Hepatitis B virus x protein induces epithelial-mesenchymal transition of hepatocellular carcinoma cells by regulating long non-coding RNA

Background

It has been widely accepted that hepatitis B virus X protein (HBx) plays an important role in hepatocellular carcinoma (HCC). This study aimed to explore the function of long non-coding RNAs (lncRNAs) in the epithelial-mesenchymal transition (EMT) induced by HBx.

Methods

The association between HBx and EMT markers was detected using immunohistochemistry in HCC tissues. The effect of HBx on HCC EMT was assessed through morphological analysis, transwell assay, metastatic in vivo study and detection of EMT markers. LncRNA microarray was used to screen the differently expressed lncRNAs. Small interfering RNA and Western blot were used to analyse the function and mechanism of the locked lncRNA.

Results

HBx was negatively correlated with the epithelial marker E-cadherin but positively correlated with the mesenchymal marker vimentin in HCC tissues. HBx induced the mesenchymal phenotype and improved the metastatic ability of HCC cells. Meanwhile, HBx down-regulated E-cadherin, whereas it up-regulated vimentin. In HCC cells, HBx altered the expression of 2002 lncRNAs by more than 2-fold. One of them was ZEB2-AS1. Inhibition of ZEB2-AS1 can compensate for the EMT phenotype and reverse the expression of EMT markers regulated by HBx. Additionally, HBx affected the Wnt signalling pathway.

Conclusions

HBx promotes HCC cell metastasis by inducing EMT, which is at least partly mediated by lncRNAs.

     

Blockade of ARHGAP11A reverses malignant progress via inactivating Rac1B in hepatocellular carcinoma

Background

The molecular signaling events involving in high malignancy and poor prognosis of hepatocellular carcinoma (HCC) are extremely complicated. Blockade of currently known targets has not yet led to successful clinical outcome. More understanding about the regulatory mechanisms in HCC is necessary for developing new effective therapeutic strategies for HCC patients.

Methods

The expression of Rho GTPase-activating protein 11A (ARHGAP11A) was examined in human normal liver and HCC tissues. The correlations between ARHGAP11A expression and clinicopathological stage or prognosis in HCC patients were analyzed. ARHGAP11A was downregulated to determine its role in the proliferation, invasion, migration, epithelial-to-mesenchymal transition (EMT) development, and regulatory signaling of HCC cells in vitro and in vivo.

Results

ARHGAP11A exhibited high expression in HCC, and was significantly correlated with clinicopathological stage and prognosis in HCC patients. Moreover, ARHGAP11A facilitated Hep3B and MHCC97-H cell proliferation, invasion, migration and EMT development in vitro. ARHGAP11A knockdown significantly inhibited the in vivo growth and metastasis of HCC cells. Furthermore, ARHGAP11A directly interacted with Rac1B independent of Rho GTPase- activating activity. Rac1B blockade effectively interrupted ARHGAP11A-elicited HCC malignant phenotype. Meanwhile, upregulation of Rac1B reversed ARHGAP11A knockdown mediated mesenchymal-to-epithelial transition (MET) development in HCC cells.

Conclusion

ARHGAP11A facilitates malignant progression in HCC patients via ARHGAP11A-Rac1B interaction. The ARHGAP11A/Rac1B signaling could be a potential therapeutic target in the clinical treatment of HCC.

     

Monoacylglycerol lipase promotes progression of hepatocellular carcinoma via NF-κB-mediated epithelial-mesenchymal transition

Background

Monoacylglycerol lipase (MAGL), a critical lipolytic enzyme, has emerged as a key regulator of tumor progression, yet its biological function and clinical significance in hepatocellular carcinoma (HCC) is still unknown.

Methods

In this study, we used a tissue microarray containing samples from 170 HCC patients to evaluate the expression of MAGL and its correlation with other clinicopathologic characteristics. In addition, we investigated the regulating effects of MAGL on various HCC lines. Finally, we identified the NF-κB signaling pathway participated in MAGL-mediated epithelial-mesenchymal transition (EMT) using HCC cell lines with different metastatic potentials.

