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Kinesin family member 2C (KIF2C), a substantial mitotic regulator, has been verified to exert a malignant function in several cancers. However, its function in hepatocellular carcinoma (HCC) remains unclear. In this study, the expression profile of KIF2C in HCC was characterized through the dataset from the TCGA and clinical tissue microarrays containing 220 pairs of resected HCC tissues and adjacent nontumor tissues in our hospital. The results indicated that KIF2C was substantially higher expression in tumor tissues than adjacent nontumor tissues. High expression of KIF2C significantly correlated with large tumor (>5.0 cm) (P = .001) and implied a dismal postoperative overall survival (OS) (hazard ratio [HR] = 1.729; P = .002) in our cohort of patients. Gain and loss of function assays displayed that KIF2C promoted HCC cell proliferation, accelerated cell cycle progression, and impeded apoptosis. By bioinformatic tools and mechanistic investigation, we found that KIF2C interacted with various cell-cycle-related proteins and was significantly involved in growth-promoting pathways. KIF2C upregulated PCNA and CDC20 expression. Subsequently, we investigated the regulation of KIF2C by competing endogenous RNA and elucidated that has-miR-6715a-3p was directly bond to the 3'-untranslated region of KIF2C through dual luciferase assays, thereby inhibiting KIF2C expression. Furthermore, the long noncoding RNA GS1-358P8.4 was found to be a candidate of KIF2C for has-miR-6715a-3p binding. HCC patients with high lncRNA-GS1-358P8.4 expression had shorter OS and relapse-free survival compared to those with low expression, which was accordance with the KIF2C. Taken together, KIC2C aggravated HCC progression, it could serve as a prognostic indicator and confer a novel target for clinical treatment., (© 2020 Wiley Periodicals, Inc.)

Background: The predictive model of postsurgical recurrence for solitary early hepatocellular carcinoma (SE-HCC) is not well established. The aim of this study was to develop a novel model for prediction of postsurgical recurrence and survival for patients with hepatitis B virus (HBV)-related SE-HCC ≤10 cm., Patients and Methods: Data from 1,081 patients with HBV-related SE-HCC ≤10 cm who underwent curative liver resection from 2003 to 2016 in our center were collected retrospectively and randomly divided into the derivation cohort (n = 811) and the internal validation cohort (n = 270). Eight hundred twenty-three patients selected from another four tertiary hospitals served as the external validation cohort. Postsurgical recurrence-free survival (RFS) and overall survival (OS) predictive nomograms were generated. The discriminatory accuracies of the nomograms were compared with six conventional hepatocellular carcinoma (HCC) staging systems., Results: Tumor size, differentiation, microscopic vascular invasion, preoperative α-fetoprotein, neutrophil-to-lymphocyte ratio, albumin-to-bilirubin ratio, and blood transfusion were identified as the risk factors associated with RFS and OS. RFS and OS predictive nomograms based on these seven variables were generated. The C-index was 0.83 (95% confidence interval [CI], 0.79-0.87) for the RFS-nomogram and 0.87 (95% CI, 0.83-0.91) for the OS-nomogram. Calibration curves showed good agreement between actual observation and nomogram prediction. Both C-indices of the two nomograms were substantially higher than those of the six conventional HCC staging systems (0.54-0.74 for RFS; 0.58-0.76 for OS) and those of HCC nomograms reported in literature., Conclusion: The novel nomograms were shown to be accurate at predicting postoperative recurrence and OS for patients with HBV-related SE-HCC ≤10 cm after curative liver resection., Implications for Practice: This multicenter study proposed recurrence or mortality predictive nomograms for patients with hepatitis B virus-related solitary early hepatocellular carcinoma ≤10 cm after curative liver resection. A close postsurgical surveillance protocol and adjuvant therapy should be considered for patients at high risk of recurrence., (© 2020 AlphaMed Press.)

