TLE4 promotes colorectal cancer progression through activation of JNK/c-Jun signaling pathway.

Shu-Yang Wang,Liu-Qing He,Dan-Ling Deng,Ya-Ping Ye,Yan-Qing Ding,Zhi-Yuan Xiao,Hong-Li Jiao,Wen-Ting Liao,Juan-Juan Cai,Li Liang,Ting-Ting Li,Ke Gao,Run-Wei Yang

doi:10.18632/oncotarget.6694

Abstract

The Groucho transcriptional co-repressor TLE4 protein has been shown to be a tumor suppressor in a subset of acute myeloid leukemia. However, little is known about its role in development and progression of solid tumor. In this study, we found that the expression of TLE4 in colorectal cancer (CRC) tissues was significantly higher than that in their matched adjacent intestine epithelial tissues. In addition, high expression of TLE4 was significantly correlated with advanced Dukes stage, lymph node metastasis and poor prognosis of CRC. Moreover, enforced expression of TLE4 in CRC cell lines significantly enhanced proliferation, invasion and tumor growth. On the contrary, knock down of TLE4 repressed cell proliferation, invasion and tumor growth. Furthermore, our study exhibited that the TLE4 promoted cell proliferation and invasion partially via activation of JNK-c-Jun pathway and subsequently increased cyclinD1 and decreased P27Kip1 expression. In conclusion, these results suggested that TLE4, a potential prognostic biomarker for CRC, plays an important role in the development and progression of human CRC.

Highlights

Colorectal cancer (CRC) is one of the most common types of malignant tumor with high morbidity and mortality
Our results revealed that TLE4 was differently expressed in all the 10 CRC cell lines. (Figure 1A, 1B)
The results showed that TLE4 protein located both in the cytoplasm (Figure 2A, middle) and nucleus (Figure 2A, right), and the expression of TLE4 increased markedly in 64% (86/134) CRC tumor tissue (Figure 2A middle and right) compared with that in adjacent non-tumor tissue (Figure 2A left)

Summary

Introduction

Colorectal cancer (CRC) is one of the most common types of malignant tumor with high morbidity and mortality. The initiation and progression of CRC is a complicated network with multiple genetic and epigenetic genetic changes [1]. It has been well documented that several key signaling pathways were activated via mutational inactivation of tumor suppressors and mutational activation of oncogenes. Mutation in APC or β-Catenin results in activation of canonical Wnt pathway. Mutational activation of KRAS leads to activation of PI3K/AKT, ERK, and NF-κB pathways [2, 3]. Despite the early diagnosis and advanced treatments in recent years, the clinical outcome and prognosis of CRC patients remain pessimistic. Efforts to elucidate newer biomarkers and more effective therapies are still imperative in order to improved survival for CRC patients [4]

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