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Roles of microRNA-186 and vascular endothelial growth factor in hepatocellular carcinoma complicated with portal vein tumor thrombus.

ABSTRACT: The present study aims to investigate the role and underlying mechanism of microRNA (miR)-186 in patients with hepatocellular carcinoma (HCC) complicated with portal vein tumor thrombus. Blood samples from 29 HCC patients with portal vein tumor thrombus were collected between January 2014 and September 2015 in Huai'an First People's Hospital, while blood from 36 HCC patients without vein tumor thrombus was also collected in the same period. In addition, tumor thrombus specimens were collected from the HCC patients with portal vein tumor thrombus, and peritumoral tissues of the tumor thrombus were used as the control. Reverse transcription-quantitative polymerase chain reaction, ELISA and western blot analyses were applied to detect vascular endothelial growth factor (VEGF) expression at the mRNA and protein levels. Bioinformatics prediction was used to predict the target of miR-186, and then miR-186 expression was detected. Furthermore, dual-luciferase reporter assay was used to validate whether miR-186 directly targeted VEGF. Following transfection with agomiR-186, the expression levels of miR-186 and VEGF were detected, while MTT assay was used to detect EA.hy926 cell proliferation subsequent to small interfering RNA (siRNA) silencing. The results identified that VEGF was significantly increased in the tumor thrombus and blood samples of HCC patients with vein tumor thrombus at the mRNA and protein levels, while miR-186 expression was significantly decreased (P<0.05). Following silencing VEGF by siRNA transfection, the proliferation of EA.hy926 cells was inhibited. In addition, VEGF expression was significantly decreased and cell proliferation was reduced when upregulating miR-186. Dual-luciferase reporter assay demonstrated that miR-186 regulated VEGF expression through complementary binding to 3'-untranslated region. In conclusion, VEGF was significantly increased in tumor thrombus and blood samples from HCC patients with vein tumor thrombus, which may be associated with the downregulation of miR-186. Thus, miR-186 may promote the development and progression of vein tumor thrombus in HCC.

SUBMITTER: Yuan W

PROVIDER: S-EPMC7444326 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Roles of microRNA-186 and vascular endothelial growth factor in hepatocellular carcinoma complicated with portal vein tumor thrombus.

Yuan Weidong W Li Fuguang F

Experimental and therapeutic medicine 20200803 4

The present study aims to investigate the role and underlying mechanism of microRNA (miR)-186 in patients with hepatocellular carcinoma (HCC) complicated with portal vein tumor thrombus. Blood samples from 29 HCC patients with portal vein tumor thrombus were collected between January 2014 and September 2015 in Huai'an First People's Hospital, while blood from 36 HCC patients without vein tumor thrombus was also collected in the same period. In addition, tumor thrombus specimens were collected fr ...[more]

PMID: 32855736

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Project description:Rationale: Hepatocellular carcinoma (HCC) is primarily characterized by a high incidence of vascular invasion. However, the specific mechanism underlying portal vein tumor thrombus (PVTT) in HCC remains unclear. As a consequence of myeloid cell developmental arrest, CD71+ erythroid progenitor cells (EPCs) and myeloid-derived suppressor cells play important roles in HCC; however, their roles in PVTT remain unclear. Methods: The role of CD71+ EPCs in the HCC tumor microenvironment (TME) was evaluated via morphological, RNA-sequencing, enzyme-linked immunosorbent assay, and flow cytometric analyses. Co-culture techniques were employed to assess the CD45+ EPCs and their vascular compromising effect. Additionally, the PVTT-promoting function of CD45+ EPCs was explored in vivo in a murine model. Results: The CD45+EPCs in HCC tissues exhibited increased myeloid cell features, including morphology, surface markers, transforming growth factor (TGF)-β generation, and gene expression, compared with those in circulation. Hence, a large proportion of CD45+EPCs, particularly those in TMEs, comprise erythroid-transdifferentiated myeloid cells (EDMCs). Additionally, the expression of C-C chemokine receptor type 2 (CCR2) mRNA was upregulated in CD45+EPCs within the TME. Tumor macrophages from HCC tissues induced substantial migration of CD45+EPCs in a dose-dependent manner. Meanwhile, results from immunofluorescence analyses revealed that these two cell types are positively associated in the TME and circulation. That is, EDMCs are chemoattracted by HCC macrophages mainly via CCR2 from CD45+ EPCs in the circulation. Additionally, the expressions of FX, FVII, FGB, C4b, CFB, and CFH were elevated in CD45+EPCs within the TME compared with those in the spleen. The CD45+EPCs from the HCC TME promoted vessel endothelial cell migration and compromised tube formation through TGF-β and FGB, respectively. Additionally, CD45+EPCs from the TME induced HCC cell migration. HCC macrophage-induced CD45+EPCs to exhibit higher levels of FX, FVII, FGB, and TGF-β. Meanwhile, upregulation of CCAAT/enhancer binding protein beta expression induced FGB and TGF-β generation in CD45+EPCs in the TME. WTAP, a major RNA m6A writer, stabilized FX and FVII mRNA and enhanced their nuclear export in CD45+EPCs from the TME. CD45+EPCs from the TME were positively associated with PVTT and poor prognosis. Splenectomy reduced the level of CD45+EPCs in the circulation and TME, as well as the incidence of microvascular invasion. The incidence of microvascular invasion increased following the transfer of HCC tissue CD45+EPCs to splenectomized HCC-bearing mice. Conclusions: The CD45+EPCs enriched in the HCC microenvironment are EDMCs, which are induced by HCC macrophages to migrate from the circulation to the TME. Subsequently, EDMCs promote PVTT by compromising the blood vessel endothelium, aggravating coagulation, and promoting HCC cell migration.

