The role of extracellular vesicles in mediating progression, metastasis and potential treatment of hepatocellular carcinoma

Yang, Naibin; Li, Shanshan; Li, Guoxiang; Zhang, Shengguo; Tang, Xiaozhi; Ni, Shun-Lan; Jian, Xiao-Min; Xu, Cunlai; Zhu, Jiayin; Lu, Mingqin

doi:10.18632/oncotarget.12465

Cited by 83 publications

(70 citation statements)

References 93 publications

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“…The exchange of exosomal packages between the cells could influence the tumor microenvironment and contribute to the tumor development [4][5][6]12]. Exosomes are easy to obtain from nearly all body fluids, including blood, urine, saliva, semen and ascites.…”

Section: Discussionmentioning

confidence: 99%

Serum exosomal hnRNPH1 mRNA as a novel marker for hepatocellular carcinoma

Dong

Chen

et al. 2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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Background: Distinctive exosomal contents could be useful for cancer diagnosis and prognosis. However, little is known about whether serum exosomal heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) mRNA is a satisfactory biomarker for hepatocellular carcinoma (HCC). Methods: Two hundred and ninety-one participants divided into four age-and gender-matched groups, including a HCC group (n = 88), a liver cirrhosis (LC) group (n = 67), a chronic hepatitis B (CHB) group (n = 68) and a healthy control group (n = 68), were enrolled. Serum exosomal hnRNPH1 mRNA and GAPDH mRNA were measured using TaqMan real-time PCR, and the relative expression levels were calculated. Receiver operating characteristic (ROC) curves were constructed to evaluate the effectiveness of hnRNPH1 mRNA alone and in combination with α-fetoprotein (AFP) in the diagnosis of HCC. The correlation between hnRNPH1 mRNA levels and clinicopathological characteristics and overall survival (OS) in HCC was determined. Results: The serum exosomal hnRNPH1 mRNA levels in HCC patients were remarkably higher than in the other groups (p < 0.05). The hnRNPH1 mRNA discriminated HCC from CHB with an area under the ROC curve (AUC) of 0.865, with sensitivity of 85.2% and specificity of 76.5% at cut-off value of 0.670. The AUC for hnRNPH1 mRNA in combination with AFP was further improved. The exosomal hnRNPH1 mRNA levels in HCC patients were associated with the Child-Pugh classification, portal vein tumor emboli, lymph node metastasis, TNM stage and OS (p < 0.05). Conclusions: These findings suggested that serum exosomal hnRNPH1 mRNA could be an effective marker for HCC in high HBV prevalence areas.

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Section: Discussionmentioning

confidence: 99%

Serum exosomal hnRNPH1 mRNA as a novel marker for hepatocellular carcinoma

Dong

Chen

et al. 2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…The ability to package and transfer diverse cargoes from cell to cell makes EVs important mediators of intercellular communication events that are involved in normal physiological processes, as well as in pathological conditions, such as cancer (41)(42)(43). In malignancy, EVs play a major role in cell growth, invasion, and metastasis (44,45). In the case of virus-infected cells, EVs can transfer modified protein and RNA cargo to uninfected cells, which can enhance viral pathogenesis (34,35).…”

mentioning

confidence: 99%

Transmembrane Domains Mediate Intra- and Extracellular Trafficking of Epstein-Barr Virus Latent Membrane Protein 1