Results

The expression of MAGL was significantly higher in HCC tumors than in matched peritumor tissues. Specifically, high MAGL expression was found in tumors with larger tumor size, microvascular invasion, poor differentiation, or advanced TNM stage. In addition, the clinical prognosis for the MAGL^high group was markedly poorer than that for the MAGL^low group in the 1-, 3-, and 5-year overall survival times and recurrence rates of HCC patients. MAGL expression was an independent prognostic factor for both survival and recurrence after curative resection. Furthermore, the upregulation of MAGL in HCC cells promoted cell growth and invasiveness abilities, and accompanied by EMT. In contrast, downregulation of MAGL obviously inhibited these characteristics. Moreover, further investigations verified that MAGL facilitates HCC progression via NF-κB-mediated EMT process.

Conclusions

Our findings demonstrate MAGL could promote HCC progression by the induction of EMT and suggest a potential therapeutic target, as well as a biomarker for prognosis, in patients with HCC.

     

miR-1260b promotes cell migration and invasion of hepatocellular carcinoma by targeting the regulator of G-protein signaling 22

Objectives

To investigate whether miR-1260b can regulate migration and invasion of hepatocellular carcinoma (HCC) by targeting RGS22.

Results

miR-1260b was up-regulated in HCC tissues compared with their corresponding non-cancerous tissues. Over-expression of miR-1260b increased migration and invasion of HepG2 and SMMC-7721 cells associated with HCC. Regulator of G-protein signaling 22 (RGS22) was identified as a directly target of miR-1260b and was inhibited by miR-1260b. Knockdown of RGS22 increased proliferation of HCC cells.

Conclusions

The new identified miR-1260b/RGS22 axis provides useful therapeutic methods for treatment of HCC deepening on our understanding of underlying mechanisms of HCC tumorigenesis.

     

Relationship between TRAF6 and deterioration of HCC: an immunohistochemical and in vitro study

Objective

To explore the relationship between tumor necrosis factor receptor-associated factor 6 (TRAF6) and the clinicopathological features in HCC as well as its biological function.

Methods

Totally, 412 liver tissues were collected, including 171 hepatocellular carcinoma (HCC) and their corresponding non-tumor tissues, 37 cirrhosis and 33 normal liver tissues. The expression of TRAF6 was assessed by immunohistochemistry. Then, analysis of the correlations between TRAF6 expression and clinicopathological parameters in HCC was conducted. Furtherer, in vitro experiments on HepG2 and Hep3B cells were performed to validate the biological function of TRAF6 on HCC cells. TRAF6 siRNA was transfected into HepG2 and Hep3B cell lines and TRAF6 expression was evaluated with RT-qPCR and western blot. The assays of cell viability, proliferation, apoptosis and caspase-3/7 activity were carried out to investigate the effects of TRAF6 on HCC cells with RNA interference. Cell viability was assessed with Cell Titer-Blue kit. Cell proliferation was tested with MTS kit. Cell apoptosis was checked through morphologic detection with fluorescence microscope, as well as caspase-3/7 activity was measured with fluorogenic substrate detection.

Results

The positive expression rate of TRAF6 protein was 49.7 % in HCC, significantly higher than that of normal liver (12.1 %), cirrhosis (21.6 %) and adjacent non-cancerous tissues (36.3 %, all P < 0.05). Upregulated TRAF6 was detected in groups with metastasis (Z = ?2.058, P = 0.04) and with low micro-vessel density (MVD) expression (Z = ?2.813, P = 0.005). Spearman correlation analysis further showed that the expression of TRAF6 was positively correlated with distant metastasis (r = 0.158, P = 0.039) and negatively associated with MVD (r = ?0.249, P = 0.004). Besides, knock-down of TRAF6 mRNA in HCC cell lines HepG2 and Hep3B both resulted in cell viability and proliferation inhibition, also cell apoptosis induction and caspase-3/7 activity activation.

Conclusions

TRAF6 may contribute to metastasis and deterioration of the HCC via influencing cell growth and apoptosis. Thus, TRAF6 might become a predictive and therapeutic biomarker for HCC.

     

RNA-binding protein Dnd1 inhibits epithelial–mesenchymal transition and cancer stem cell-related traits on hepatocellular carcinoma cells

Objectives

To investigate the roles of Dead end 1 (Dnd1) in modulating cancer stem cell-related traits of hepatocellular carcinoma (HCC).

Results

Dead end (Dnd1) inhibited spheroid formation, suppressed the expression of stemness-related genes, and increased sensitivity to sorafenib in HCC cells. Mechanistically, Dnd1 could bind to 3′-UTR of LATS2, the key kinase of Hippo pathway, thus elevating LATS2 mRNA stability and its expression, subsequently leading to phosphorylation of YAP and its cytoplasmic retention. As a result, epithelial–mesenchymal transition (EMT) was weakened and therefore the generation of HCC stem cell properties was suppressed.

