Predicting Value of ALCAM as a Target Gene of microRNA-483-5p in Patients with Early Recurrence in Hepatocellular Carcinoma.

Xin-Yuan Lu,Zhiao Chen,Di Chen,Ming Yao,Qian Zhao,Ying-Jun Zhao,Xiang-Huo He,Xiao-Yuan Gu,Jie Ding,Wen-Ming Cong

doi:10.3389/fphar.2017.00973

Abstract

The long-term survival rate of hepatocellular carcinoma (HCC) is poor. One of the reasons for the poor rate of survival is the high rate of recurrence caused by intrahepatic metastas is that adversely affects long-term outcome. Many studies have indicated that microRNAs play an important role in HCC, but there has been no research of clonal origins on recurrent HCC (RHCC) by analzing microRNAs. In the present study, we found that miR-483-5p was significantly upregulated in RHCC tissues of short-term recurrence (≤ 2 years) by miRNA microarray screening, and can significantly promote migration and invasion of HCC cells in vitro and increase intrahepatic metastasis in nude mice in vivo. Furthermore, we demonstrated that activated leukocyte cell adhesion molecule (ALCAM), which significantly suppressed migration and invasion of HCC cells, was a direct target of miR-483-5p, and the re-introduction of ALCAM expression could antagonize the promoting effects of miR-483-5p on the capacity of HCC cells for migration and invasion. In addition, expression level of ALCAM was negatively correlated with microvascular invasion and tumor size recognized as prognostic factors. The cases which were negative for ALCAM expression had shorter time to recurrence than positive cases, and univariate and multivariate survival analyses showed that ALCAM was an independent risk factor of HCC recurrence. qRT-PCR and Western blotting showed that the expression of EMT related genes (MMP-2, MMP-9, E-caherin and vimentin) significantly changed as a result of interfering or overexpression of ALCAM, and ALCAM was significantly associated with EMT in HCC. These results suggest that the miR-483-5p/ALCAM axis is an important regulator in invasion and metastasis and biomarker for recurrence risk assessment of HCC.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed cancer, and the third leading cause of cancer death in the world
These findings indicate that the miR-483-5p/activated leukocyte cell adhesion molecule (ALCAM) axis is an important regulator in intrahepatic metastasis of hepatocellular carcinoma (HCC) and can serve as prognostic markers and basis of individualized treatment
These results suggested that upregulation of miR-483-5p is related to the short-term recurrence of HCC, and may play an important role in the metastasis and recurrence process

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed cancer, and the third leading cause of cancer death in the world. Surgical resection remains the first choice of treatment of HCC; the long-term survival rate is poor. One of the reasons for the poor rate of survival is the high rate of recurrence caused by intrahepatic metastasis that adversely affects long-term outcome. A greater understanding of the molecular mechanisms under lying recurrence and intrahepatic metastasis of HCC may have a significant effect on improving prognosis and systematic treatment of this disease. Accumulating evidence suggests that the levels of miRNAs are deregulated and can play an important role in evolution and progression of HCC (Yang et al, 2016), especially by affecting invasion and metastasis of tumor cells. The variation of miRNAs in recurrent HCC (RHCC) caused by intrahepatic metastasis is rarely reported, and the underlying molecular mechanisms for intrahepatic metastasis remain unclear

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Conclusion