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. 2020 Feb;34(2):e23071.
doi: 10.1002/jcla.23071. Epub 2019 Nov 6.

Clinical value of LHPP-associated microRNAs combined with protein induced by vitamin K deficiency or antagonist-II in the diagnosis of alpha-fetoprotein-negative hepatocellular carcinoma

Zeyu Tian  1 , Tanbo Yu  2 , Hongyan Wei  2 , Ning Ning  3
Affiliations

Clinical value of LHPP-associated microRNAs combined with protein induced by vitamin K deficiency or antagonist-II in the diagnosis of alpha-fetoprotein-negative hepatocellular carcinoma

Zeyu Tian et al. J Clin Lab Anal. 2020 Feb.

Abstract

Background: Alpha-fetoprotein (AFP) has received extensive attention in the differential diagnosis of hepatocellular carcinoma (HCC), especially for AFP-negative HCC (AFP-NHCC). The current study aimed to explore the value of targeted regulation of LHPP expression-related microRNAs (miRs) and protein induced by vitamin K deficiency or antagonist-II (PIVKA-II) in the differential diagnosis of AFP-NHCC.

Methods: A retrospective study was conducted on a testing set-including 214 AFP-NHCC patients, 200 cirrhosis, and 210 controls, and a validation set-including 140 AFP-NHCC patients, 134 cirrhosis, and 128 controls recruited from The First Affiliated Hospital of Hunan Normal University. Serum miRs were examined using quantitative real-time PCR method. Serum PIVKA-II was measured by enzyme-linked immunosorbent assay.

Results: Compared with adjacent tissues, LHPP protein levels in cancer tissues were significantly decreased (P < .05). Predictive software and dual-luciferase reporter assays showed that miR-363-5p and miR-765 can target LHPP expression. Serum miR-363-5p, miR-765, and PIVKA-II levels were significantly higher in AFP-HCC patients than in cirrhosis and controls. A logistic regression model combining miR-363-5p, miR-765, and PIVKA-II was performed. This model presented a high discriminating value (AUC: 0.930, sensitivity/specificity: 79.4%/95.4%) than any single indicator. In the validation set, this model still showed a high discriminating value (AUC: 0.936, sensitivity/specificity: 83.6%/94.7%).

Conclusion: Current model combining serum miR-363-5p, miR-765, and PIVKA-II has potential significance for diagnosis of AFP-NHCC.

Keywords: alpha-fetoprotein; diagnosis; hepatocellular carcinoma; microRNA; protein induced by vitamin K deficiency or antagonist-II.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Figure 1
Figure 1
LHPP protein expression levels in AFP‐NHCC patients and prediction and validation of miRs regulating LHPP expression. A, Detection of protein levels in tissues of AFP‐NHCC patients by immunohistochemistry; (B) detection of protein levels in tissues of AFP‐NHCC patients by Western blot; (C) Targetscan, miRanda, miRDB, and TangetMiner software to predict the miRs targeting LHPP; (D‐H): luciferase reporter gene assay: (D) miR‐363‐5p; (E): miR‐765; (F): miR‐632; (G): miR‐30b‐3p; (H): miR‐644a
Figure 2
Figure 2
Relationship between serum miR‐363‐5p, miR‐765, and PIVKA‐II levels and clinical value in AFP‐NHCC patients. A, The melting peak of miR‐363‐5p. B, The melting peak of miR‐765. C, miR‐363‐5p level in serum. D, miR‐765 level in serum. E, PIVKA‐II level in serum. F, Differential diagnosis value of single index for AFP‐NHCC. G, Differential diagnosis value of two indicators for AFP‐NHCC. H, Differential diagnosis value of three indicators for AFP‐NHCC. * P < .05
Figure 3
Figure 3
Correlation of miR‐363‐5p, miR‐765, and PIVKA‐II levels in relation to clinical parameters of the AFP‐NHCC cases. A, Correlation between miR‐765 and differentiation. B, Correlation between miR‐765 and tumor size. C, Correlation between miR‐765 and TNM stage. D, Correlation between miR‐363‐5p and differentiation. E, Correlation between miR‐363‐5p and tumor size. F, Correlation between miR‐363‐5p and TNM stage. G, Correlation between PIVKA‐II and differentiation. H, Correlation between PIVKA‐II and tumor size. I, Correlation between PIVKA‐II and TNM stage
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