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Clin Chem. 2019 Jul;65(7):905-915. doi: 10.1373/clinchem.2018.301150. Epub 2019 Apr 17.

Noncoding RNAs Serve as Diagnosis and Prognosis Biomarkers for Hepatocellular Carcinoma.

Tan C1,2, Cao J1,2, Chen L3,4,5, Xi X1, Wang S1, Zhu Y1, Yang L1, Ma L6, Wang D1, Yin J7, Zhang T8,4,5, John Lu Z9.

Author information

1
MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.
2
Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
3
Tianjin Medical University Cancer Institute and Hospital, Department of Hepatobiliary Cancer, National Clinical Research for Cancer, Tianjin, China.
4
Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
5
Tianjin's Clinical Research for Cancer, Tianjin, China.
6
Department of Epidemiology, Second Military Medical University, Shanghai, China.
7
Department of Epidemiology, Second Military Medical University, Shanghai, China. hawkyjh163@163.com zhangti@tjmuch.com zhilu@tsinghua.edu.cn.
8
Tianjin Medical University Cancer Institute and Hospital, Department of Hepatobiliary Cancer, National Clinical Research for Cancer, Tianjin, China; hawkyjh163@163.com zhangti@tjmuch.com zhilu@tsinghua.edu.cn.
9
MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China; hawkyjh163@163.com zhangti@tjmuch.com zhilu@tsinghua.edu.cn.

Abstract

BACKGROUND:

Reliable noninvasive biomarkers for hepatocellular carcinoma (HCC) diagnosis and prognosis are urgently needed. We explored the potential of not only microRNAs (miRNAs) but other types of noncoding RNAs (ncRNAs) as HCC biomarkers.

METHODS:

Peripheral blood samples were collected from 77 individuals; among them, 57 plasma cell-free RNA transcriptomes and 20 exosomal RNA transcriptomes were profiled. Significantly upregulated ncRNAs and published potential HCC biomarkers were validated with reverse transcription (RT)-qPCR in an independent validation cohort (60-150 samples). We particularly investigated the diagnosis and prognosis performance and biological function for 1 ncRNA biomarker, RN7SL1, and its S fragment.

RESULTS:

We identified certain circulating ncRNAs escaping from RNase degradation, possibly through binding with RNA-binding proteins: 899 ncRNAs were highly upregulated in HCC patients. Among them, 337 genes were fragmented long noncoding RNAs, 252 genes were small nucleolar RNAs, and 134 genes were piwi-interacting RNAs. Forty-eight candidates were selected and validated with RT-qPCR, of which, 16 ncRNAs were verified to be significantly upregulated in HCC, including RN7SL1, SNHG1, ZFAS1, and LINC01359. Particularly, the abundance of RN7SL1 S fragment discriminated HCC samples from negative controls (area under the curve, 0.87; 95% CI, 0.817-0.920). HCC patients with higher concentrations of RN7SL1 S fragment had lower survival rates. Furthermore, RN7SL1 S fragment alone promoted cancer cell proliferation and clonogenic growth.

CONCLUSIONS:

Our results show that various ncRNA species, not only miRNAs, identified in the small RNA sequencing of plasma are also able to serve as noninvasive biomarkers. Particularly, we identified a domain of srpRNA RN7SL1 with reliable clinical performance for HCC diagnosis and prognosis.

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