INTRODUCTION:Hepatocellular carcinoma (HCC) is a leading cause of global cancer fatality. Understanding its molecular mechanisms is crucial for developing effective treatments. METHODS:Differentially expressed genes (DEGs) in the cancer genome atlas (TCGA)-liver hepatocellular carcinoma (LIHC) and GSE101685 data sets were analyzed using the "limma" tool in R. Weighted Gene Co-expression Network Analysis (WGCNA) identified the key turquoise module. Bioinformatics analyzed the prognostic significance and expression of CCDC137. Functional analyses assessed the effects of CCDC137 on cell behavior and tumor growth. The connection between CCDC137 and DGCR8 and their impact on the AKT/mTOR signaling pathway and glycolysis were also examined. RESULTS:A total of 670 overlapping DEGs were identified, and CCDC137, located within the turquoise module, was found to be significantly associated with HCC. CCDC137 was upregulated in HCC, correlating with worse prognostic outcomes. Experimental validation demonstrated that CCDC137 knockdown significantly reduced HCC cell proliferation, migration, invasion, and tumor growth. Mechanistically, CCDC137 may promote aerobic glycolysis through modulation of the AKT/mTOR signaling pathway, potentially mediated via its interaction with DGCR8. CONCLUSIONS:These findings suggest that the CCDC137/DGCR8 axis may contribute to HCC progression by regulating cellular metabolism through the AKT/mTOR pathway. Targeting this regulatory network may offer a promising direction for future therapeutic exploration in HCC.

BACKGROUND Posthepatectomy liver failure (PHLF) is one of the most important causes of death following liver resection. Heparin, an established anticoagulant, can protect liver function through a number of mechanisms, and thus, prevent liver failure. AIM To look at the safety and efficacy of heparin in preventing hepatic dysfunction after hepatectomy. METHODS The data was extracted from Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) v1. 4 pinpointed patients who had undergone hepatectomy for liver cancer, subdividing them into two cohorts: Those who were injected with heparin and those who were not. The statistical evaluations used were unpaired t -tests, Mann-Whitney U tests, chi-square tests, and Fisher’s exact tests to assess the effect of heparin administration on PHLF, duration of intensive care unit (ICU) stay, need for mechanical ventilation, use of continuous renal replacement therapy (CRRT), incidence of hypoxemia, development of acute kidney injury, and ICU mortality. Logistic regression was utilized to analyze the factors related to PHLF, with propensity score matching (PSM) aiming to balance the preoperative disparities between the two groups. RESULTS In this study, 1388 patients who underwent liver cancer hepatectomy were analyzed. PSM yielded 213 matched pairs from the heparin-treated and control groups. Initial univariate analyses indicated that heparin potentially reduces the risk of PHLF in both matched and unmatched samples. Further analysis in the matched cohorts confirmed a significant association, with heparin reducing the risk of PHLF (odds ratio: 0.518; 95% confidence interval: 0.295-0.910; P = 0.022). Additionally, heparin treatment correlated with improved short-term postoperative outcomes such as reduced ICU stay durations, diminished requirements for respiratory support and CRRT, and lower incidences of hypoxemia and ICU mortality. CONCLUSION Liver failure is an important hazard following hepatic surgery. During ICU care heparin administration has been proved to decrease the occurrence of hepatectomy induced liver failure. This indicates that heparin may provide a hopeful option for controlling PHLF.

目的:探讨黄色肉芽肿性胆囊炎的临床诊断以及疗效。方法:回顾性分析海军军医大学第三附属医院2016年2月至2022年2月收治的病理证实为黄色肉芽肿性胆囊炎患者的临床资料。结果:155例均行手术治疗，所有患者均痊愈出院。男103例，女52例，男女人数比2∶1，年龄17~86(59.6±12.0)岁，术前诊断合并胆囊结石占78.7%(122/155)，CA199(糖类抗原199)升高占40.7%(61/150)，血脂升高占17.5%(20/114)；彩超测量胆囊壁厚度3~35(8.92±4.84)mm，彩超诊断为黄色肉芽肿性胆囊炎占1.4%(2/141)，诊断为胆囊癌占55.3%(78/141)；影像学[电子计算机断层扫描(CT)或核磁共振成像(MRI)]诊断为黄色肉芽肿性胆囊炎占13.7%(19/139)，诊断为胆囊癌占45.3%(63/139)。术中冰冻组(108例)和术中未冰冻组(47例)的性别、年龄、病程、住院时间、血清CA199、血脂差异无统计学意义(均 P>0.05)，胆囊壁厚度(彩超测量)差异有统计学意义( P＝0.033)；两组在手术方式方面采用胆囊癌根治术的比例差异有统计学意义( P＝0.006)，采用腹腔镜下胆囊切除术、开腹胆囊切除术、胆囊及胆囊床肝组织切除术、胆囊切除及胆总管切开探查术、胆囊切除和胆总管探查及胆囊床肝组织切除术的比例差异无统计学意义(均 P>0.05)。 结论:黄色肉芽肿性胆囊炎治疗以胆囊切除为主，由于其影像学检查和CA199指标常与胆囊癌类似，术前及术中易误诊为胆囊癌，为避免不必要的扩大切除，术中冰冻是必要的。

