Dihydropyrimidine dehydrogenase predicts survival and response to interferon-\u03b1 in hepatocellular carcinoma

Wei-Ping Zhu,Qi Pan,Miao Wang,Long-Rong Wang,Ze-Yang Liu,Yi-Ming Zhao,Di-Hua Zhan,Xi-Gan He,Jia-Min Zhou,De-Ning Ma,Lu Wang,Ning Zhang

doi:10.1038/s41419-017-0098-0

Abstract

Metastasis and recurrence contribute to poor prognosis of hepatocellular carcinoma (HCC). Recently, we reported that interferon-α (IFN-α) can suppress metastasis of HCC; however, the underlying mechanism has not been fully described. In this study, we demonstrated that expression of dihydropyrimidine dehydrogenase (DPYD), a pyrimidine catabolic enzyme, was dose-dependently downregulated by IFN-α in HCC tissues from nude mice. Notably, DPYD expression was found to be significantly increased in HCC cell lines with higher metastatic potentials compared with their controls. Moreover, upregulation of DPYD in HCC cells could promote in vitro migration, invasion, and in vivo lung metastasis, and inducing changes characteristic of epithelial-mesenchymal transition (EMT). In contrast, knockdown of DPYD inhibited these processes. Mechanistically, DPYD functioned as a positive regulator of EMT in HCC by targeting the p38/NF-κB/Snail1 pathway. Clinically, tissue microarray analysis showed that high DPYD expression was positively associated with aggressive tumor characteristics, including larger tumor size, tumor recurrence, and advanced tumor node metastasis (TNM) stage, and independently correlated with poorer overall survival times after curative resection. HCC patients with low DPYD expression have better response to IFN-α therapy. Taken together, our findings elucidate that IFN-α could downregulate DPYD expression to inhibit EMT and HCC metastasis, and suggest that DPYD might be a potential prognostic biomarker and a therapeutic target for HCC.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, and nowadays rises to the second commonest leading cause of cancer death[1]
Identification of dihydropyrimidine dehydrogenase (DPYD) as a therapeutic target of IFN-α Previously, we have found that IFN-α can inhibit tumor metastasis in nude mice bearing human HCC xenografts with high metastatic potential[4]
These results indicated that DPYD might participate in IFN-α-inhibited HCC metastasis, we focused on the roles and mechanisms of DPYD in driving HCC metastasis

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, and nowadays rises to the second commonest leading cause of cancer death[1]. The poor prognosis of HCC is mainly attributed to metastasis and recurrence[2,3]. Exploring a therapeutic strategy that can effectively inhibit the metastasis and recurrence of HCC becomes urgently needed. We found that interferon-α (IFN-α) could inhibit tumor metastasis in nude mice bearing human HCC xenografts[4], and this effectiveness was validated by our clinical trials[5,6]. IFN-α has been shown to be a promising drug for HCC7,8. Some HCC patients are not sensitive to IFN-α therapy. A better understanding of the antitumor mechanism of IFN-α would provide clinical benefit

Methods

Results

Conclusion