Tenofovir hampers the efficacy of sorafenib in prolonging overall survival in hepatocellular carcinoma

Kung Hao Liang*, Sung Fang Chen, Yu Hua Lin, Yu De Chu, Yang Hsiang Lin, Ming Wei Lai, Chih Lang Lin, Chau Ting Yeh

*此作品的通信作者

研究成果: 雜誌貢獻期刊論文同行評審

摘要

Sorafenib is a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). These patients may simultaneously receive anti-hepatitis B treatment if they are viremic. The N-Acetylgalactosaminyltransferase 14 (GALNT14) gene can serve as a biomarker to guide HCC treatments. However, the enzyme substrates of its gene product, GalNAc-T14 (a glycosyltransferase), remained uncharacterized. Here, we conducted a glycoproteome-wide search for GalNAc-T14 substrates using lectin affinity chromatography followed by tandem mass spectrometry. Seventeen novel GalNAc-T14 substrates were identified. A connective map analysis showed that an antiviral drug, tenofovir, was the leading medicinal compound to down-regulate the expression of these substrates. In vitro assays showed that HCC cells were resistant to sorafenib if pretreated by tenofovir but not entecavir. Clinical analysis showed that the concomitant use of tenofovir and sorafenib was a previously unrecognized predictive factor for unfavorable overall survival (hazard ratio = 2.060, 95% confidence interval = [1.256, 3.381], p = 0.004) in a cohort of 181 hepatitis-B-related, sorafenib-treated HCC patients (concomitant tenofovir versus entecavir treatment; p = 0.003). In conclusion, by conducting a glycoproteome-wide search for GalNAc-T14 substrates, we unexpectedly found that tenofovir was a major negative regulator of GalNAc-T14 substrates and an unfavorable anti-hepatitis B drug in HCC patients receiving sorafenib.

原文英語
文章編號1539
期刊Biomedicines
9
發行號11
DOIs
出版狀態已發佈 - 2021 十一月

ASJC Scopus subject areas

  • 醫藥(雜項)
  • 生物化學、遺傳與分子生物學 (全部)

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