Abstract
Heterogeneity is prevalent in cancer both between and within individuals. Although a few studies have identified several circulating microRNAs (miRNAs) for cancer diagnosis, the complete plasma miRNA profile for hepatocellular carcinoma (HCC) remains undefined, and whether the plasma miRNA profiles are heterogeneous is unknown. Here, we obtained individualized plasma miRNA profiles of both healthy subjects and HCC patients via genome-wide deep sequencing. Compared with the highly stable miRNA profile of the healthy subjects, the profile of the HCC patients was highly variable. Seven miRNAs were optimized as potential plasma-based biomarkers for HCC diagnosis. Combined with the clinical data of The Cancer Genome Atlas (TCGA) cohort, three out of the seven miRNAs were correlated with the survival of the HCC patients. To investigate the effect of cancer cells on the plasma miRNAs profile, we compared the most differentially expressed miRNAs between plasma and tissues. Furthermore, miRNAseq data of HCC patients from TCGA were recruited for comparisons. We found that the differences between plasma and tissue were inconsistent, suggesting that other cells in addition to cancer cells also contribute to plasma miRNAs. Using two HCC cancer cell lines, we examined the levels of seven differentially expressed miRNAs. The reverse direction of certain miRNAs alterations between cancer cells and media further confirmed that miRNAs may be selectively pump out by cancer cells.
Highlights
Cancer heterogeneity has been recognized as an important clinical determinant of patient outcomes, such as response or resistance to anti-cancer therapies [1,2]
The plasma miRNA expression profile is more variable among hepatocellular carcinoma (HCC) patients than that among healthy subjects
The expression level of circulating miRNAs was quite stable among the healthy subjects, which is consistent with the observations of Chen et al [8]
Summary
Cancer heterogeneity has been recognized as an important clinical determinant of patient outcomes, such as response or resistance to anti-cancer therapies [1,2]. Since plasma is more accessible and easier to process and microRNAs (miRNAs) are highly stable in blood, plasma miRNA profile analysis will indisputably open a new era in biomarker research and provide a new paradigm for non-invasive characterization of cancer, both for diagnosis and therapy monitoring. Lu et al successfully classified poorly differentiated tumors using miRNA expression profiles [7] Their findings demonstrated that miRNAs can be used as biomarkers for cancer diagnosis. Mitchell et al found that tumor-derived miRNAs were detectable in plasma from a mouse prostate cancer xenograft model and in clinical serum specimens from prostate cancer patients [10]. Cancer heterogeneity has been well studied at the DNA, RNA, protein, and even microenvironment levels [11,12] It is unclear whether there is heterogeneity in serum/plasma miRNA profiles between cancer patients. Since dysregulation of miRNAs is considered an early event in tumorigenesis, miRNAs are promising biomarkers for early diagnosis of cancer [13,14]
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