Conclusions

Dnd1 functions as a tumor suppressor by prohibiting CSC-like characteristics via activating Hippo pathway in HCC cells. Dnd1 could thus be a novel therapeutic target for HCC patients.

     

MYO18B promotes hepatocellular carcinoma progression by activating PI3K/AKT/mTOR signaling pathway

Background

MYO18B has been identified as a novel tumor suppressor gene in several cancers. However, its specific roles in the progression of hepatocellular carcinoma (HCC) has not been well defined.

Methods

We firstly identified the expression and prognostic values of MYO18B in HCC using TCGA cohort and our clinical data. Then, MYO18B knockdown by RNA inference was implemented to investigate the effects of MYO18B on HCC cells. Quantitative RT-PCR and Western blot were used to determine gene and protein expression levels. CCK-8 and colony formation assays were performed to examine cell proliferation capacity. Wound healing and transwell assays were used to evaluate the migration and invasion of HepG2 cells.

Results

MYO18B was overexpressed and correlated with poor prognosis in HCC. MYO18B expression was an independent risk factor for overall survival. Knockdown of MYO18B significantly inhibited the proliferation, migration and invasion of HepG2 cells. Meanwhile, MYO18B knockdown could effectively suppress the phosphorylation of PI3K, AKT, mTOR and P70S6K, suggesting that MYO18B might promote HCC progression by targeting PI3K/AKT/mTOR signaling pathway.

Conclusions

MYO18B promoted tumor growth and migration via the activation of PI3K/AKT/mTOR signaling pathway. MYO18B might be a promising target for clinical intervention of HCC.

     

miR-93 enhances hepatocellular carcinoma invasion and metastasis by EMT via targeting PDCD4

Objectives

To clarify the potential biological function of miR-93 and its related molecular mechanism underlying metastasis in human hepatocellular carcinoma (HCC).

Results

miR-93 was significantly up-regulated in HCC tissues and was associated with poor 5-year overall survival in HCC patients. Transwell assays showed that over-expression of miR-93 increased HCC cell migration and invasion in vitro. Programmed cell death 4 (PDCD4) was a target gene of miR-93 and miR-93 could down-regulate the expression of PDCD4 by directly targeting its 3′-UTR. The re-expression of PDCD4 could attenuate the HCC cell invasion and migration induced by miR-93, while the knockdown of PDCD4 would promote HCC cell migration and invasion via the epithelial-mesenchymal transition (EMT) pathway.

Conclusions

miR-93 provides new insight into the molecular mechanisms of pathogenesis and progression in HCC and offer a potential therapeutic target for the treatment of HCC patients.

     

Silencing TRIP13 inhibits cell growth and metastasis of hepatocellular carcinoma by activating of TGF-β1/smad3

Background

TRIP13 is highly expressed in several cancers and is closely connected with cancer progression. However, its roles on the growth and metastasis of hepatocellular carcinoma (HCC), and the underlying mechanism are still unclear.

Methods

Combining bioinformatics with previous studies, the correlation between TRIP13 and HCC was predicted. TRIP13 expressions from 52 HCC patients and several cell lines were determined. The effects of silencing TRIP13 on cell viability, apoptosis, migration and invasion were respectively detected using CCK-8, flow cytometry and Transwell. qRT-PCR and western blot were performed to reveal associated mechanism. A HCC model was established in BALB/c-nu mice by transplanting HepG2 cells. TRIP13 protein expression and apoptosis in mice tissues were accordingly detected by Immunohistochemistry and TUNEL.

Results

High expression of TRIP13 in HCC affected the survival rate and it was enriched in RNA degradation and fatty acid metabolism according to bioinformatics and prediction from previous literature. Increased expression of TRIP13 in HCC patient tissues was associated with the progression of HCC. Silencing TRIP13 inhibited cell viability, migration and invasion, and induced cell apoptosis. TRIP13 knockdown also suppressed the formation of tumor in vivo. Meanwhile, silencing TRIP13 decreased the expressions of Ki67 and MMP-2 and increased the expressions of TIMP-2, active-caspase-3 and TGF-β1/smad3 signaling- related genes.