e16121 Background: Surgical resection is the most important treatment for patients with hepatocellular carcinoma (HCC) to obtain long-term survival. However, the 5-year recurrence rate after hepatectomy is as high as 40%-60% and above. Reducing the postoperative recurrence rate is the key to improve the overall efficacy of HCC. This study aimed to evaluate the efficacy and safety of donafenib combined with TACE as adjuvant therapy in HCC patients with high-risk recurrence factors after surgical resection. Methods: This single-center retrospective study enrolled primary HCC patients with high-risk recurrence factors who underwent surgical resection at Shanghai Eastern Hepatobiliary Surgery Hospital from April 2021 to October 2022. High-risk recurrence factors included: the number of tumors ≥ 3, tumor diameter ≥ 5 cm, portal vein tumor thrombus, microvascular invasion (MVI) and satellite lesions. Patients received adjuvant therapy of donafenib combined with TACE after surgery. Patients’ demographic characteristics, etiological characteristics, 1-year recurrence-free survival rate (RFSR), recurrence-free survival (RFS), overall survival (OS), and treatment-related safety were analyzed. Results: A total of 40 patients were enrolled with a median age of 55.5 years (21-78), 39 patients (97.5%) in BCLC stage B and 1 patient (2.5%) in BCLC stage C. 33 patients (82.5%) were co-infected with HBV. All 40 patients had ECOG PS scores of 0 and Child-Pugh scores of A. A total of 34 patients (85%) with MVI were pathologically reported after surgery, 23 patients (57.5%) with tumor diameter ≥5cm, 9 patients (22.5%) with portal vein cancer thrombus, and 6 patients (15%) with satellite lesions. All patients received at least one TACE treatment after surgery, 31 patients (77.5%) received the TACE treatment one month after surgery, and 9 patients (22.5%) received the TACE treatment within one month after surgery. The initial dose of donafenib was 200mg/day. As of the cut-off date of data collection, the median follow-up time was 9 months (95%CI: 7.73-10.27), 4 patients relapsed and 2 patients died. The median RFS was 18 months (95% CI: 13.673-22.327), the one-year RFSR was 83.3% (95% CI: 61.9%-93.8%), and the one-year OS rate was 95.8% (95% CI: 75.2%-99.6%). 21 patients (52.5%) had combined treatment-related adverse events (TRAE), of which 4 patients (10%) had Grade 3 TRAE and no grade 4 or 5 TRAE were reported. Common adverse events included hand-foot skin reaction (9 patients, 22.5%), diarrhea (9 patients, 22.5%), rash (5 patients, 12.5%), hypertension, and gastrointestinal reactions (2 patients each, 5%). Conclusions: Donafenib combined with TACE was used for adjuvant therapy in patients with high-risk recurrence of HCC, which has a high one-year recurrence-free survival rate and was well tolerated.

原发性肝癌尤其是其中最为常见的肝细胞癌为我国高发的恶性肿瘤,其发病率和死亡率位居恶性肿瘤的前列.目前外科手术仍然是肝癌首选的治疗方案,但由于早期不易发现,大部分患者确诊时已属中晚期,错过了手术切除的最佳时机;而手术切除以后较高的复发率也是影响肝癌外科手术疗效的重要原因.随着现代医学的不断进步,靶向和免疫治疗、液体活检、机器人辅助手术等逐步应用于肝癌的临床治疗,肝癌外科治疗决策需要及时进行优化,不仅能扩大肝癌外科治疗的受益范围,同时也能在很大程度上提高肝癌外科治疗的效果.本文拟从术前评估的优化,术中手术方式的优化,以及术后抗复发和转移治疗的优化三个方面进行阐述,目的是探讨提高肝癌外科治疗水平、改善患者生存的有效途径.

