suggesting the critical role of miR-10b in this signaling pathway. Germany), or miR negative control (10nM, ABI) were performed according to the manufacturer's instructions and as described previously [47].…”

Phosphoinositide-Dependent Signaling in Cancer: A Focus on Phospholipase C Isozymes

“…In addition, PLCε knockout mice, generated by two different groups, showed contrasting oncogenic roles played by PLCε: one being pro-oncogenic [68] and the other one being anti-oncogenic [69]. Recent studies have reported PLCδ1 as a tumor suppressor in breast cancer [70] and ESCC [65]. Even as all these reports support the fact that PLCs are involved in cancer, very little has been done at the clinical level.…”

“…In cancer, alterations in cell growth, proliferation, survival and cell migration are central in the development and progression of the disease. PLCs have been demonstrated to be involved in these essential processes in cancer [70,74,75].…”

“…The study by Shao et al showed that PLCδ1 expression was downregulated in breast cancer and that, PLCδ1 activity inhibited breast cancer cell migration via the inhibition of the ERK1/2/β-catenin/MMP pathway (Table 1). Most importantly, this activity was dependent on Kinesin-Like Protein KIF3A (KIF3A) signaling [70]. Indeed, KIF3A is a downstream effector of PLCδ1 and its expression is inversely correlated to PLCδ1 expression.…”

Contribution of Matrix Metalloproteinase-7 Genotypes to the Risk of Non-solid Tumor, Childhood Leukemia

“…MMP7 is commonly expressed in ductal epithelium of exocrine glands in skin, salivary glands, pancreas, glandular epithelium of intestine and reproductive organ, liver, and breast, and is highly expressed in the luminal surface of dysplastic glands in human colorectal cancer (29). In clinical practice, MMP7 inhibitors can potentially be applied to control the invasive capacity of cancer cells (30,(32)(33)(34). In 2013, MMP7 was found to be highly expressed in advanced colorectal adenomatous and involved in converting colorectal adenomas into a malignant state and facilitating the cancer growth (35).…”