Cathepsin C Interacts with TNF-α/p38 MAPK Signaling Pathway to Promote Proliferation and Metastasis in Hepatocellular Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Although cathepsin C (CTSC) has been reported to maintain malignant biological properties in various cancers, its functions in hepatocellular carcinoma (HCC) remain obscure. We aimed to investigate the potential role of CTSC in HCC. @*Materials and Methods@#HCC tissue microarrays (n=122) were employed to analyze the correlation between CTSC expression and clinicopathological characteristics through immunohistochemistry staining. Quantitative real-time polymerase chain reaction, western blot assay, Cell Counting Kit-8 assay, colony formation, cell migration, and invasion assays, xenograft mice model were adopted to validate what had been indicated by the bioinformatic web tools. @*Results@#By bioinformatic tools and tissue microarrays, CTSC was found upregulated in HCC compared with normal liver tissues, and its higher expression was correlated with poor prognosis of HCC patients (hazard ratio, 2.402; 95% confidence interval, 1.493 to 3.865; p < 0.001). By gain/loss-of-function assays, we implicated that CTSC functioned as an oncogene to promote the proliferation and metastasis of HCC cells. Mechanistically, we revealed that CTSC was involved in several cancer-related signaling pathways by Gene Set Enrichment Analysis, among which tumor necrosis factor α (TNF-α)/p38 pathway was verified to be activated by CTSC. Furthermore, we found that TNF-α could activate CTSC expression in a concentration- dependent manner. Ralimetinib, an oral p38 mitogen-activated protein kinase (MAPK) inhibitor could inhibit CTSC expression. These indicated a potential positive feedback loop between CTSC and TNF-α/MAPK (p38) signaling. @*Conclusion@#Taken together, CTSC plays an important role in the growth and metastasis of HCC and may be a promising therapeutic target upon HCC.

Low expression of SLC22A1 is associated with a poor prognosis of hepatocellular carcinoma: analysis of 303 patients / 南方医科大学学报

<p><b>OBJECTIVE</b>To evaluate the association between SLC22A1 expression and the outcomes of hepatocellular carcinoma (HCC) patients.</p><p><b>METHODS</b>A tissue microarray of 303 HCC and matched adjacent noncancerous liver tissues (ANLTs) were constructed. The expression of SLC22A1 was tested by immunohistochemistry (IHC) and scored by two pathologists according to a 12-score scale (a score>6 was defined as high expression, and a score≤6 as low expression). The correlation of SLC22A1 expression with the clinicopathological features and the patients' outcome was analyzed.</p><p><b>RESULTS</b>All the ANLTs had a IHC score of 12, as compared to only 29 (9.6%) of the HCC tissues. The patients were divided into 2 groups based on the IHC scores: 59% (180/303) in low expression group and 41% (123/303) in high expression group. The disease-free survival (DFS) rates and overall survival (OS) rates were significantly lower in low SLC22A1 expression group than in the high expression group. The 1-, 3-, and 5-year DFS rates were 43%, 31% and 27% in the low expression group, and were 58%, 47% and 43% in the high expression group, respectively. The 1-, 3-, and 5-year OS rates were 66%, 38% and 32% in low expression group, and were 80%, 57% and 50% in the high expression group, respectively. A low expression of SLC22A1 was positively correlated with the tumor diameter, BCLC stage, tumor differentiation, and AFP levels (P<0.05), and was an independent predictor of poor overall survival (HR=1.454; 95% CI, 1.050-2.013).</p><p><b>CONCLUSIONS</b>Down-regulation of SLC22A1 is a malignant feature and a potential prognostic marker of HCC.</p>

Radiofrequency-assisted anterior approach right hepatectomy for hepatocellular carcinoma / 中华外科杂志