The first laparoscopic hepatectomy (LH) in China was performed in 1990s. Thereafter, the technique of LH has evolved over three stages: the initial exploration, the exchange and development, and the promotion and application period. The indications of LH have been expanded from small liver tumors located at anterolateral segments to larger tumor of all segments (i.e., caudate lobe, segment VIII, and segment VII). The feasibility, safety and efficacy of LH have been demonstrated by increasing evidence. The techniques of LH has become sophisticated and standardized. And yet, the technique of LH remains challenging in the surgical indications, the control of intraoperative blood loss, the status of resected margins, and long-term outcome in patients with liver malignancies. With the update of laparoscopic instruments, the advancement of techniques, and improved operation skills, the indications for laparoscopic surgery are now very similar to open surgery. The application of new techniques including a low central venous pressure and transhepatic inflow blood ligation without portal dissection can minimize the intraoperative blood loss. Meanwhile, the availability of laparoscopic ultrasound and fluorescent imaging technique maximize the possibility of pursuing a tumor-free margin. Large-scale, multi-centre, prospective, randomized controlled studies are warranted to evaluate the long-term efficacy of laparoscopic hepatoma resection.

Hepatocellular cancer (HCC) has been reported to belong to one of the highly vascularized solid tumours accompanied with angiogenesis of human umbilical vein endothelial cells (HUVECs). KDM5A, an attractive drug target, plays a critical role in diverse physiological processes. Thus, this study aims to investigate its role in angiogenesis and underlying mechanisms in HCC. ChIP-qPCR was utilized to validate enrichment of H3K4me3 and KDM5A on the promotor region of miR-433, while dual luciferase assay was carried out to confirm the targeting relationship between miR-433 and FXYD3. Scratch assay, transwell assay, Edu assay, pseudo-tube formation assay and mice with xenografted tumours were conducted to investigate the physiological function of KDM5A-miR-433-FXYD3-PI3K-AKT axis in the progression of HCC after loss- and gain-function assays. KDM5A p-p85 and p-AKT were highly expressed but miR-433 was down-regulated in HCC tissues and cell lines. Depletion of KDM5A led to reduced migrative, invasive and proliferative capacities in HCC cells, including growth and a lowered HUVEC angiogenic capacity in vitro. Furthermore, KDM5A suppressed the expression of miR-433 by demethylating H3K4me3 on its promoterregion. miR-433 negatively targeted FXYD3. Depleting miR-433 or re-expressing FXYD3 restores the reduced migrative, invasive and proliferative capacities, and lowers the HUVEC angiogenic capacity caused by silencing KDM5A. Therefore, KDM5A silencing significantly suppresses HCC tumorigenesis in vivo, accompanied with down-regulated miR-433 and up-regulated FXYD3-PI3K-AKT axis in tumour tissues. Lastly, KDM5A activates the FXYD3-PI3K-AKT axis to enhance angiogenesis in HCC by suppressing miR-433.

Background: This study aimed to establish a model predicting the prognosis of intrahepatic cholangiocarcinoma (ICC) patients with cirrhosis before liver resection (LR). Methods: An Eastern Hepatobiliary Surgery Hospital (EHBH) model using the preoperative factors was established in a training cohort (305 patients from 2006 to 2011) and validated in an internal validation cohort (113 patients from 2012 to 2014). Predictive performance and discrimination were evaluated and compared with other staging systems. Results: The EHBH model containing preoperative factors of carbohydrate antigen 19-9 (CA19-9), radiological tumor diameter, tumor number, and satellite nodules outperformed other staging systems in predicting the prognosis of ICC. A contour plot of 3-year survival probability and a nomogram to form two differentiated groups of patients (high-risk group and low-risk group) were constructed based on the EHBH model to help surgeons predicting the overall survival (OS) before LR. Patients from the high-risk group (>86.56 points) in the training cohort had worse OS rates compared with those from the low-risk group (≤86.56 points). The one-, three-, and five-year OS rates were 50.4%, 29.0%, and 21.0% for the high-risk group and 68.2%, 45.5%, and 39.7% for the low-risk group, respectively (P<0.001). The same results were obtained in the internal validation patients. Conclusion: The contour plot is an easy-to-use tool to individually show the 3-year prognosis of ICC patients with different preoperative CA19-9 values and radiological characteristics before surgery. The EHBH model was suitable for selecting cirrhotic patients for LR to acquire a better survival.

