Circulating microRNA profiles in plasma: identification of miR-224 as a novel diagnostic biomarker in hepatocellular carcinoma independent of hepatic function

Okajima, Wataru; Komatsu, Shuhei; Ichikawa, Daiju; Miyamae, Mahito; Ohashi, Toya; Imamura, Takaaki; Kiuchi, Jun; Taniguchi, Hiroki; Otsuji, Eigo

doi:10.1016/s0959-8049(16)61544-7

Cited by 6 publications

(7 citation statements)

References 79 publications

(116 reference statements)

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“…Over 60% of human protein-coding genes are predicted to be targeted and modulated by miRNAs. Numerous studies have shown that miRNAs are implicated in almost all cellular processes, including cell differentiation, proliferation, apoptosis, invasion and migration [7][8][9][10][11] . The dysregulation of miRNAs in cancer has been reported in different tumor types, including lung cancer.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-4458 suppresses the proliferation of human lung cancer cells in vitro by directly targeting Lin28B

Liu

et al. 2017

Acta Pharmacol Sin

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Previous studies have shown that the expression of microRNA-4458 (miR-4458) is dysregulated in hepatocellular carcinoma and colon cancer. In this study, we investigated the direct target of miR-4458 and its biological functions in human lung cancer cells. By using the database TargetScan, we identified Lin28B, an oncogene, as a direct target gene of miR-4458. In dual-luciferase reporter assay, we found that miR-4458 mimics dose-dependently inhibited the luciferase activity of the wild-type 3'UTR of Lin28B in human lung cancer A549 and NCI-H1299 cell lines without affecting its mutant forms, whereas anti-miR-4458, an inhibitor of miR-4458, dose-dependently promoted the luciferase activity of the wild-type 3'UTR of Lin28B in A549 and NCI-H1299 cell lines without affecting its mutant forms. Overexpression of miR-4458 significantly decreased the protein levels of Lin28B in the cells, and inhibited the cell growth and colony formation. Conversely, knockdown of miR-4458 with anti-miR-4458 significantly increased the protein levels of Lin28B, and promoted the cell proliferation, which could be reverted by knockdown of Lin28B expression. In addition, we detected the expression of Lin28B using RT-PCR in 40 human lung cancer tissues and matched peritumoral tissues, and found that Lin28B was overexpressed in lung cancer tissues and negatively correlated with miR-4458 expression (r=-0.694, P<0.05). We conclude that miR-4458 is a tumor suppressor, and Lin28B is the direct target of miR-4458. These results suggest the modulation of miR-4458/Lin28B expression offers a potential therapeutic strategy for lung cancer.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-4458 suppresses the proliferation of human lung cancer cells in vitro by directly targeting Lin28B

Liu

et al. 2017

Acta Pharmacol Sin

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“…miR-141 has been reported to confer resistance to 5-flurouracil in HCC cells [45]. Importantly, miR-18a and 224 have been proposed as serum biomarkers for diagnosis of HCC [46,47]. Thus, most of the 11 miRNAs are associated with imparting tumorigenic properties in HCC cells and their increased expression in Ep1CIRs reflects their transformed status.…”

Section: Discussionmentioning

confidence: 99%

EpCAM+ Liver Cancer Stem-Like Cells Exhibiting Autocrine Wnt Signaling Potentially Originate in Cirrhotic Patients

Khosla

Rastogi

Ramakrishna

et al. 2017

Stem Cells Translational Medicine

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Hepatocellular carcinoma (HCC) is believed to originate from cancer stem cells (CSCs). While epithelial cell adhesion molecule (EpCAM) is a marker of normal hepatic stem cells (HSCs), EpCAM+ cells from HCC behave like CSCs. Since HCC mostly develops on a cirrhotic background, we sought to determine whether CSC‐like EpCAM+ cells exist in patients with advanced cirrhosis. Both flow cytometry and immunohistochemistry showed that frequency of EpCAM+ cells in advanced cirrhosis was increased as compared to control. To determine whether increased EpCAM population in advanced cirrhosis harbors any CSC‐like cells, we compared molecular and functional features of EpCAM+ cells from advanced cirrhosis (Ep+CIR; n = 20) with EpCAM+ cells from both HCC (Ep+HCC; n = 20) and noncancerous/noncirrhotic (control) (Ep+NSC; n = 7) liver tissues. Ep+CIRs displayed similarity with Ep+HCC cells including upregulated expression of stemness and Notch pathway genes, enhanced self‐renewal in serial spheroid assay and generation of subcutaneous tumors in nonobese diabetic/severe combined immunodeficiency mice. Moreover, transcriptome and miRNome of Ep+CIRs appeared closer to that of Ep+HCC cells than Ep+NSCs. Interestingly, more than 50% micro RNAs (miRNAs) and transcripts specifically expressed in Ep+HCCs were also expressed in Ep+CIRs. However, none of Ep+NSC specific miRNAs and only 7% Ep+NSC specific transcripts were expressed in Ep+CIRs. Further, according to gene expression and in vitro Wnt inhibition analysis, autocrine Wnt signaling appeared to be a distinct feature of Ep+CIR and Ep+HCC cells, which was absent from Ep+NSCs. EpCAM+ cells in advanced cirrhosis possibly include a population of CSC‐like cells which can be explored for early diagnosis of HCC development. Stem Cells Translational Medicine 2017;6:807–818