Conclusions

Silencing TRIP13 acts as a tumor suppresser of HCC to repress cell growth and metastasis in vitro and in vivo, and such a phenomenon possibly involved activation of TGF-β1/smad3 signaling.

     

STARD13 promotes hepatocellular carcinoma apoptosis by acting as a ceRNA for Fas

Objectives

To study the roles of STARD13 in cellular apoptosis of hepatocellular carcinoma (HCC).

Results

Quantitative real-time PCR and immunohistochemistry analyses showed that the expression levels of STARD13 and Fas were lower in clinical HCC tissues than in normal tissues and were positively correlated, which is consistent with the results analyzed by The Cancer Genome Atlas (TCGA) data. Patients with higher STARD13 or Fas expression levels had longer overall survival. Additionally, STARD13 3′-UTR enhanced cellular apoptosis and the 3′-UTRs of STARD13 and Fas were predicted to harbor nine similar miRNA binding sites. And STARD13 3′-UTR promoted Fas expression in a 3′-UTR- and miRNA-dependent way and increased the sensitivity of HCC cells to chemotherapy. Importantly, the coding sequence of STARD13 did not increase Fas expression.

Conclusions

STARD13 3′-UTR promotes HCC apoptosis through acting as a ceRNA for Fas.

     

Metastatic tumor cells – genotypes and phenotypes

Background

Metastasis is the primary cause of mortality in cancer patients. Therefore, elucidating the genetics and epigenetics of metastatic tumor cells and the mechanisms by which tumor cells acquire metastatic properties constitute significant challenges in cancer research.

Objective

To summarize the current understandings of the specific genotype and phenotype of the metastatic tumor cells.

Method and Result

In-depth genetic analysis of tumor cells, especially with advances in the next-generation sequencing, have revealed insights of the genotypes of metastatic tumor cells. Also, studies have shown that the cancer stem cell (CSC) and epithelial to mesenchymal transition (EMT) phenotypes are associated with the metastatic cascade.

Conclusion

In this review, we will discuss recent advances in the field by focusing on the genomic instability and phenotypic dynamics of metastatic tumor cells.

     

Erythropoietin promoted the proliferation of hepatocellular carcinoma through hypoxia induced translocation of its specific receptor

Background

Erythropoietin (EPO) is a hypoxia-inducible stimulator of erythropoiesis. Besides its traditional application in anemia therapy, it offers an effective treatment in the cancer patients, especially those who receive chemotherapy. Several reports indicated that it could promote the tumor cell proliferation through its specific receptor (EPOR). Unfortunately, the role of EPO/EPOR in hepatocellular carcinoma (HCC) progressing is still uncertain.

Methods

Protein in tumor tissue from HCC patients or H22 tumor-bearing mice was detected with immunohistochemistry. Cells were cultured under 1% oxygen to establish hypoxia. RT-PCR and western blotting were used to measure mRNA and protein of EPO/EPOR, respectively. MTT, flow cytometry and PCNA staining were used to detect cell proliferation. Immunofluorescence staining was applied to study the expression and location of cellular EPOR. The EPOR binding studies were performed with ¹²⁵I-EPO radiolabeling assay.

Results

EPO and EPOR protein were up-regulated in HCC tissue of patients and H22-bearing mice. These were positively correlated with hypoxia-inducible factor -1 α and ki-67. Hypoxia up-regulated the expression of EPO and EPOR in HepG2 cells. It also induced the proliferation and increased the percentage of divided cells after 24, 48 and 72 h treatment. These were inhibited in cells pre-treated with 0.5 μg/mL soluble-EPOR. Immunofluorescence staining presented that EPOR was obviously translocated from nucleus to cytoplasm and membrane under hypoxia. EPOR binding activity was also increased after exposure to hypoxia. Recombinant human erythropoietin obviously elevated cell proliferation rate and the percentage of divided under hypoxia but not normoxia, which were also inhibited by soluble-EPOR.

Conclusions

Our result indicated for the first time that EPO promoted the proliferation of HCC cells through hypoxia induced translocation of it specific receptor. Trial registration TJC20141113, retrospectively registered

     

Targeted analysis of omega-6-derived oxylipins and parent polyunsaturated fatty acids in serum of hepatitis B virus-related hepatocellular carcinoma patients

Introduction

Arachidonic acid (AA)-derived prostaglandins recently have been implicated in pathogenesis of hepatocellular carcinoma (HCC). However, current understanding of omega-6-derived oxylipins that promote this disease remains limited, particularly on oxylipins derived from linoleic acid (LA).