Background: This study developed a novel inflammation score system to predict survival outcomes using preoperational inflammatory markers in hepatocellular carcinoma (HCC) after surgery. Materials and Methods: An inflammation score system was developed using five preoperative inflammatory markers based on the clinical data of 455 HCC patients (training cohort) receiving radical resection in the Eastern Hepatobiliary Surgery Hospital. The system was validated using a cohort from a different hospital (external validation). Kaplan-Meier curves and log-rank test were used to compare the survival of patients with different inflammation scores. A nomogram including inflammation scores for survival prediction was created to exhibit the risk factors of overall survival (OS). Results: The patients in the low-score group showed better OS and recurrence-free survival (RFS) in the training and external validation cohorts than those from the high-score group. Subgroup analysis showed that compared with patients in the training cohort from the high-score group, stage I (eighth TNM stage) patients in the low-score group exhibited better prognosis results, whereas the findings for Stage II and III patients were different. Multivariate Cox analysis revealed that high inflammation score is an independent risk factor of OS and RFS. The nomogram established using the inflammation score with the C-index value of 0.661 (95% confidence interval=0.624-0.698) revealed a good three- and five-year calibration curves. Conclusions: The inflammation score system based on five preoperative inflammatory markers well predicted the survival of HCC patients after surgery, especially in those at the early stage (Stage I).

肝细胞癌(HCC)往往伴有肝炎和肝硬化,根据其疾病分期、肿瘤部位及肝功能等情况进行精准治疗的要求很高.临床上多种诊疗方法均对HCC具有一定的疗效,故如何有效地对患者进行预后分析,从而选择合适的个体化治疗方案,成为亟需解决的问题.针对HCC的预后,有多种预测系统,其中列线图因能够较好地针对HCC患者进行个体化分析而备受关注.目前,根据不同类型的HCC已建立了多种列线图预测模型,这些模型纳入了一些临床和病理指标,如肿瘤标志物、肝功能、HBV指标、微血管癌栓等,其对不同患者计算出不同的风险评分,能够较好地预测预后.同时,可以根据不同的风险等级指导患者选择合适的治疗方式和术后抗复发治疗,从而达到个体化治疗的目的.

Over-expression of aspartyl (asparagynal)-β-hydroxylase (ASPH) contributes to hepatocellular carcinoma (HCC) invasiveness, but the role of ASPH hydroxylase activity in this process remains to be defined. As such, the current study investigated the role of ASPH hydroxylase activity in downstream signalling of HCC tumorgenesis and, specifically, metastasis development. Over-expression of wild-type ASPH, but not a hydroxylase mutant, promoted HCC cell migration in vitro, as well as intrahepatic and distant metastases in vivo. The enhanced migration and epithelial to mesenchymal transition (EMT) activation was notably absent in response to hydroxylase activity blockade. Vimentin, a regulator of EMT, interacted with ASPH and likely mediated the effect of ASPH hydroxylase activity with cell migration. The enhanced hydroxylase activity in tumor tissues predicted worse prognoses of HCC patients. Collectively, the hydroxylase activity of ASPH affected HCC metastasis through interacting with vimentin and regulating EMT. As such, ASPH might be a promising therapeutic target of HCC.

