Multiplexed Proteomic Approach for Identification of Serum Biomarkers in Hepatocellular Carcinoma Patients with Normal AFP

Alpha fetoprotein (AFP) has been used as a serologic indicator of hepatocellular carcinoma (HCC). We aimed to identify an HCC-specific serum biomarker for diagnosis using a multiplexed proteomic technique in HCC patients with normal AFP levels. A total of 152 patients were included from Guro Hospital, Korea University. Among 267 identified proteins, 28 and 86 proteins showed at least a two-fold elevation or reduction in expression, respectively. Multiple reaction monitoring (MRM) analysis of 41 proteins revealed 10 proteins were differentially expressed in patients with liver cirrhosis and HCC patients with normal AFP. A combination of tripartite motif22 (Trim22), seprase, and bone morphogenetic protein1 had an area under receiver operating characteristic of 0.957 for HCC diagnosis. Real-time PCR and western blot analysis of the paired tumor/non-tumor liver tissue in HCC revealed a reduced expression of Trim22 in the tumor tissue. Also, serum levels of Trim22 were significantly reduced in HCC patients with normal AFP compared to those with liver cirrhosis (p = 0.032). Inhibition of Trim22 increased cellular proliferation in human hepatoma cell lines, whereas overexpression of Trim22 decreased cellular proliferation in hepatoma cell lines. In conclusion, the combination of three serum markers improved the chance of diagnosing HCC. MRM-based quantification of the serum protein in patients with normal AFP provides the potential for early diagnosis of HCC.

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Aberrant expression of serine/threonine kinase Pim‐3 in hepatocellular carcinoma development and its role in the proliferation of human hepatoma cell lines

International Journal of Cancer ◽

10.1002/ijc.20719 ◽

2004 ◽

Vol 114 (2) ◽

pp. 209-218 ◽

Cited By ~ 58

Author(s):

Chifumi Fujii ◽

Yasunari Nakamoto ◽

Peirong Lu ◽

Koichi Tsuneyama ◽

Boryana K. Popivanova ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Lines ◽

Hepatoma Cell ◽

Human Hepatoma ◽

Human Hepatoma Cell ◽

Serine Threonine Kinase ◽

Aberrant Expression ◽

Threonine Kinase ◽

Hepatoma Cell Lines

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Melatonin Inhibits the Progression of Hepatocellular Carcinoma through MicroRNA Let7i-3p Mediated RAF1 Reduction

International Journal of Molecular Sciences ◽

10.3390/ijms19092687 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2687 ◽

Cited By ~ 9

Author(s):

Tong-Hong Wang ◽

Chuen Hsueh ◽

Chin-Chuan Chen ◽

Wan-Syuan Li ◽

Chau-Ting Yeh ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Lines ◽

Hepatoma Cell ◽

Mitogen Activated Protein Kinase ◽

Migration And Invasion ◽

Small Rna Sequencing ◽

Human Hepatoma Cell ◽

Melatonin Treatment ◽

Hepatoma Cell Lines ◽

Mitogen Activated Protein

Melatonin is the main pineal hormone that relays light/dark-cycle information to the circadian system. Recent studies have examined the intrinsic antitumor activity of melatonin in various cancers, including hepatocellular carcinoma (HCC), the primary life-threatening malignancy in both sexes in Taiwan. However, the detailed regulatory mechanisms underlying melatonin’s anti-HCC activity remain incompletely understood. Here, we investigated the mechanisms by which the anti-HCC activity of melatonin is regulated. Human hepatoma cell lines were treated with 1 and 2 mM melatonin, and functional assays were used to dissect melatonin’s antitumor effect in HCC; small-RNA sequencing was performed to identify the microRNAs (miRNAs) involved in the anti-HCC activity of melatonin; and quantitative RT-PCR and Western blotting were used to elucidate how miRNAs regulate melatonin-mediated HCC suppression. Melatonin treatment at both doses strongly inhibited the proliferation, migration and invasion capacities of Huh7 and HepG2 cell lines, and melatonin treatment markedly induced the expression of the miRNA let7i-3p in cells. Notably, transfection of cells with a let7i-3p mimic drastically reduced RAF1 expression and activation of mitogen-activated protein kinase signaling downstream from RAF1, and rescue-assay results demonstrated that melatonin inhibited HCC progression by modulating let7i-3p-mediated RAF1 suppression. Our findings support the view that melatonin treatment holds considerable promise as a therapy for HCC.

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