Objective

Hepatitis B virus (HBV) infection is a major risk factor for HCC in Asia, we thus quantified AA- and LA-derived oxylipins and the two parent polyunsaturated fatty acids in HBV-related HCC patients to assist in understanding of the molecular pathogenesis of HCC.

Methods

Serum samples from 40 HBV-related HCC patients and 23 age-sex matched healthy controls were analyzed using liquid chromatography tandem mass spectrometry.

Results

LA, LA-derived oxylipins such as 9-hydroxyoctadecadienoic acid (9-HODE), 13-HODE, 9,10-dihydroxyoctadecenoic acid (9,10-DiHOME), and 12,13-DiHOME, as well as AA-derived oxylipins such as 5,6-dihydroxyeicosatrienoic acid (5,6-DiHETrE), 11,12-DiHETrE, and 14,15-DiHETrE, were significantly elevated in HCC patients compared to healthy controls. Of these, LA, 13-HODE, and 9-HODE showed good potential in differentiating HCC patients from healthy controls (AUC >0.8).

Conclusion

The study demonstrated LA- and AA-derived oxylipins via the lipoxygenase and cytochrome P450 pathways appeared to be most involved in the pathogenesis of HBV-related HCC.

     

CMTM5 is downregulated and suppresses tumour growth in hepatocellular carcinoma through regulating PI3K-AKT signalling

Background

Human chemokine like factor (CKLF)-like MAL and related proteins for vesicle trafficking transmembrane, domain-containing member 5 (CMTM5) has been shown to involved and may function as a tumour suppressor in tumorigenesis. The current study aimed to investigate the expression and function of CMTM5 in human hepatocellular carcinoma (HCC).

Methods

CMTM5 expression was examined by immunohistochemistry, and its clinical significance was analysed in 76 HCC specimens. The role and molecular mechanisms of CMTM5 in cell proliferation, apoptosis and invasion were examined in vitro and in vivo.

Results

CMTM5 expression was significantly downregulated in HCC tissues as well as cell lines. The expression of CMTM5 was absent in 77.6% of HCC tissues compared with 3.9% in normal liver tissues. Low CMTM5 expression was significantly correlated with poor overall survival in patients with HCC (P = 0.009). Restoring CMTM5 expression in Huh7 cells significantly inhibited cell growth, promoted cell apoptosis, and reduced cell metastatic and invasion ability compared with mock transfected cells in vitro. Overexpression of CMTM5 also suppressed xenograft tumour growth in vivo in a HCC xenograft model. Reduced cell growth and metastasis ability mediated by CMTM5 overexpression was associated with downregulation of PI3K/AKT and its downstream Bcl2, cyclinD1, cyclinE, MMP2 and MMP9 expressions, and an upregulation of p21, Bax, Bad, cleaved caspase3 expressions.

Conclusions

Our data suggest that CMTM5 might function as a tumour suppressor in human HCC, and represent a valuable potential therapeutic target for HCC.

     

Tat-DJ-1 enhances cell survival by inhibition of oxidative stress,NF-κB and MAPK activation in HepG2 cells

Objectives

To identify the protective effect of DJ-1 protein against oxidative stress-induced HepG2 cell death, we used cell-permeable wild type (WT) and a mutant (C106A Tat-DJ-1) protein.

Results

By using western blotting and fluorescence microscopy, we observed WT and C106A Tat-DJ-1 proteins were efficiently transduced into HepG2 cells. Transduced WT Tat-DJ-1 proteins increased cell survival and protected against DNA fragmentation and intracellular ROS generation levels in H₂O₂-exposed HepG2 cells. At the same time, transduced WT Tat-DJ-1 protein significantly inhibited NF-κB and MAPK (JNK and p38) activation as well as regulated the Bcl-2 and Bax expression levels. However, C106A Tat-DJ-1 protein did not show any protective effect against cell death responses in H₂O₂-exposed HepG2 cells.

Conclusions

Oxidative stress-induced HepG2 cell death was significantly reduced by transduced WT Tat-DJ-1 protein, not by C106A Tat-DJ-1 protein. Thus, transduction of WT Tat-DJ-1 protein could be a novel strategy for promoting cell survival in situations of oxidative stress-induced HepG2 cell death.

