MiR-139-5p Loss-Mediated WTAP Activation Contributes to Hepatocellular Carcinoma Progression by Promoting the Epithelial to Mesenchymal Transition.

Wenli Liu,Mingcheng Li,Bin Wang,Wengang Song,Yawen Zou,Ying Sun,Na Zhao,Xiaolong Chen,Guozhen Wang,Xiaoxian Pei,Yize Guan,Xuewei Gao,Lin Yang

doi:10.3389/fonc.2021.611544

Abstract

Background: Hepatocellular carcinoma (HCC) is a primary aggressive gastrointestinal neoplasm that affects patients worldwide. It has been shown that Wilms' tumor 1-associating protein (WTAP) is frequently upregulated in various cancers. However, the potential role of WTAP in HCC remains largely unknown.Methods: The expression levels of WTAP in human HCC tissues were determined by the western blotting and immunohistochemical (IHC) staining. A correlation between the WTAP expression, clinicopathological features, and the HCC prognosis was analyzed. The WTAP expression was silenced by short hairpin RNA (shRNA), and effects of the knockdown of WTAP on the proliferation and invasion of HCC cells were assessed. The microRNAs (miRNAs) involved in the regulation of the WTAP expression were identified by a bioinformatics analysis and further confirmed by in vitro assays.Results: The expression levels of WTAP in liver cancer tissues were significantly elevated and compared with those in the adjacent normal tissues and significantly correlated with the clinical stage and prognosis in patients with HCC. Further investigation revealed that the knockdown of WTAP drastically suppressed HCC cell proliferation and invasion abilities. Luciferase reporter assay and validation experiments confirmed that WTAP was a direct target of miR-139-5p. Moreover, the overexpression of WTAP could partly abolish the inhibitory effects of miR-139-5p on the HCC cell growth and invasion. Mechanistically, we revealed that the miR-139-5p/WTAP axis regulated the HCC progression by controlling the epithelial to mesenchymal transition (EMT).Conclusions: In summary, the results indicate that WTAP is a potential oncogene in HCC and miR-139-5p negatively regulates the WTAP expression. MiR-139-5p/WTAP can be utilized as a potential therapeutic target for HCC.

Highlights

Hepatocellular carcinoma (HCC) is a primary aggressive gastrointestinal neoplasm that affects patients worldwide
To determine the Wilms’ tumor 1-associating protein (WTAP) expression profile in HCC tissues, eight-paired surgical HCC and para-carcinoma tissues were analyzed by a western blot
The WTAP expression was positively correlated with the advanced stages of TumorNode-Metastasis (TNM) and high rates of vascular invasion (Supplementary Figure 1B)

Summary

Introduction

Hepatocellular carcinoma (HCC) is a primary aggressive gastrointestinal neoplasm that affects patients worldwide. It has been shown that Wilms’ tumor 1-associating protein (WTAP) is frequently upregulated in various cancers. Hepatocellular carcinoma (HCC) is a primary aggressive and malignant gastrointestinal tumor that affects patients worldwide and is associated with high rates of morbidity and metastasis [1]. A great progress has been made in diagnostic and therapeutic methods, the clinical outcome of most patients with HCC remains poor [2]. A poor outcome of HCC therapy is largely due to a high incidence of its recurrence and metastasis [3, 4]. Previous studies have shown that the epithelial to mesenchymal transition (EMT) process, during which epithelial cells acquire new features of mesenchyme, is a crucial mechanism that contributes to the recurrence and metastasis of cancer. An improvement in understanding the key molecules in EMT processes is urgently needed

Methods

Results

Conclusion