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

Xiaobin Cui ,Yu Zheng,Lan Yang,Li Li,Feng Li,Yong Li,Yan Qi,Hao Peng,Su Li,Na Li,Hong Zhou,Jinfang Jiang ,Hongwei Dang ,Tingting Jin ,Wei Liang ,Jianming Hu ,Xianglin Yuan ,Lianghai Wang ,Shugang Li ,Tingting Li ,Laibo Yin ,Weiwei Cao ,Jian Suo ,Chunxia Liu ,Yunzhao Chen ,Yaoyuan Shen ,Chuanyue Wu ,Yongzhong Wei ,Shumao Zhang

doi:10.18632/oncotarget.6499

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.

Highlights

Esophageal squamous cell carcinoma (ESCC), a tumor of the digestive tract, is an aggressive malignancy with poor patient survival in China
The heterozygote of Phospholipase C epsilon 1 (PLCE1) rs2274223 increases susceptibility to HPV infection in Kazakh patients with esophageal carcinoma [13]. These findings suggest that PLCE1 may increase the risk for esophageal cancer because this gene affects epidemiologic and etiologic factors involved in ESCC carcinogenesis, which is, in turn, regulated by the genotype–phenotype of PLCE1
We previously reported that PLCE1 protein expression is upregulated in Kazakh patients with ESCC [22]; we confirmed that this protein functions as an oncogene and can induce inflammation and promote esophageal cancer formation through interaction with the NF-κB signal pathway [32]

Summary

Introduction

Esophageal squamous cell carcinoma (ESCC), a tumor of the digestive tract, is an aggressive malignancy with poor patient survival in China. Patients with ESCC exhibit poor survival, with an overall 5-year survival rate following surgery of only 14% to 22%. Therapeutic strategies for this cancer type remain limited because of poor understanding of ESCC pathogenesis. Studies demonstrated that several oncogenic and tumor-suppressive factors are associated with ESCC progression. Only few of these studies are specific and conclusive, and the molecular pathogenesis of ESCC remains poorly understood [4, 5]. The biological behavior of the initiation and progression of esophageal cancer, especially ESCC, must be elucidated to develop effective diagnostic methods and therapeutic strategies

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Conclusion