The aim of our study was to elucidate the effect of tacrolimus (FK506) and of C-X-C chemokine receptor type 4 (CXCR4), which is a receptor specific to the stromal cell-derived factor-1α (SDF‑1α), on growth and metastasis of hepatocellular carcinoma (HCC). Following treatment with different concentrations of FK506, AMD3100 or normal saline (NS), the proliferation of Morris rat hepatoma 3924A (MH3924A) cells was measured by the MTT assay, the expression of CXCR4 was analyzed with immunohistochemistry, and the morphological changes and the invasiveness of cells were studied with a transwell assay and under a scanning electron microscope, respectively. In addition, August Copenhagen Irish rat models implanted with tumor were used to examine the pathological changes and invasiveness of tumor in vivo, the expression of CXCR4 in tumor tissues and the expression of SDF‑1α in the adjacent tissues to the HCC ones, using immunohistochemistry. In vitro, FK506 (100‑1,000 µg/l) significantly promoted the proliferation of MH3924A cells (P<0.01), and increased the expression of CXCR4 in MH3924A cells, albeit with no significance (P>0.05). By contrast, AMD3100 had no effect on the proliferation of MH3924A cells, but significantly reduced the expression of CXCR4 (P<0.05). The invasiveness of MH3924A cells was significantly (P<0.01) enhanced following treatment with FK506, SDF‑1α, FK506 + AMD3100, FK506 + SDF‑1α or FK506 + AMD3100 + SDF‑1α. In vivo, tumor weight (P=0.041), lymph node metastasis (P=0.002), the number of pulmonary nodules (P=0.012), the expression of CXCR4 in tumor tissues (P=0.048) and that of SDF‑1α in adjacent tissues (P=0.026) were significantly different between the FK506-treated and the NS group. Our results suggest that FK506 promotes the proliferation of MH3924A cells and the expression of CXCR4 and SDF‑1α in vivo. Therefore, inhibiting the formation of the CXCR4/SDF‑1α complex may partly reduce the promoting effect of FK506 on HCC.
Liver transplantation (LT) is one of the curative treatments for hepatocellular carcinoma (HCC). However, cancer recurrence and metastasis after LT are common in some HCC patients with high-risk factors (even in those within the Milan criteria). It remains unclear whether adjuvant therapy with sorafenib inhibits HCC recurrence and metastasis after LT. Therefore, we performed orthotopic LT in an August Irish Copenhagen (ACI) rat model of HCC. Because LT involves immune rejection and tolerance and it is unknown whether sorafenib influences the immune response, we also investigated the effects of sorafenib on immune balance. In this study, we established an allogeneic rat LT model in which liver grafts were taken from Lewis rats and transplanted into ACI rats with orthotopic HCC, and they were administered cyclosporine A to prevent acute allograft rejection. From day 7 after LT, sorafenib was administrated at 30 mg/kg/day for 3 weeks. Our results showed that the serum levels of vascular endothelial growth factor and hepatocyte growth factor significantly increased after LT, and the T helper 1 (T(h)1)/T helper 2 (T(h)2) immune balance was shifted toward a T(h)2 response after immunosuppressant administration. In comparison with controls, the rats in the sorafenib group showed significantly inhibited extracellular signal-regulated kinase phosphorylation and improved progression-free survival and overall survival. The tumor proliferation rate and angiogenesis in posttransplant recurrent tumor tissues decreased in the sorafenib group, and the tumor apoptosis rate increased. There was no significant difference in the T(h)1/T(h)2 immune balance between the sorafenib and control groups. In conclusion, adjuvant therapy with sorafenib is highly effective at inhibiting cancer recurrence and metastasis without influencing the immune balance after LT for HCC with high expression of phosphorylated extracellular signal-regulated kinase. This study suggests that sorafenib may have potential, particularly as part of a stratified medicine approach to HCC treatment after LT.