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“…MicroRNAs can be detected in the circulation . Studies have identified a variety of miRNAs that differentiate HCC patients from healthy controls . Overexpression of tissue miRs‐34a, 200a, 221 and serum miR‐224 have been associated with poor prognosis in HCC patients .…”

Section: Introductionmentioning

confidence: 99%

“…Studies have identified a variety of miRNAs that differentiate HCC patients from healthy controls . Overexpression of tissue miRs‐34a, 200a, 221 and serum miR‐224 have been associated with poor prognosis in HCC patients . Limited experimental information has been revealed about miRNAs in aflatoxin‐induced HCC but several investigations to date have focused on an acute exposure period and genotoxic effects of aflatoxin on miRNAs …”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19][20][21][22][23][24][25] Overexpression of tissue miRs-34a, 200a, 221 and serum miR-224 have been associated with poor prognosis in HCC patients. 11,17,[26][27][28] Limited experimental information has been revealed about miRNAs in aflatoxin-induced HCC but several investigations to date have focused on an acute exposure period and genotoxic effects of aflatoxin on miRNAs. 29,30 Our previous study identified a panel of miRNAs that were dysregulated in hepatic tissue and sera at the end of a 4-week carcinogenic AFB 1 dosing regimen both with and without chemoprotection.…”

mentioning

confidence: 99%

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Serum miR‐182 is a predictive biomarker for dichotomization of risk of hepatocellular carcinoma in rats

Livingstone

Johnson

Roebuck

et al. 2019

Molecular Carcinogenesis

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Exploration of animal models leads to discoveries that can reveal candidate biomarkers for translation to human populations. Herein, a model of hepatocarcinogenesis and protection was used in which rats treated with aflatoxin (AFB1) daily for 28 days (200 µg/kg BW) developed tumors compared with rats completely protected from tumors by concurrent administration of the chemoprotective agent, 1‐[2‐cyano‐3‐,12‐dioxooleana‐1,9(11)‐dien‐28‐oyl]imidazole (CDDO‐Im). Differential expression of miRNAs in tumors (AFB1) and nontumor (AFB1 + CDDO‐Im) bearing livers and their levels in sera over the life‐course of the animals was determined. miRNA transcriptome analysis identified 17 miRNAs significantly upregulated at greater than five‐fold in the tumors. The ten most dysregulated miRNAs judged by fold‐change and biological significance were selected for further study, including liver‐specific miR‐122‐5p. Validation of sequencing results by real‐time PCR confirmed the upregulation of the majority of these miRNAs in tumors, including miR‐182, as well as miR‐224‐5p as the most dysregulated of these miRNAs (over 400‐fold). The longitudinal analysis of levels of miR‐182 in sera demonstrated significant and persistent increases (5.13‐fold; 95% CI: 4.59‐5.70). The increase in miR‐182 was detected months before any clinical symptoms were present in the animals. By the terminal time point of the study, in addition to elevated levels of serum miR‐182, serum miR‐122‐5p was also found to be increased (>1.5‐fold) in animals that developed hepatocarcinomas. Thus, using the data from an unbiased discovery approach of the tissue findings, serum miR‐182 was found to track across the complex, multistage process of hepatocarcinogenesis opening an opportunity for translation to human populations.

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Circulating microRNA profiles in plasma: identification of miR-224 as a novel diagnostic biomarker in hepatocellular carcinoma independent of hepatic function

Cited by 6 publications

References 79 publications

MicroRNA-4458 suppresses the proliferation of human lung cancer cells in vitro by directly targeting Lin28B

MicroRNA-4458 suppresses the proliferation of human lung cancer cells in vitro by directly targeting Lin28B

EpCAM+ Liver Cancer Stem-Like Cells Exhibiting Autocrine Wnt Signaling Potentially Originate in Cirrhotic Patients

Serum miR‐182 is a predictive biomarker for dichotomization of risk of hepatocellular carcinoma in rats

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