Background: The influence of perioperative blood transfusion (PBT) on postsurgical survival of patients with different stage of hepatocellular carcinoma (HCC) is not well clarified. This study aimed to evaluate the impact of PBT on survival outcomes of different stage of HCC patients., Methods: Consecutive patients who underwent liver resection for HCC between January 2009 and November 2015 were identified from an HCC prospective database in authors' center. The survival outcomes were compared between patients receiving PBT and those without PBT before and after propensity score matching (PSM) in different stage subsets. Cox regression analysis was performed to verify the impact of PBT on outcomes of HCC., Results: Among 1255 patients included, 804 (64.1%) were Barcelona Clinic Liver Cancer (BCLC) stage 0-A, and 347 (27.6%) received PBT. Before PSM, patients with PBT had worse disease free survival (DFS) and overall survival (OS) compared with those without PBT in both BCLC 0-A subset and BCLC B-C subset (all P < 0.05). After PSM, 288 pairs of patients (with and without PBT) were created. In the subset of BCLC 0-A, the median DFS of patients with PBT was shorter than those without PBT (12.0 months vs. 36.0 months, P = 0.001) Similar result was observed for OS (36.0 months vs. 96.0 months, P = 0.001). In the subset of BCLC B-C, both DFS and OS were comparable between patients with PBT and those without PBT. Cox regression analysis showed that PBT involved an increasing risk of DFS (HR = 1.607; P < 0.001) and OS (HR = 1.756; P < 0.001) for this subset. However, PBT had no impact on DFS (P = 0.126) or OS (P = 0.139) for those with stage B-C HCC., Conclusions: PBT negatively influenced oncologic outcomes of patient with BCLC stage 0-A HCC, but not those with stage B-C after curative resection.

Fructose-1,6-bisphosphatase (FBP1), one of the rate-limiting gluconeogenic enzymes, plays critical roles in several cancers and is treated as a tumour suppressor. However, its role in hepatocellular carcinoma (HCC) is unclear. Here, we demonstrated that FBP1 was significantly inhibited during Snail-induced epithelial to mesenchymal transition (EMT) and tissues in HCC. Restoration of FBP1 expression in HCC cancer cells suppressed EMT phenotype, tumour migration and tumour growth induced by Snail overexpression in SMMC-7721 cells. Gene set enrichment analyses revealed significantly enriched terms, including WNT, Notch, ESC, CSR and PDGF, in the group with high Snail and low FBP1 compared with those with low Snail and high FBP1. Low FBP1 expression was significantly correlated with higher AFP level, satellite nodules, portal vein tumour thrombus, and advanced tumour stage. Survival analyses showed that FBP1 was an independent prognostic factor for overall survival and recurrence-free survival. In conclusion, our study revealed a vital role for FBP1 in Snail-induced EMT and prognostic prediction in HCC.

Background: The function of hornerin (HRNR), a member of the S100 protein family, is poorly clarified in the development of human tumors. The role of HRNR in hepatocellular carcinoma (HCC) progression is investigated in the study., Methods: The expression levels of HRNR were assessed in tumor samples from a cohort of 271 HCC patients. The effect of HRNR on proliferation, colony formation and invasion of tumor cells was examined. We further determined the role of HRNR in tumor growth in vivo by using xenograft HCC tumor models. The possible mechanism of the HRNR promotion of HCC progression was explored., Results: We found that HRNR was overexpressed in HCC tissues. The high expression of HRNR in HCCs was significantly associated with vascular invasion, poor tumor differentiation, and advanced TNM stage. The disease-free survival (DFS) and overall survival (OS) of HCC patients with high HRNR expression were poorer than those in the low HRNR expression group. HRNR expression was an independent risk factor linked to both poor DFS (HR = 2.209, 95% CI = 1.627-2.998,P <  0.001) and OS (HR = 2.459,95% CI = 1.736-3.484, P <  0.001). In addition, the knockdown of HRNR by shRNAs significantly inhibited the proliferation, colony formation, migration and invasion of HCC tumor cells. HRNR silencing led to the decreased phosphorylation of AKT signaling. Notably, tumor growth was markedly inhibited by HRNR silencing in a xenograft model of HCC., Conclusions: HRNR promotes tumor progression and is correlated with a poor HCC prognosis. HRNR may contribute to HCC progression via the regulation of the AKT pathway.