To investigate the surgical outcome of the hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) after surgery and the time-dependency of the factors influencing survival.The clinicopathological data of 382 HCC patients with macroscopic PVTT who had undergone resection of HCC were analyzed. The survival rte was calculated using Kaplan-Meier method. Stratified Cox model was used to identify the factors independently influencing the short- and long-term survival rates.The 1-, 2-, 3-, 5-, and 10-year survival rates of the 382 patients were 47%, 23%, 16%, 12%, and 6% respectively. The 1-, 3-, and 5-year survival rates re-calculated from the time of re-resection because of recurrence within 2 years after the first operation were 36%, 14%, and 0% 1 respectively. However, the 1-, 3-, and 5-year survival rates re-calculated from the time of re-resection because of recurrence 2 years after the first operation were 85%, 53%, and 32%, all significantly higher than those re-calculated from the time of re-resection within 2 years after the first operation (all P < 0.05). Multivariate analysis showed that portal infusion chemotherapy, serum alpha-fetoprotein < 20 microg/L and negative surgical margin were significant favorable prognostic factors within 2 years after operation. Alanine aminotransferase > 80 U/L was the only significant unfavorable factor beyond 2 years after operation.The prognosis of the patients with macroscopic PVTT who suffer from liver tumor recurrence occurring more than 2 years after the first operation is much better than those with the recurrence occurring within 2 years. Evaluation of the time-dependency of risk factors may have important clinical implication in determining the therapeutic strategy.
Abstract Liver transplantation (LT) is one of the best therapeutic options for nonresectable hepatocellular carcinoma (HCC). Unfortunately, some HCC patients succumb to the disease after LT, which reduces long- and medium-term survival. To identify the proteins associated with HCC invasion and metastasis, HCC patients undergoing LT with complete follow-up data were included in this study and were categorized into recurrence and nonrecurrence groups. We extracted the total protein from the acquired homogeneous tumor cells and applied a cleavable isotope-coded affinity tag technology to quantitate relative changes in protein levels between the two groups. We identified a total of 149 proteins with two-dimensional liquid chromatography coupled with tandem mass spectrometry, including 52 differentially expressed proteins by at least two-fold. Among them, calpain small subunit 1 (Capn4), a protein with relevant interactions with many migration–invasion-related proteins, has attracted more attention. First, Capn4 overexpression in the recurrence group was confirmed via real-time polymerase chain reaction and western blotting in another cohort of 40 HCC patients undergoing LT. Second, Capn4 was associated with enhanced invasiveness in vitro. The small interfering RNA–mediated knockdown expression of Capn4 in HCC cell lines significantly inhibited its mobile and invasive ability. Tissue microarray in a further 192 cases revealed that Capn4 significantly correlated with invasive phenotype of HCC, and univariate and multivariate analyses indicated that Capn4 is an independent prognostic factor for recurrence and survival of HCC patients. Conclusion : Our study revealed that Capn4 overexpression underlies invasion and metastasis after LT for HCC and might be a candidate biomarker for future diagnosis and a target for therapy. (Hepatology 2008.)
e16610 Background: Combination therapy of anti-angiogenic therapy and anti-PD-1 antibody had shown promising anti-tumor effects for advanced hepatocellular carcinoma (HCC) in clinical trials. Here we report the effectiveness and safety of the combination therapy of lenvatinib and anti-PD-1 antibodies in a cohort of unresectable or advanced HCC pts. Methods: From Sep 2018 to Jan 2020, 77 consecutive pts received a combination treatment of lenvatinib and an anti-PD-1 antibody. Lenvatinib was given 8 mg/d regardless of patient body weight and anti-PD-1 antibody was used either q2wk (nivolumab or camrelizumab) or q3wk (pembrolizumab, sintilimab or toripalimab). pts who completed at least one efficacy and safety assessment were eligible for this study. Tumor response were evaluated with abdominal contrast-enhanced MRI/CT and/or chest CT every 2 mo (± 1 wk). Laboratory tests were monitored every 2-3 wk. Results: 59 pts were eligible for this study. Of them, 1 (1.7%) were BCLC stage A, 10 (16.9%) were BCLC stage B, 48 (81.4%) were BCLC stage C (including 20 pts in China Liver Cancer [CNLC] stage IIIa and 28 in CNLC stage IIIb). 43 (72.9%) pts were treated as first-line therapy. The table below shows efficacy results. R0 resection was performed in 6 (10.2%) pts due to tumor regression. By the data cut-off date, 13 pts died, and mOS was not mature. Overall, the combination treatment was well tolerated. 28 (47.5%) pts had at least one ≥ grade 3 treatment-emergent adverse event. 3 (5.1%) pts died from immune-related adverse events, 2 of them died from immune-related adverse events after hepatectomy. Conclusions: The combination of lenvatinib + anti-PD-1 antibody is effective and well-tolerated in pts with HCC as first-line or second-line treatment. It is also noted that initially unresectable HCC may be converted to resectable HCC following this combination treatment. [Table: see text]