Niemann-Pick C1-like 1 (NPC1L1) and Niemann-Pick C2 (NPC2) is a critical mediator of cholesterol absorption. The aim of the present study was to investigate the prognostic value of NPC1L1 and NPC2 in human primary hepatocellular carcinoma (HCC). The expression level of NPC1L1 and NPC2 were evaluated by Immunohistochemistry, Westen blot and Real-time Quantitative PCR. Protein expression level in tissue was represented by integral optic density (IOD). For prognosis analyses, outcome-based cut-point was calculated by X-tile software. Kaplan-Meier analysis, Cox regression analysis were used evaluate prognostic value of NPC1L1 and NPC2 and NPC1L1/NPC2 combination. Both of NPC1L1 and NPC2 were significantly decreased in HCC tissues than peritumoral liver tissues (61 pairs of tissue for Immunohistochemistry and 10 pairs of tissues for Western blot and Real-time Quantitative PCR), respectively. (n=61: p=0.0005 for NPC1L1 and p=0.0001 for NPC2; n=10: p=0.0002 for NPC1L1 and p=0.0489 for NPC2). Kaplan-Meier analyses in 265 HCC cases were showed that the low expression level of NPC1L1 and NPC2 and NPC1L1/NPC2 combination were significantly correlated with poor overall survival (OS) and shorter time to recurrence (TTR). In addition, univariate and multivariate Cox analyses showed that the expression level of NPC1L1/NPC2 combination in HCC was an independent prognostic factor for OS and TTR. Conclusion: NPC1L1 and NPC2 were lowly expressed in HCC compared with peritumoral liver tissues, and low expression of NPC1L1 and NPC2 in HCC tissues may indicate poor outcome of HCC patients after surgery. NPC1L1/NPC2 combination is an independent prognostic factor for OS and TTR in postoperative HCC patients.

[摘要] 目的 探讨术前糖类抗原 19-9(CA19-9)水平对不同甲胎蛋白(AFP)水平肝细胞癌患者术后预后的 影响。方法 前瞻性收集 2008 年 1 月 4 日至 2010 年 12 月 31 日在我院因肝细胞癌首次接受肝切除术治疗的 3 791 例患者的临床及随访资料。以 400 ng/mL 为术前 AFP 水平的截断值,32 U/mL 为术前 CA19-9 水平的截断值,将患 者分为双阳性组(DP 组)、CA19-9 单阳性组 [SP(CA19-9)组]、AFP 单阳性组 [SP(AFP)组] 和双阴性组(DN 组),比较各组患者的肿瘤学特征。采用 Kaplan-Meier 法和 log-rank 检验分析各组患者的总生存(OS)和无瘤生存 (DFS)情况。采用 Cox 回归模型进行单因素和多因素分析,筛选影响肝细胞癌患者预后的危险因素。结果 4 组 患者有不同的肿瘤学特征。与 DN 组相比,SP(AFP)组、DP 组患者的肿瘤最大径更大、病理 EdmondsonSteiner 分级为 III~IV 级的比例和微血管侵犯(MVI)发生率更高(P<0.01),且 DP 组患者的多发肿瘤比例更高 (P<0.05);而 SP(CA19-9)组患者的肿瘤最大径更小(P<0.05),多发肿瘤的比例更高(P<0.01)。按 DN 组、SP(CA19-9)组、SP(AFP)组与 DP 组的顺序,患者的 1 年、3 年和 5 年 OS 率均依次降低(P 均<0.01); DN 组患者的 1 年、3 年和 5 年 DFS 率最高(P<0.01),DP 组最低(P<0.01),SP(CA19-9)组与 SP(AFP)组 差异无统计学意义。术前 AFP 水平分层分析结果表明,CA19-9<32 U/mL 组患者的 1 年、3 年和 5 年 OS 率及 DFS 率均高于 CA19-9≥32 U/mL 组患者(P<0.05)。多因素分析结果显示,AFP≥400 ng/mL、CA19-9≥32 U/mL、术 中出血≥600 mL、肿瘤最大径≥5 cm、肿瘤多发、肿瘤包膜缺如、MVI、Edmondson-Steiner 分级为 III~IV 级是影 响患者 OS 的独立危险因素(P<0.05);乙型肝炎病毒表面抗原(+)、AFP≥400 ng/mL、CA19-9≥32 U/mL、肿 瘤最大径≥5 cm、肿瘤多发、肿瘤包膜缺如、MVI 是影响患者 DFS 的独立危险因素(P<0.05)。结论 术前血清 AFP≥400 ng/mL 和 CA19-9≥32 U/mL 均是影响肝细胞癌患者 OS 和 DFS 的独立危险因素。对于不同术前 AFP 水平 的肝细胞癌患者,术前 CA19-9 水平是进一步评估预后的重要指标。 [关键词] 肝肿瘤;甲胎蛋白;糖类抗原 19-9;肝细胞癌;预后;肝切除术 [中图分类号] R 735.7 [文献标志码] A [文章编号] 0258-879X(2018)06-0603-07