Nkosi

Howell

Cheerathodi

et al. 2018

J Virol

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EBV latent membrane protein 1 (LMP1) is released from latently infected tumor cells in small membrane-enclosed extracellular vesicles (EVs). Accumulating evidence suggests that LMP1 is a major driver of EV content and functions. LMP1-modified EVs have been shown to influence recipient cell growth, migration, differentiation, and regulation of immune cell function. Despite the significance of LMP1-modified exosomes, very little is known about how this viral protein enters or manipulates the host EV pathway. In this study, LMP1 deletion mutants were generated to assess protein regions required for EV trafficking. Following transfection of LMP1 or mutant plasmids, EVs were collected by differential centrifugation, and the levels of specific cargo were evaluated by immunoblot analysis. The results demonstrate that, together, the N terminus and transmembrane region 1 of LMP1 are sufficient for efficient sorting into EVs. Consistent with these findings, a mutant lacking the N terminus and transmembrane domains 1 through 4 (TM5-6) failed to be packaged into EVs, and exhibited higher colocalization with endoplasmic reticulum and early endosome markers than the wild-type protein. Surprisingly, TM5-6 maintained the ability to colocalize and form a complex with CD63, an abundant exosome protein that is important for the incorporation of LMP1 into EVs. Other mutations within LMP1 resulted in enhanced levels of secretion, pointing to potential positive and negative regulatory mechanisms for extracellular vesicle sorting of LMP1. These data suggest new functions of the N terminus and transmembrane domains in LMP1 intra- and extracellular trafficking that are likely downstream of an interaction with CD63. EBV infection contributes to the development of cancers, such as nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin's disease, and posttransplant lymphomas, in immunocompromised or genetically susceptible individuals. LMP1 is an important viral protein expressed by EBV in these cancers. LMP1 is secreted in extracellular vesicles (EVs), and the transfer of LMP1-modified EVs to uninfected cells can alter their physiology. Understanding the cellular machinery responsible for sorting LMP1 into EVs is limited, despite the importance of LMP1-modified EVs. Here, we illustrate the roles of different regions of LMP1 in EV packaging. Our results show that the N terminus and TM1 are sufficient to drive LMP1 EV trafficking. We further show the existence of potential positive and negative regulatory mechanisms for LMP1 vesicle sorting. These findings provide a better basis for future investigations to identify the mechanisms of LMP1 targeting to EVs, which could have broad implications in understanding EV cargo sorting.

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“…Deregulation of miRNAs has been observed in a wide range of human diseases, including HCC or other cancers . Our previous study identified several deregulated miRNAs in HCC tumor tissues (data not shown), of which miR‐199a‐5p was the most significance (Fold change: 0.0023, p <0.001).…”

Section: Introductionmentioning

confidence: 89%

“…9 Deregulation of miRNAs has been observed in a wide range of human diseases, including HCC or other cancers. [10][11][12][13][14][15] Our previous study identified several deregulated miRNAs in HCC tumor tissues (data not shown), of which miR-199a-5p was the most significance (Fold change: 0.0023, p<0.001). Although down-regulation of miR-199a-5p has been reported by others, the roles of miR-199a-5p and its novel targets are still worthy to be studied.…”

Section: Introductionmentioning

confidence: 99%

MiR‐199a‐5p suppresses tumorigenesis by targeting clathrin heavy chain in hepatocellular carcinoma

Huang

Song

et al. 2017

Cell Biochemistry & Function

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The deregulation of microRNA (miRNA) is frequently associated with a variety of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the expression and possible role of miR-199a-5p in HCC. The expression of miR-199a-5p was measured by quantitative RT-PCR in HCC. The effect of miR-199a-5p was evaluated by cell viability and colony formation assays in HCC cell lines and tumor cell growth assay in xenograft nude mice. Quantitative real time PCR results showed that miR-199a-5p was down-regulated in 77.9 % (67/86) of HCC tissues compared with adjacent nontumor tissues. MiR-199a-5p mimic reduced cell viability and colony formation by induction of cell arrest in HCC cell lines and inhibited tumor cell growth in xenograft nude mice, but miR-199a-5p inhibitor increased cell viability and colony formation in HCC cell lines and tumor cell growth in xenograft nude mice. Furthermore, CLTC was defined as a potential direct target of miR-199a-5p by MiRanda and TargetScan predictions. The dual-luciferase reporter gene assay results showed that CLTC was a direct target of miR-199a-5p. The use of miR-199a-5p mimic or inhibitor could decrease or increase CLTC protein levels in HCC cell lines. We conclude that the frequently down-regulated miR-199a-5p can regulate CLTC and might function as a tumor suppressor in HCC. Therefore, miR-199a-5p may serve as a useful therapeutic agent for miRNA-based HCC therapy.

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The role of extracellular vesicles in mediating progression, metastasis and potential treatment of hepatocellular carcinoma

Cited by 83 publications

References 93 publications

Serum exosomal hnRNPH1 mRNA as a novel marker for hepatocellular carcinoma

Serum exosomal hnRNPH1 mRNA as a novel marker for hepatocellular carcinoma

Transmembrane Domains Mediate Intra- and Extracellular Trafficking of Epstein-Barr Virus Latent Membrane Protein 1

MiR‐199a‐5p suppresses tumorigenesis by targeting clathrin heavy chain in hepatocellular carcinoma

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