Background: Liver resection is effective for hepatocellular carcinoma (HCC) exceeding the Milan criteria in selected patients. However, the benefit of anatomical resection (AR) versus non-anatomical resection (NAR) has not been clarified in this patient subgroup. This study aimed to compare outcomes between AR and NAR for HCC exceeding the Milan criteria., Methods: Data on consecutive patients with HCC exceeding the Milan criteria who underwent liver resection with curative intent over a recent 6-year interval were extracted from a prospective single-centre HCC database and examined retrospectively. The postoperative outcomes of patients were compared before and after propensity score matching., Results: Some 546 patients were included: 264 in the AR and 282 in the NAR group. In the original cohort, the AR group contained more patients with larger tumours, multiple tumours, macroscopic portal vein tumour thrombi, incomplete tumour capsules and microscopic vascular invasion. After propensity score matching, 177 pairs of patients were selected. The baseline data, including liver function and tumour burden, were similar in the matched groups. The 3-year recurrence-free survival rate was comparable between the matched NAR and AR groups (36·5 versus 28·5 per cent; P = 0·448). Similar results were observed for 3-year overall survival (57·5 versus 50·3 per cent; P = 0·385), recurrence patterns and early recurrence rates (57·6 per cent versus 59·9 per cent; P = 0·712)., Conclusion: AR and NAR achieved favourable and similar outcomes for HCC exceeding the Milan criteria in selected patients., (© 2016 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background & Aims: BCAT1 initiates the catabolism of branched-chain amino acids. Here, we investigated the function of BCAT1 and its transcriptional regulatory mechanism in hepatocellular carcinoma (HCC)., Methods: RNASeq was used to evaluate BCAT1 mRNA levels in HCC and normal matched specimens. After the exogenous expression of BCAT1 in BEL-7404 cells and the suppression of endogenous BCAT1 expression with shRNA in HepG2 cells, the cell proliferation, clone-forming ability and cell-cycle changes were measured with MTT assay, colony-forming assay and flow cytometry respectively. A xenograft model was used to investigate the effect of BCAT1 on cancer growth in vivo. Chromatin immunoprecipitation and luciferase reporter technologies were used to confirm the transcriptional regulation of the BCAT1 gene by MYC. The expression of the BCAT1 and MYC proteins in 122 HCC tissues was determined with an immunohistochemical analysis., Results: BCAT1 mRNA was clearly increased in HCC tissues and hepatomas. The ectopic expression of BCAT1 in BEL-7404 cells enhanced their proliferation, clone formation, tumourigenic properties, S-G 2 /M phase transition and chemoresistance to cisplatin. The suppression of BCAT1 expression in HepG2 cells significantly inhibited their proliferation, clone formation, and S-G 2 /M phase transition and caused their chemosensitization to cisplatin. MYC affected the transcriptional regulation of BCAT1. Clinical data showed that BCAT1 expression correlated with a significantly poorer prognosis., Conclusion: BCAT1 plays a pathogenic role in HCC by causing cell proliferation and chemoresistance. The MYC transcription factor is involved in regulating the transcriptional activity of BCAT1. BCAT1 expression has prognostic significance for the survival of patients with HCC., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To confirm the anticancer effect of total annonaceous acetogenins (TAAs) abstracted from Annona squamosa Linn. on human hepatocarcinoma., Methods: The inhibitory effect of TAAs was demonstrated in H22-bearing mice. The potency of TAAs was confirmed as its 50% inhibiting concentration (IC50) on Bel-7402 cell under Sulfur Rhodamine B staining. Both underlying mechanisms were explored as cellular apoptosis and cell cycle under flow cytometry. Mitochondrial and recipient apoptotic pathways were differentiated as mitochondrial membrane potential under flow cytometry and caspases activities under fluorescence analysis., Results: The inhibitory rate of TAAs in mice was 50.98% at 4 mg/kg dose. The IC50 of TAAs on Bel-7402 was 20.06 µg/mL (15.13-26.61µg/mL). Effective mechanisms of TAAs were confirmed as both of arresting cell cycle at G1 phase and inducing apoptosis dose- and time-dependently. Mitochondrial and recipient pathways involved in apoptotic actions of TAAs., Conclusion: TAAs is effective for hepatocarcinoma, via inhibiting proliferation and inducing apoptosis.

Neutrophil-to-lymphocyte ratio (NLR), an inflammation index, is considered a prognostic predictor of hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic value of preoperative peripheral NLR in patients with hepatitis B virus (HBV)-associated HCC after radical hepatectomy. Clinical data were collected from patients with HBV-associated HCC who underwent radical hepatectomy. NLR was calculated from lymphocyte and neutrophil counts on preoperative routine blood tests. Demographics, laboratory analyses, and histopathological data were analyzed. A total of 282 patients were selected and divided by the cutoff NLR value of 2. Multivariate analysis showed that NLR > 2 was an independent prognostic predictor of poor disease-free survival [hazard ratio (HR) = 1.362; 95% confidence interval (CI) 1.025-1.811; P = 0.033] and overall survival (HR = 1.434; 95% CI 1.044-1.970; P = 0.023). NLR had a good predictive value for prognosis in patients with HBV-associated HCC who had normal serum AFP level. These results suggested that NLR is an independent indicator of both disease-free survival and overall survival in patients with HBV-associated HCC after radical hepatectomy, including AFP-normal patients.