Abstract Background Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, the relationship between radiographic and histopathological response remains unclear. Methods We retrospectively examined patients with initially unresectable HCC who received tyrosine kinase inhibitor (TKI) plus anti–programmed death 1 (PD-1) therapy before undergoing liver resection between March 2019 and September 2021 across 7 hospitals in China. Radiographic response was evaluated using mRECIST. A pCR was defined as no viable tumor cells in resected samples. Results We included 35 eligible patients, of whom 15 (42.9%) achieved pCR after systemic therapy. After a median follow-up of 13.2 months, tumors recurred in 8 non-pCR and 1 pCR patient. Before resection, there were 6 complete responses, 24 partial responses, 4 stable disease cases, and 1 progressive disease case, per mRECIST. Predicting pCR by radiographic response yielded an area under the receiver operating characteristic curve (AUC) of 0.727 (95% CI: 0.558–0.902), with an optimal cutoff value of 80% reduction in the enhanced area in MRI (called major radiographic response), which had a 66.7% sensitivity, 85.0% specificity, and a 77.1% diagnostic accuracy. When radiographic response was combined with α-fetoprotein response, the AUC was 0.926 (95% CI: 0.785–0.999); the optimal cutoff value was 0.446, which had a 91.7% sensitivity, 84.6%, specificity, and an 88.0% diagnostic accuracy. Conclusions In patients with unresectable HCC receiving combined TKI/anti–PD 1 therapy, major radiographic response alone or combined with α-fetoprotein response may predict pCR.
Objective To evaluate the dynamic balance of Th1, Th2, Th17 and iTreg cells in the process of acute rejection (AR) , orthotopic liver transplantation (OLT) was performed from LEW rats to BN rats. Methods OLT donated by male inbred LEW rats was performed on male inbred BN rats by Kamada' s two-cuff technique without liver arterial anastomosis, AR severity was graded using the Banff schema ,and the immunohistological method was applied to detect the expression of T-bet+, GATA-3+, RORγt+, and FOXP3+ cells in liver allografts. Results The number of T-bet+ cells (Control group: 19. 3±5. 1;Mild AR group: 63. 7±9. 7;Moderate AR group: 40. 9±13. 6;Severe AR group: 32. 3±3. 3) and RORγt + (Control group: 6. 5±1. 4;Mild AR group: 6.4±3. 1;Moderate AR group: 23. 2±9. 1;Severe AR group: 42. 6±14. 1) was significantly increased in mild, moderate and severe AR groups as compared with control group (all P 0. 05) , while it was significantly higher in moderate and severe AR group (P 0. 05), but it was significantly decreased in moderate and severe AR group (all P<0.01). The ratio of T-bet + cells/GATA-3+cells was more significantly associated with AR than that of RORγt+cells/FOXP3+ cells in the early stage. Conclusion There is dynamic change in T-het+,GATA-3+,RORγt+and FOXP3+cells in the liver allografts.The T-bet+,GATA-3,RORγt'and FOXP3+cells were involved in AR,and the ratio of T-bet+cell/sGATA-3+cells was more significantly associated with AR than that of RORγt+cells/FOXP3+cells in the early stage.
Key words:
Liver transplantation; Acute rejection; Nuclear transcriptional factors
MicroRNAs (miRNAs) are endogenous small non-coding RNAs that repress their targets at post transcriptional level. Existing studies have shown that miRNAs are important regulatory genes in hepatocellular carcinoma (HCC), as either tumor suppressors or oncogenes. MiR-122 is normally downregulated in HCC and regarded as a tumor suppressor. Recently miR-122 has been reported to be regulated by CEBPA, which is then involved in a novel pathway to influence proliferation of tumor cells. However it is unknown whether CEBPA is regulated by miRNAs in HCC. In this study, we find that miR-182 is upregulated in HCC model rat, and represses CEBPA in both rat and human. This further improves the current CEBPA/miR-122 pathway that controls the proliferation of tumor cells. These results suggest that miR-182 is a potential oncogene in HCC and could be used as a diagnostic marker and drug target of HCC.
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