Objective To establish a nomogram model for predicting posthepatectomy liver failure (PHLF) in patients with HBV-related hepatocellular carcinoma (HCC). Methods Clinical data of 628 patients with HBV-related HCC who underwent radical hepatectomy in Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University between January 2010 and December 2010 were retrospectively analyzed. According to the operation time, all patients were divided into the model establishment group (n=471) and validation group (n=157). In the model establishment group, 409 cases were males and 62 females, aged (52±21) years old on average. In the validation group, 135 cases were males and 22 females, aged (52±11) years old on average. The informed consents of all patients were obtained and the local ethical committee approval was received. The independent risk factors of PHLF in the model establishment group were identified by Logistic regression analysis. Based upon the independent risk factors, the nomogram model for predicting PHLF of HCC was established. The accuracy of nomogram model for predicting PHLF was respectively detected in two groups by computer consistency coefficient (C-index) and calibration graph method. Results Multivariate Logistic regression analysis for the model establishment group revealed that, PT>13 s (OR=2.522, 95%CI:1.384-4.596; P 17.1 μmol/L (OR=2.088, 95%CI:1.342-3.251; P 44 U/L (OR=1.710, 95%CI:1.141-2.562; P<0.05), positive HBeAg (OR=1.658, 95%CI: 1.058-2.597; P<0.05), intraoperative blood transfusion (OR=3.407, 95%CI:1.945-5.967; P<0.05) and liver cirrhosis (OR=1.835, 95%CI:1.200-2.805; P<0.05) were the independent risk factors for PHLF. After the establishment of nomogram model, the C-index was respectively 0.727 and 0.719 in the model establishment group and validation group. In the calibration graph, the standard curve was properly fit with the predicting calibration curve, suggesting that the model consistency was fine. Conclusions The nomogram model for predicting PHLF in patients with HBV-related HCC is successfully established. And the model offers certain guiding significance for clinical treatment of HBV-related HCC. Key words: Carcinoma, hepatocellular; Hepatitis B; Liver failure; Nomogram; Risk factors

BACKGROUND:The aim of this study was to explore the impact of antiviral therapy (AVT) on short- and long-term outcomes after rehepatectomy for patients with recurrent hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). STUDY DESIGN:We analyzed data from 583 consecutive patients who underwent rehepatectomy for intrahepatic recurrence of HBV-related HCC after initial hepatectomy, between 2006 and 2011 at the Eastern Hepatobiliary Surgery Hospital. Tumor re-recurrence, recurrence to death survival (RTDS), and overall survival (OS) were compared using the Kaplan-Meier method and log-rank test. The independent risk factors of prognoses were analyzed using the Cox proportional hazards model. Postoperative viral reactivation, surgical morbidity, and mortality were also observed. RESULTS:Preoperative AVT reduced viral reactivation rate after rehepatectomy (5.8% for AVT patients, 16.3% and 16.6% for non-AVT patients with viral level ≤ or >2,000 IU/mL, respectively; p ≤ 0.028). Viral reactivation and non-AVT were independent risk factors of tumor re-recurrence (hazard ratios 1.446 and 1.778, respectively), RTDS (1.691 and 2.457, respectively), and OS (1.781 and 1.857, respectively). The AVT improved long-term outcomes as compared with non-AVT with a viral level of ≤ or >2,000 IU/mL (5-year re-recurrence rate: 69% vs 81% vs 96%, respectively; 5-year RTDS rate: 47% vs 27% vs 17%, respectively; all p ≤ 0.016). Pre- plus postoperative AVT achieved a better 5-year OS rate than postoperative AVT alone (83% vs 60%; p = 0.045); there were insignificant differences in 5-year re-recurrence and RTDS rates (61% vs 77%, p = 0.102; 50% vs 44%, p = 0.395). CONCLUSIONS:Preoperative AVT decreased viral reactivation rate, and AVT initiated either before or after rehepatectomy contributed to better long-term prognoses after rehepatectomy for recurrent HBV-related HCC.

Repeat hepatectomy (re-hepatectomy) is an effective treatment for patients with intrahepatic recurrence following liver resection for hepatocellular carcinoma (HCC).