     

Hypoxia promotes the migration and invasion of human hepatocarcinoma cells through the HIF-1α–IL-8–Akt axis

Background

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. The 5-year survival rate remains low despite considerable research into treatments of HCC, including surgery, radiotherapy and chemotherapy. Many mechanisms within HCC still require investigation, including the influence of hypoxia, which has a crucial role in many cancers and is associated with metastasis. Hypoxia inducible factor-1α (HIF-1α) is known to regulate the expression of many chemokines, including interleukin-8 (IL-8), which is associated with tumor metastasis. Although many studies have reported that HIF-1α is associated with HCC migration and invasion, the underlying mechanisms remain unknown.

Methods

The expression level of HIF-1α was determined in HCC cells. The correlation of IL-8 and HIF-1α expressions was assessed via knockdown of HIF-1α. HCC cells were also used to assess the influence of HIF-1α on HCC cell migration and invasion. LY294002, an inhibitor of the Akt pathway, was used to confirm the associated signaling pathways.

Results

We observed a significant attenuation of cell migration and invasion after silencing of HIF-1α. Exogenously expressing IL-8 restored migration and invasion. Akt was found to be involved in this process.

Conclusion

Hypoxia promotes HCC cell migration and invasion through the HIF-1α–IL-8–Akt axis.

     

Anti-hyperglycemic effect of loquat leaf extract is associated with the redistribution of glucose carbon to its metabolites: a <Superscript>13</Superscript>C-tracing study in HepG2 cells

Introduction

Loquat leaf extract (LLE) is commonly used in China for a variety of ailments including diabetes. Several recent reports implicate LLE and a sesquiterpene glycoside, one of its components, as being an anti-hyperglycemic agent. However, the underlying mechanism of action of this anti-hyperglycemic agent has not been reported.

Objective

We have conducted a tracer-based metabolomics study to investigate the effects of sesquiterpene and loquat extract on the balance of flux of central glucose metabolism in HepG2 cells and to compare with those of “insulin sensitizers”, metformin and rosiglitazone.

Methods

Human hepatoma HepG2 cells in confluence culture were incubated in Dulbecco’s modified Eagle’s medium containing 50% [1, 2 ¹³C₂]-glucose in the presence of rosiglitazone, metformin, LLE or pure sesquiterpene. Cells were harvested in 48 h. Mass isotopomers of metabolites (glycogen, ribose, deoxyribose, glutamate and palmitate) were determined.

Results

¹³C labeling in metabolic intermediates were summarized in a mass isotopomer matrix. Treatment with loquat extract/sesquiterpene, metformin and rosiglitazone each produced distinctive mass isotopomer patterns reflecting disparate effects on the contribution of glucose to various metabolites production, and on several metabolic flux ratios. The overall effect of LLE and sesquiterpene on glucose metabolism is clearly different from those of the known “insulin sensitizers”.

Conclusion

Our study demonstrates the utility of isotopomer matrix in summarizing metabolic actions of LLE on the balance of fluxes occurring within the central glucose metabolism in HepG2 cells. ¹³C carbon tracing (tracer-based metabolomics) is a useful systems biology tool to elucidate glucose metabolic pathways affected by diabetes and its treatment.

     

Prognostic significance of microvascular invasion in tumor stage for hepatocellular carcinoma

Background

The presence of microvascular invasion (McVI) in hepatocellular carcinoma (HCC) has been proposed as a cause of recurrence and poor survival, although this has not been officially emphasized in staging systems. Thus, we conducted a retrospective study to investigate the prognostic importance of McVI in tumor staging in patients with HCC who underwent hepatic resection.

Methods

A retrospective analysis was performed of patients who underwent hepatic resection for HCC at our center from 1994 to 2012. Patients with HCC were classified into four groups based on the presence of McVI and extent of gross vascular invasion (VI).

Results

The 5-year overall and recurrence-free survival rates of 676 patients were 63.3 and 42.6%, respectively. There was no difference in tumor recurrence or survival rate between patients with HCC and McVI without gross VI and those with gross VI confined to segmental/sectional branches. Multivariate analysis revealed that the extent of VI based on the presence of McVI and gross VI was independently associated with tumor recurrence and overall survival.

Conclusions

McVI was revealed to be an important risk factor similar to gross VI confined to a segmental/sectional branch in patients with HCC who underwent hepatic resection. This finding should be considered when estimating the stage for prognosis.