Project description:BackgroundThis study aimed to assess the effectiveness and safety of vascular intervention combined with lenvatinib versus vascular intervention alone in the treatment of advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT), and to identify prognostic factors associated with the treatment outcomes.MethodsWe conducted a retrospective analysis of data from 92 patients with advanced HCC and PVTT who were treated between February 2016 and February 2023. Among them, 56 patients underwent vascular intervention alone (transarterial chemoembolization, TACE), while 36 patients received vascular intervention (TACE or hepatic arterial infusion chemotherapy [HAIC]) combined with lenvatinib. The primary outcomes included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Survival rates were estimated by the Kaplan-Meier method, and confounders were adjusted using inverse probability of treatment weighting (IPTW). Prognostic factors were determined through the Cox regression model.ResultsThe median follow-up duration was 20.07 months (interquartile range: 6.41-25.36). The combination therapy group had a significantly longer median PFS (11.00 vs. 5.00 months, P<0.05) and OS (12.91 vs. 6.83 months, P<0.05) in comparison to the monotherapy group, and these findings remained consistent after IPTW matching. Moreover, the combination therapy group showed a higher ORR (55.56% vs. 26.79%, P<0.05) based on mRECIST criteria. Cox multivariate analysis identified extrahepatic metastasis and maximum tumor diameter as risk factors for PFS, while age, tumor number, and maximum tumor diameter influenced OS. Combined treatment emerged as a protective factor for OS. In the combination therapy group, hypertension was the most frequent adverse event, with grade 3 or 4 adverse events occurring rarely.ConclusionThe combination of vascular intervention with lenvatinib has demonstrated improved PFS and OS in advanced HCC patients with PVTT, and its safety profile appears to be acceptable. Adoption of this combined treatment strategy at an earlier stage may enhance patient outcomes.

Project description:Background: Survival benefit of surgical resection for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) has been approved recently. However, risk factors for in-hospital mortality in these patients remain unclear. We aimed to determine risk factors and reduce the mortality of these patients. Methods: We analyzed data for 521 of all 1531 HCC patients with PVTT underwent surgery. The primary outcome measure was in-hospital mortality after surgical resection. Univariate and Multivariate cox-regression were performed to identify independent predictors of in-hospital mortality. The methods of Kaplan-Meier, bootstrap and ten-fold-cross validation were applied to validate the risk factors. Results: 521 of 1531 patients in 2004-2012 occurred for the diagnosis of HCC associated with PVTT and underwent surgical resection as a training cohort. Other 325 patients in 2013-2016 were included as a validation cohort. Overall mortality of postoperative in-patients was 3.3% (17/521) and 2.8 % (9/325), respectively. Univariate analysis of mortality revealed that frequency of hospitalization, total albumin, different types of PVTT, bleeding volume, blood transfusion, resection volume, and tumor volume were related with mortality. Therefore, the bootstrap validation reflected that the risk factors of multivariate cox regression in model1(frequency of hospitalization, bleeding volume, and tumor volume) and model 2 (frequency of hospitalization, bleeding volume and total albumin) were stable with mortality in hospital. Ten-fold cross-validation of cox regression analysis showed that the mean C-statistic with 95%CI of model1 and model2 respectively were 0.887(0.779-0.976) and 0.867(0.789-0.966) for predicting in-hospital mortality. Consistency results of models were in the training cohort and validation cohort. Conclusion: Total albumin, tumor volume, intraoperative bleeding and frequency of hospitalization were independent predictive factors for in-hospital mortality in HCC patients with PVTT under surgery. Further study is warranted to utilize these factors to lower in-hospital mortality.

Dataset Information

Roles of microRNA-186 and vascular endothelial growth factor in hepatocellular carcinoma complicated with portal vein tumor thrombus.

Publications

Roles of microRNA-186 and vascular endothelial growth factor in hepatocellular carcinoma complicated with portal vein tumor thrombus.

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