<p><b>OBJECTIVE</b>To investigate the safety and efficacy of radiofrequency-assisted anterior approach right hepatectomy for hepatocellular carcinoma (HCC).</p><p><b>METHODS</b>The clinic data of 12 HCC patients who underwent radiofrequency-assisted anterior approach right hepatectomy from January 2010 to July 2011 was analyzed retrospectively. Surgical techniques and treatment response were retrospectively reviewed. All the 12 patients were male, aging from 38 to 57 years with a mean of (48 ± 6) years. Ten of the 12 patients were infected with hepatitis B virus. A retrohepatic tunnel anterior to the surface of the inferior vena cava (IVC) was developed. The liver was hanged away from the IVC and radiofrequency was carried out along the Cantline's line. Scalpel was used to cut off the liver parenchyma along the middle of the ablated area until the parenchyma was fully resected. After short hepatic veins and the right hepatic vein were ligated, ligaments of right liver were fully isolated and right liver was resected. The t test was performed between 2 groups.</p><p><b>RESULTS</b>The surgical time was 165 to 295 minutes, with a mean of (230 ± 55) minutes. The bleeding was 150 to 1500 ml, with a mean of (516 ± 378) ml, which was better than those of anterior approach right hepatectomy ((1291 ± 1159) ml) and classical right hepatectomy ((2129 ± 2012) ml; t = 1.236, 3.265; P < 0.05). The postoperative hospital stay was 8 - 19 days, with a mean of (12 ± 4) days. There were no medical complications and no postoperative death. All patients were cured and discharged.</p><p><b>CONCLUSIONS</b>Radiofrequency-assisted anterior approach right hepatectomy for HCC is safe and effective and could effectively decrease intra-operative bleeding and shorten surgical time.</p>

Combination with vascular resection and reconstruction in resection of hilar cholangiocarcinoma / 中华外科杂志

<p><b>OBJECTIVE</b>To investigate the value of vascular resection and reconstruction in resection of hilar cholangiocarcinoma.</p><p><b>METHODS</b>The clinical data of 17 patients with hilar cholangiocarcinoma received resection in combination with vascular resection and reconstruction from January 2000 to September 2009 was retrospectively analyzed. Among the 17 patients, 6 underwent portal vein segmental resection and end-to-end anastomosis, 3 underwent portal vein wedge resection, 1 underwent hepatic artery ligature, 2 underwent hepatic artery segmental resection and end-to-end anastomosis, 1 underwent portal vein arterialization, 1 underwent portal vein wedge resection and hepatic artery ligature simultaneously, 2 underwent portal vein segmental resection and hepatic artery segmental resection and end-to-end anastomosis simultaneously, 1 underwent portal vein segmental resection and right hepatic artery and gastroduodenal artery end-to-end anastomosis simultaneously.</p><p><b>RESULTS</b>Four patients died and the mortality was 4/17. Three patients died of renal dysfunction followed with multiple organ dysfunction and 1 patient died of sepsis shock. Among the 13 survive patients, 6 had a smooth postoperative recover and 7 developed complications: 3 had bile leakage, 1 had respiratory failure, 1 had cholangitis due to obstruction of U tube, 1 had abdominal infection and thrombosis in portal vein system and 1 had portal vein stenosis and liver abscess. Follow-up investigation showed that the median survival time was 18 months and four patients still alive.</p><p><b>CONCLUSIONS</b>Combination of vascular resection and reconstruction in the resection of hilar cholangiocarcinoma may help to improve the resection rate but still have a high postoperative risk. The complications of renal dysfunction should be alert during the postoperative observation. The procedure of hepatic arterial reconstruction may help to reduce postoperative morbidity.</p>

Long-term outcome and prognostic factors of intrahepatic cholangiocarcinoma / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The management of intrahepatic cholangiocarcinoma (ICC) remains a challenge due to poor prognosis. The aim of this study was to summarize the surgical management experience in recent 10 years and to identify the influencing factors related to outcome of patients with ICC in a single hepatobiliary center.</p><p><b>METHODS</b>From January 1995 to June 2005, 136 patients with ICC undergoing surgery were reviewed retrospectively. Survival rates of patients were calculated using the Kaplan-Meier method and compared by using the log-rank test. The prognostic factors were identified by the Cox regression model.</p><p><b>RESULTS</b>Seventy-nine of 136 patients underwent resection, and 65 of 79 patients were curative (R0). The surgical mortality was 2.2%. The 1-, 3- and 5-year survival rates of patients undergoing R0 resection were 72.1%, 35.6% and 20.1% respectively, which were significantly longer than those who underwent palliative resection and exploration, respectively (P < 0.01). At stage IV of the disease, 10 patients who underwent aggressive curative resection achieved a better median survival than those (n = 12) without resection (14 months vs 3 months, P < 0.001). The independent prognostic factors of the whole group were TNM stage (OR, 2.013, P = 0.008) and curative resection (OR, 2.957, P = 0.003). Higher TNM stage (OR, 1.894, P = 0.004) and lymph node metastasis (OR, 4.248, P = 0.005) linked to poor prognosis after R0 resection. For patients without lymph node metastasis, the median survival of those who underwent regional lymphadenectomy was comparable with those who did not (18 months vs 22 months, P = 0.817).</p><p><b>CONCLUSIONS</b>R0 resection is mandatory for ICC patient to achieve long-term survival. Aggressive resection benefits for selected patients with local advanced disease. Higher TNM stage and lymph node metastasis were poor prognostic factors for ICC patients after R0 resection.</p>

