Serum exosomal miR-125b is a novel prognostic marker for hepatocellular carcinoma
OncoTargets and Therapy
serum exosomal mir-125b is a novel prognostic marker for hepatocellular carcinoma
Kaiqian Zhou 1 2
Zheng Wang 1 2
Zhi Dai 1 2
n Zhou 1 2 3 4
0 Department of h epatobiliary and Pancreatic s urgery, the s econd a ffiliated h ospital, Zhejiang University school of Medicine , hangzhou, china
1 Key l aboratory of carcinogenesis and cancer invasion, Fudan University , Ministry of education, shanghai, china
2 liver cancer institute, Zhongshan hospital, Fudan University , shanghai, china
3 s hanghai Key l aboratory of Organ Transplantation , shanghai, china
4 institute of Biomedical sciences, Fudan University , shanghai, china
5 c ancer r esearch institute, c entral s outh University, Key l aboratory of carcinogenesis and cancer invasion, Ministry of education , changsha, china
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide with high mortality. Circulating miRNA has been demonstrated as a novel noninvasive biomarker for many tumors. This study aimed to investigate the potential of circulating miR-125b as a prognostic marker of HCC. Exosomes were extracted from serum samples collected from two independent cohorts: cohort 1: HCC (n=30), chronic hepatitis B (CHB, n=30), liver cirrhosis (LC, n=30); cohort 2: HCC (n=128). We found that miR-125b levels were remarkably increased in exosomes compared to those in serum from patients with CHB, LC, and HCC (P,0.01, respectively). However, miR-125b levels in exosomes and the serum from HCC patients were inferior to that of CHB (P,0.01 and P=0.06) and LC patients (P,0.01 for all). Additionally, miR-125b levels in exosomes were associated with tumor number (P=0.02), encapsulation (P,0.01), and TNM stage (P,0.01). Kaplan-Meier analysis indicated that HCC patients with lower exosomal miR-125b levels showed reduced time to recurrence (TTR) (P,0.01) and overall survival (OS) (P,0.01). Furthermore, multivariate analysis revealed that miR-125b level in exosomes, but not in serum, was an independent predictive factor for TTR (P,0.001) and OS (P=0.011). Exosomal miR-125b levels predicted the recurrence and survival of HCC patients with an area under the ROC curve of 0.739 (83.0% sensitivity and 67.9% specificity) and 0.702 (82.5% sensitivity and 53.4% specificity). In conclusion, exosomal miR-125b could serve as a promising prognostic marker for HCC.
exosome; miR-125b; hepatocellular carcinoma; prognosis; serum
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open access to scientific and medical research
O r i g i n a l r e s e a r c h
Weifeng liu 1–3,*
Jie hu 1,2,*
Introduction
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second
leading cause of cancer mortality globally.1 Hepatic resection and orthotopic liver
transplantation is still the most effective treatment for HCC. However, the efficacy
of current therapeutic regimens is poor due to the high frequency of recurrence and
metastasis of HCC.2,3 Therefore, the identification of specific and sensitive biomarkers
for the recurrence and prognosis of HCC is urgently needed.
miRNAs are crucially implicated in a diverse range of human diseases, including
cancer.4,5 Accumulating evidence indicates that dysregulation of miRNAs, especially
within natural carriers and exosomes, contributes to the onset and progression of
various human tumors such as breast and liver cancer.6–9 Exosomes are small membrane
vesicles (40–120 nm) which play key roles in intercellular communication via delivery
of active biological molecules.10,11 Extracellular miRNAs in exosomes are relatively
stable and shielded against extracellular RNase degradation.12–14 Therefore, exosomal
miRNAs may serve as noninvasive biomarkers for the diagnosis and prognosis of
various malignancies.8,12,15
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Previous studies reported that miR-125b was
downregulated in HCC tissue, and plasma miR-125b may be a diagnostic
marker for HCC.5,16–20 However, the potential significance of
circulating exosomal miR-125b in HCC has not been explored.
In this study, we aimed to determine whether the detection of
exosomal miR-125b in HCC patients will provide information
for predicting the recurrence and prognosis of HCC.
Materials and methods
Patients and samples
Clinical samples were collected from two independent
cohorts of patients recruited from Zhongshan Hospital, Fudan
University (Shanghai, China) between January and June
2012. Cohort 1 comprised 30 patients with HCC, 30 with
chronic hepatitis B (CHB), and 30 with liver cirrhosis (LC);
cohort 2 comprised 128 patients with HCC. HCC patients
in both cohorts had undergone curative resection and were
histologically diagnosed. Clinical samples were collected
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