The prognostic value of the fibroblast growth factor-inducible 14 (Fn14) expression in hepatocellular carcinoma (HCC) is unknown. Real-time PCR (RT-PCR), western blot assays and immunohistochemistry analysis were here performed in order to compare Fn14 expressions in paired liver samples of HCC and normal liver tissue. Most of the tumor tissues expressed significantly higher levels of Fn14 compared to adjacent non-tumor tissues, with Fn14High accounting for 54.6% (142/260) of all patients. The Pearson χ(2) test indicated that Fn14 expression was closely associated with serum alpha fetal protein (AFP) (P=0.002) and tumor number (p=0.019). Univariate and multivariate analyses revealed that along with tumor diameter and portal vein tumor thrombosis (PVTT ) type, Fn14 was an independent prognostic factor for both overall survival (OS) (HR=1.398, p=0.008) and recurrence (HR=1.541, p=0.001) rates. Fn14 overexpression HCC correlated with poor surgical outcome, and this molecule may be a candidate biomarker for prognosis as well as a target for therapy.

Background: The aim of this study was to evaluate the clinical value of adjuvant chemobiotherapy via portal vein for patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombi (PVTT) following hepatectomy plus thrombectomy., Methods: Eighty-six HCC patients with tumor thrombi in the portal trunk and/or the first-order branch were divided into groups A (n = 33) and B (n = 53). Patients in group A were treated with hepatectomy plus portal thrombectomy in combination with postoperative adjuvant chemobiotherapy administered via portal vein. The chemobiotherapy regimen consisted of 5-FU, adriamycin, cisplatin, and IFNalpha. Patients in Group B were subjected to hepatectomy plus thrombectomy alone. Survival rates of the two groups were compared and prognostic factors were identified using Cox proportional hazards model., Results: Group A had a significantly longer median tumor-free survival time and median survival time compared with group B, i.e., 5.1 vs. 2.5 months (p = 0.017) and 11.5 vs. 6.2 months (p = 0.007), respectively. One-, two-, and three-year tumor-free survival rates were remarkably higher in group A than in group B, i.e., 18.4% vs. 8.4%, 13.8% vs. 4.2%, and 9.2% vs. 4.2%, respectively. One-, two-, and three-year survival rates were markedly greater in group A than in group B, i.e., 46.8% vs. 23.4%, 14.4% vs. 5.8%, and 9.6% vs. 5.8%, respectively. Multivariate analysis using the Cox proportional hazards model revealed that adjuvant chemobiotherapy, pathologic grading, and tumor size were independent prognostic factors for survival time (p = 0.000, 0.001, and 0.013, respectively), and chemobiotherapy and pathologic grading were independent prognostic factors for tumor-free survival time (p = 0.002 and 0.003, respectively)., Conclusions: Surgical resection combined with adjuvant chemobiotherapy via portal vein is an effective and safe treatment modality for hepatocellular carcinoma with major portal vein thrombus.

Objective: To evaluate the efficacy of surgical treatment combined with immunochemotherapy via portal vein for hepatocellular carcinoma (HCC) with major portal vein tumor thrombus (PVTT)., Methods: Between January 2001 and December 2005 76 HCC patients with tumor thrombus in portal trunk and (or) the first-order branch were recruited into the study. Patients were divided into group A (n = 29) and B (n = 47). Patients in group A were treated with hepatectomy plus portal thrombectomy in combination with postoperative adjuvant immunochemotherapy administered via portal vein. The immunochemotherapy regimen consisted of 5-Fluorouracil, Adriamycin, platinol and alpha-Interferon (PIAF). Patients in group B were subjected to hepatectomy plus thrombectomy alone. Survival rates were compared between two groups, and prognostic factors were identified., Results: Half-, One-, two- and three-year cumulative survival rates were markedly greater in group A than group B, being 82.3% vs 52.7%, 46.5% vs 20.2%, 14.3% vs 5.8%, 14.3% vs 5.8%, respectively. Group A had a significantly longer median survival time and median tumor-free survival time as compared with group B, being 11.5 months vs 6.0 months (P = 0.010), 4.5 months vs 2.4 months (P = 0.032), respectively. Multivariate analysis revealed that immunochemotherapy, pathological grading and tumor size were independent factors for survival times. And immunochemotherapy and pathological grading were independent factors for tumor-free survival time., Conclusions: Surgical resection combined with adjuvant immunochemotherapy via portal vein represents as an effective modality for HCC with PVTT.