The impact of preoperative biliary drainage on surgical morbidity in hilar cholangiocarcinoma patients / 中华外科杂志

<p><b>OBJECTIVE</b>To evaluate the impact of preoperative biliary drainage on surgical morbidity in hilar cholangiocarcinoma patients underwent surgery.</p><p><b>METHODS</b>One hundred and eleven consecutive patients with hilar cholangiocarcinoma whose serum total bilirubin (TBIL) level > 85 micromol/L and underwent surgery in the period from June 1998 to August 2007 were enrolled. There were 67 male and 44 female patients, aged from 26 to 82 years old with a mean of 56 years old.</p><p><b>RESULTS</b>Fifty-five patients underwent preoperative biliary drainage with a mean of 11.4 d of drainage period (drainage group), the other (n = 56) were the non-drainage group. The preoperative TBIL level of drainage group was (154 +/- 69) micromol/L, which was significantly lower than the value of pre-drainage (256 +/- 136) micromol/L (P = 0.000) and the value of non-drainage group (268 +/- 174) micromol/L (P = 0.005). ALT and GGT levels could be lowered by preoperative biliary drainage. The postoperative complications of these two groups were comparable (36.3% vs. 28.6%, P = 0.381). Four patients in drainage group and 5 patients in non-drainage group died of liver failure. Multivariate logistic regression indicated that hepatectomy (OR = 0.284, P = 0.003) was the independent risk factor associated with postoperative morbidity. Bismuth-Corlette classification (OR = 0.211, P = 0.028) was the independent risk factor linked to postoperative mortality.</p><p><b>CONCLUSIONS</b>Preoperative biliary drainage could alleviate liver injury due to hyperbilirubin, but it could not decrease the surgical morbidity and postoperative mortality. Concomitant hepatectomy and Bismuth-Corlette classification were independent risk factors linked to surgical risks.</p>

Changes in TGF-beta1/Smads signaling pathway in rats with chemical hepatocarcinogenesis / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the changes in transforming growth factor beta 1 (TGF-beta1)/Smads signaling pathway in rats with chemical hepatocarcinogenesis.</p><p><b>METHODS</b>Fresh diethylnitrosamine (DENA) solution was administered in SD rats to induce hepatocellular carcinoma (HCC). The protein expressions of TGF-beta1, phosphorylated Smad2, Smad4 and Smad7 were detected in these rats with immunohistochemistry, and the mRNA expression of Smad4 was evaluated with RT-PCR.</p><p><b>RESULTS</b>Cirrhotic nodules occurred in the rats 8 weeks after DENA treatment, and HCC nodules were found 16 weeks after the treatment. In the normal liver tissue, very low levels of TGF-beta1 and Smad4 expressions, low Smad7 expression and high phosphorylated Smad2 expression were detected. The development of liver cirrhosis was accompanied by increased expressions of TGF-beta1, Smad4 and Smad7 but at 8 weeks after DENA treatment, the expression of phosphorylated Smad2 was significantly decreased, followed then by gradual increment till nearly the normal level. Twenty-two weeks after DENA treatment, Smad4 expression in liver tissue decreased markedly as compared with the levels at 8 and 16 weeks. The expressions of Smad4 and phosphorylated Smad2 in the HCC tissue was significantly lower than those in normal liver tissue.</p><p><b>CONCLUSION</b>Hepatocarcinogenesis involves very complex mechanisms, can can be related partially to the decreased Smad4 and phosphorylated Smad2 expression and TGFbeta1 and Smad7 overexpression in advanced stage of liver cirrhosis.</p>

The timing of hepatectomy for hepatolithiasis complicated with acute cholangitis / 中华外科杂志

