Targeting oncogenic PLCE1 by miR-145 impairs tumor proliferation and metastasis of esophageal squamous cell carcinoma

Abstract

Phospholipase C epsilon 1 (PLCE1) is a susceptibility gene in esophageal squamous cell carcinoma (ESCC). Nevertheless, the role of PLCE1 in ESCC tumorigenesis has not been elucidated. In this study, we determined the function of PLCE1 and its regulatory microRNA (miRNA) in ESCC. PLCE1 protein was excessively expressed in ESCC and precancerous lesions compared with that in normal tissues. High PLCE1 expression levels in ESCC were significantly linked with poor overall survival. Knockdown of PLCE1 promoted the apoptosis, cytokine-induced apoptosis, and sensitivity of cancer cells to chemotherapeutic drugs but abrogated the proliferation and EMT phenotype of ESCC in vitro. Notably, miR-145 was newly identified as a potent repressor of PLCE1 expression by directly targeting the 3′UTR of PLCE1. MiR-145 also inhibited cell proliferation, migration, and metastasis, as well as controlled the cytoskeleton dynamics of esophageal cancer. Moreover, miR-145 was expressed at low levels in a large cohort of patients with ESCC and was inversely correlated with PLCE1 protein expression in cancer cells and tissues. These findings demonstrate that PLCE1 functions as tumor promoter in ESCC and can be suppressed by miR-145 through inhibition of PLCE1 translation. Hence, delivery of PLCE1-targeting miR-145 is a potential therapeutic approach for esophageal cancer.

PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

“…PLCe1 has been characterized as a direct effector of Ras (13), and recent work has shown a tumor suppressor role for this protein in Rastriggered cancers (20,21). PLCe1 was also shown to modulate adrenergic receptor-dependent cardiac contraction and to inhibit cardiac hypertrophy (22,23).…”

Phospholipase C ε‑1 gene polymorphisms and prognosis of esophageal cancer patients from a high‑incidence region in northern China

“…Hu et al (10) and Li et al (24) reported decreased mRNA in ESCC tumors compared with that in the adjacent normal esophagus, but no difference in protein expression. By contrast, ESCC tissues exhibited a higher PLCE1 protein expression compared with normal tissues in other studies (3,23,(28)(29)(30). This disparity may be attributed to differences in sample size, genetic background or experimental methods.…”

“…This disparity may be attributed to differences in sample size, genetic background or experimental methods. It is worth mentioning that downregulation of PLCE1 inhibited ESCC cell proliferation and promoted cell apoptosis in vitro (23,29).…”

“…It was previously demonstrated that PLCE1 was involved in the development and progression of various cancers, including esophageal cancer (3,10,(16)(17)(18)(19)(20)(21)(22). In addition, the expression of PLCE1 was associated with the survival of patients with esophageal cancer (23,24). In fact, identifying applicable biomarkers for ESCC prognosis may be helpful in improving the outcome of ESCC patients.…”

The controversial role of phospholipase C epsilon (PLCε) in cancer development and progression

“…Interesting data has been obtained by Han et al who showed that microRNA-328 (miR-328) can reduce the expression of PLCε at both mRNA and protein levels in ESCC cell lines EC109 and EC9706 38. Not only miR-328, but also miR-145 can have the same impact on PLCε expression in ESCC cells, as shown by Cui et al 39. Cui and coauthors demonstrated that PLCε expression level was elevated in tumor tissues compared to normal, and upregulation of PLCε significantly correlated with low overall survival rate in ESCC patients.…”