Early detection of hepatocellular carcinoma via liquid biopsy: panel of small extracellular vesicle‐derived long noncoding RNAs identified as markers

Abstract

This study investigated the diagnostic potential of serum small extracellular vesicle-derived long noncoding RNAs (EV-lncRNAs) for hepatocellular carcinoma (HCC). Driver oncogenic lncRNA candidates were selected by a comparative analysis of lncRNA expression profiles from two whole transcriptome human HCC datasets (Catholic_LIHC and TCGA_LIHC). Expression of selected lncRNAs in serum and small EVs was evaluated using quantitative reverse transcription PCR. Diagnostic power of serum EV-lncRNAs for HCC was determined in the test (n = 44) and validation (n = 139) cohorts. Of the six promising driver onco-lncRNAs, DLEU2, HOTTIP, MALAT1, and SNHG1 exhibited favorable performance in the test cohort. In the validation cohort, serum EV-MALAT1 displayed excellent discriminant ability, while EV-DLEU2, EV-HOTTIP, and EV-SNHG1 showed good discriminant ability between HCC and non-HCC. Furthermore, a panel combining EV-MALAT1 and EV-SNHG1 achieved the best area under the curve (AUC; 0.899, 95% CI = 0.816-0.982) for very early HCC, whereas a panel with EV-DLEU2 and alpha-fetoprotein exhibited the best positivity (96%) in very early HCC. Serum small EV-MALAT1, EV-DLEU2, EV-HOTTIP, and EV-SNHG1 may represent promising diagnostic markers for very early-stage HCC.

Advances in Multi-Omics Applications in HBV-Associated Hepatocellular Carcinoma

“…LncRNAMALAT1 induces murine HCC experimentally, H19 expression is upregulated in HBV-associated HCC, HOTAIR is overexpressed in tumor tissues from HCC patients and in liver cancer cell lines, and is related with poor prognosis of HCC, HBx upregulates lncRNAHULC by inhibiting P18 and promoting the occurrence of HCC ( 103 , 105 , 107 , 108 ). Additionally, the up-regulated expressions of lncRNA-HEIH and HOTTIP promoted tumor progression and significantly associated with tumor progression and disease outcome in HCC patients ( 109 , 110 ). Low expression of lncRNA-MEG3 was observed in HCC tissues and cells, and overexpression of lncRNA-MEG3 could inhibit the proliferation, migration and invasion of HCC cells ( 111 ).…”

Exosomal Non-Coding RNAs: New Insights into the Biology of Hepatocellular Carcinoma

“…In addition, they have numerous advantages over AFP in the diagnosis of very early-stage HCC. In very early-stage HCC, the combined use of EV-MALAT1 and EV-SNHG1 provides the optimal biomarker panel [ 12 ]. Certain lncRNAs can also distinguish early-stage HCC patients from healthy individuals, as well as those with chronic hepatitis or cirrhosis.…”

“…Despite the high specificity of AFP, the low sensitivity of AFP puts forward a higher demand for the early diagnosis of HCC. Thus, cancer-derived exosomes are a worthy research direction [ 11 , 12 ], as they may lead to the development of novel diagnostic and therapeutic approaches for improving the clinical outcomes of HCC.…”

Roles of small extracellular vesicles in the development, diagnosis and possible treatment strategies for hepatocellular carcinoma (Review)

“…Notably, sEVs-carrying miR-122, hsa-circRNA-G004213 and DANCR are also potential markers to evaluate the efficacy of HCC surgical and interventional treatment (153,(159)(160)(161). In addition to the above, a panel of tumor specific biochemical indicators has been proposed for a higher sensitivity and specificity compared with single one (162)(163)(164)(165)(166). For example, Sorop et al (167) established exosomal miR HCC Score including serum AFP and the level of plasma sEVs-carrying miR-21-5p and miR-92a-3p with a great diagnostic ability of HCC (AUC=0.85).…”