<p><b>OBJECTIVE</b>To evaluate the optimal timing of hepatectomy for intrahepatic lithiasis complicated with acute cholangitis.</p><p><b>METHODS</b>One hundred and twenty-six patients with hepatolithiasis who had a history of acute cholangitis and underwent hepatectomy were reviewed retrospectively. According to the period between the surgery and last attack of acute cholangitis, 126 patients were divided into 3 groups: > 3 months (group A, n = 73), 1 approximately 3 months (group B, n = 28), < 1 month (group C, n = 25). The operation time, blood loss, hospital stay, postoperative complications and stone residual rate were compared among the groups.</p><p><b>RESULTS</b>The intraoperative blood loss of C group was (644.0 +/- 625.7) ml, which was significantly higher than those of A and B group [(409.2 +/- 250.7) ml and (423.2 +/- 237.1) ml, respectively]. The numbers of patients who needed transfusion and the amount of blood transfusion in group C were also higher than those of group A and B. The incidence rate of complications, residual stone in group C were all markedly higher than those of group A and B. The period of hospital stay in group C was much longer than that in group A and B.</p><p><b>CONCLUSIONS</b>The optimal timing of hepatectomy for hepatolithiasis complicated with acute cholangitis is at least one month after subsidence of cholangitis.</p>

Experience of surgical resection of 103 hilar cholangiocarcinoma / 中华外科杂志

<p><b>OBJECTIVE</b>To summarize the experience of surgical resection of 103 hilar cholangiocarcinoma.</p><p><b>METHODS</b>One hundred and three consecutive cases of hilar cholangiocarcinoma who underwent surgical resection at our hospital over the past ten years were reviewed retrospectively. The clinical data and long-term outcome were analyzed.</p><p><b>RESULTS</b>Out of 103 cases, 43 patients underwent radical resection (41.7%), and 60 patients underwent palliative resection. There were 34 patients developed postoperative complications and 8 patients died in hospital. For the radical resection group, the median survival time was 29.9 months and 1-year, 3-year, 5-year survival rate was 69.6%, 42.0%, 20.9%, respectively, which was significant greater than 34.1%, 10.2%, 0 of the palliative resection group (P < 0.05). Over the past five years, 42 cases underwent pre-operative drainage of bile and the rate of combined liver resection reached 53.8%. The tumor radical resection rate has increased to 45.7%, the median survival time have reached 24.7 months (P < 0.05).</p><p><b>CONCLUSIONS</b>Improvement of pre-operative management, intraoperative pathology for resection margin, and combined liver resection may help in increasing the radical resection rate. Radical resection can improve postoperative survival, and produce a satisfactory outcome for patient with hepatic hilar cholangiocarcinoma.</p>

The study of inhibition effect of octreotide on the growth of hepatocellular carcinoma xenografts in situ in nude mice / 中华外科杂志

<p><b>OBJECTIVE</b>To observe the effect of octreotide (OCT) on inhibiting hepatocellular carcinoma (HCC) and investigate its mechanisms.</p><p><b>METHODS</b>Nude mice bearing xenografts in situ were treated with OCT or saline control for 7 weeks since tumor implantation. The immunohistochemistry for somatostatin receptor 2 (SSTR2), cMet, transforming growth factor beta1 (TGFbeta1), phospho-Smad2, Smad4 and Smad7 was performed. SSTR2 and Smad4 mRNA expression was measured by semi-quantitative RT-PCR.</p><p><b>RESULTS</b>After OCT treatment, the mean tumor weight in mice given OCT (0.17 +/- 0.14 g) was significantly lower than that of the control group (0.53 +/- 0.06 g). The inhibition rate of tumor was 67.9%. mRNA and protein expression of SSTR2, Smad4 in tumor cells of the treatment group were significantly more than that of the control group. cMet expression in OCT group was remarkably lower than that in control group. Between two groups, the expression of TGFbeta1, phospho-Smad2 and Smad7 were not remarkably different. In addition, phospho-Smad2 expression in HCC was significantly less than that of the normal hepatic cell.</p><p><b>CONCLUSION</b>OCT can inhibit the growth of HCC xenografts markedly. The mechanisms of OCT-induced inhibition effect may be related to up-regulating SSTR2 expression, down-regulating cMet, and recovering the function of TGFbeta/Smads-induced antitumor. In addition, the decreased expression of phospho-Smad2 may be an important feature of Bel7402 cells.</p>