BackgroundAxl is a receptor tyrosine kinase which plays an important role in multiple human malignancies.DesignThe Axl expression was examined in several hepatocellular carcinoma(HCC) cell lines, paired tumor and nontumorous samples. Then, we examined cell growth curve, cell apoptosis and cell migration in SMMC-7721 cells over-expressed with Axl or siRNA against Axl, respectively. Finally, the prognostic value of Axl was investigated in a prospective cohort of 246 consecutive HCC patients undergoing curative hepatoectomy.ResultsWe found Axl was positive in 22% of examined tumor tissues and all four cell lines. Over-expressing Axl in SMMC-7721 cells accelerated cell growth, cell migration and inhibited cell apoptosis, while knock-down of Axl exerted opposite effect. Axl expression was closely associated with serum AFP, multiple tumors, absence of encapsulation, microvascular invasion, and advanced BCLC or TNM stage. Patients with positive Axl staining had a higher 5-year recurrence rate (92% vs. 71%, P<0.001) and a lower 5-year survival rate (9% vs. 48%, P<0.001) than those with negative staining. The multivariate analyses showed that Axl expression was an independent factor for both tumor recurrence (HR: 1.725; 95% CI: 1.219-2.441) and survival (1.847; 1.291-2.642).Conclusion Axl expression suggests more aggressive tumor invasiveness and predicts worse prognosis for HCC patients undergoing resection.

Glioma malignancy greatly depends on its aggressive invasion. The establishment of cell polarity is an important initial step for cell migration, which is essential for cell-directional translocation. However, our understanding of the molecular mechanisms underlying cell polarity formation in glioma cell invasion remains limited. Glycogen synthase kinase-3 (GSK-3) has a critical role in the formation of cell polarity. We therefore investigated whether localized GSK-3β, a subtype of GSK-3, is important for glioma cell invasion. We reported here that the localized phosphorylation of GSK-3β at the Ser9 (pSer9-GSK-3β) was critical for glioma cell invasion. Scratching glioma cell monolayer up-regulated pSer9-GSK-3β specifically at the wound edge. Inhibition of GSK-3 impaired the cell polarity and reduced the directional persistence of cell migration. Consistently, down-regulation of GSK-3α and 3β by specific small interfering RNAs inhibited glioma cell invasion. Over-expressing wild-type or constitutively active forms of GSK-3β also inhibited the cell invasion. These results indicated the polarized localization of GSK-3 regulation in cell migration might be also important for glioma cell migration. Further, EGF regulated both GSK-3α and 3β, but only pSer9-GSK-3β was enriched at the leading edge of scratched glioma cells. Up- or down-regulation of GSK-3β inhibited EGF-stimulated cell invasion. Moreover, EGF specifically regulated GSK-3β, but not GSK-3α, through atypical PKC pathways. Our results indicated that GSK-3 was important for glioma cell invasion and localized inhibition of GSK-3β was critical for cell polarity formation.

Interaction between tumor and stromal cells plays an important role in cancer progression. The aim of this study was to explore the effects of tumor-associated fibroblasts on regulation of hepatocellular carcinoma (HCC) progression. Sixty-five cases of HCC and the corresponding normal liver tissues were recruited for immunohistochemical assessment of α-smooth muscle actin (α-SMA) expression, a biomarker for activated fibroblasts. Clinicopathological data were also collected from HCC patients for association with α-SMA expression. Primary cell culture of fibroblasts from HCC tissues was used to generate conditioned medium for testing the effect on regulation of HCC cell migration capacity in the transwell cell migration assay. α-SMA protein was expressed in 84.0 % (21 out 25 cases) of the fibroblasts from the metastatic HCCs, 45 % (18/40) from HCCs without metastasis, and 19.2 % (5/26) from normal liver tissues, difference of which was statistically significant (P < 0.01). The expression of α-SMA protein in HCC tissues was associated with tumor thrombosis, poor pathology grade, advanced clinical stages, and lymph node metastasis. The conditioned medium from the primary cultured fibroblasts with α-SMA expression significantly promoted the migration capacity of HCC Hep3B cells compared to the heat-inactivated conditioned medium. The data from the current study demonstrated that expression of α-SMA protein in HCC fibroblasts associated with tumor metastasis and advanced clinical stages and that the conditioned medium from α-SMA-positive fibroblasts enhanced HCC cell migration. This study indicates that α-SMA protein might serve as a biomarker to predict HCC progression.