Guang-Shun Yang

A Long Noncoding RNA Activated by TGF-β Promotes the Invasion-Metastasis Cascade in Hepatocellular Carcinoma

The role of TGF-β-induced epithelial-mesenchymal transition (EMT) in cancer cell dissemination is well established, but the involvement of lncRNAs in TGF-β signaling is still unknown. In this study, we observed that the lncRNA-activated by TGF-β (lncRNA-ATB) was upregulated in hepatocellular carcinoma (HCC) metastases and associated with poor prognosis. lncRNA-ATB upregulated ZEB1 and ZEB2 by competitively binding the miR-200 family and then induced EMT and invasion. In addition, lncRNA-ATB promoted organ colonization of disseminated tumor cells by binding IL-11 mRNA, autocrine induction of IL-11, and triggering STAT3 signaling. Globally, lncRNA-ATB promotes the invasion-metastasis cascade. Thus, these findings suggest that lncRNA-ATB, a mediator of TGF-β signaling, could predispose HCC patients to metastases and may serve as a potential target for antimetastatic therapies.

Blockade of store-operated Ca2+ entry inhibits hepatocarcinoma cell migration and invasion by regulating focal adhesion turnover

Store-operated Ca(2+) entry (SOCE) is a main Ca(2+) influx pathway controlling the intracellular Ca(2+) concentration in normal hepatocytes and hepatocellular carcinoma (HCC) cells. Ca(2+) influx has been demonstrated to be involved in liver oncogenesis. Stromal interacting molecule (STIM) 1 acts as a sensor for the level of Ca(2+) stored in the endoplasmic reticulum, and Orai1 protein constitutes the pore-forming subunit of the store-operated channels. Recently, STIM1 and Orai1 were found critical for breast tumor cell migration and metastasis. However, the effects of Ca(2+) influx pathway on migration and metastasis have not been studied in hepatocellular carcinoma. Here, we found that STIM1 had a higher expression in hepatoma tissues than in precancerous tissues of the same patients. In general, STIM expression is elevated in HCC cell lines compared to a normal hepatocyte cell line. HCC-LM3 cell, which has a higher migration ability, expresses five times higher level of STIM than other HCC cell lines. STIM1 could then be explored as a prognostic marker to screen liver cancer patients with high metastatic potential. Inhibition of SOCE and STIM1 enhance focal adhesions and decrease the focal adhesion turnover, suggesting the therapeutic potential of SOCE and STIM1 as new molecular targets for metastatic HCC.

Hepatectomy for bilateral primary hepatolithiasis: a cohort study.

Objective:This study aimed to evaluate the perioperative and long-term results of partial hepatectomy for patients with complicated bilateral primary hepatolithiasis. Summary Background Data:Hepatolithiasis is best managed by a multidisciplinary approach. Definitive treatment can be offered using endoscopic, percutaneous, laparoscopic, or open surgical approaches. Partial hepatectomy is only indicated for recurrent, troublesome, localized, and severe disease affecting the liver. Methods:From January 2000 to December 2006, 136 consecutive patients who underwent bilateral (n = 54) or unilateral (n = 82) hepatectomy for biliary strictures and bilateral primary hepatolithiasis in our center were included in this study. All patients had concomitant bile duct exploration. Their perioperative and long-term outcomes were analyzed. Results:The immediate stone clearance rates after bilateral and unilateral hepatectomy were 81.5% and 65.9%, respectively. Additional postoperative choledochoscopic lithotripsy raised the clearance rates to 85.2% and 81.7%, respectively. The hospital mortality rates were 5.6% and 0%, respectively, and the complication rates were 46.3% and 46.3%, respectively. The 5-year overall survival rates were 98% and 91.5%, respectively. Conclusion:In selected patients with biliary strictures and bilateral hepatolithiasis, partial hepatectomy associated with choledochoscopic lithotripsy is a safe and efficacious treatment, with a high immediate stone clearance rate, a low long-term stone recurrence rate and good long-term survival.

High viral load is associated with poor overall and recurrence-free survival of hepatitis B virus-related hepatocellular carcinoma after curative resection: A prospective cohort study

PURPOSE The aim of this prospective cohort study was to investigate the impact of preoperative hepatitis B viral load, as well as postoperative antiviral therapy, on the risk of long-term survival after curative resection of hepatitis B virus-related hepatocellular carcinoma (HCC). METHODS A prospective cohort of hepatitis B virus-related HCC patients undergoing curative resection from 2002 to 2008 was studied. According to preoperative viral load (using 10,000 copies/mL of hepatitis B virus DNA level as cut-off value), two groups were compared. Prognostic factors for overall survival and recurrence-free survival were evaluated. Additionally, subgroup analysis was conducted in patients with high viral load to investigate prediction of postoperative antiviral therapy on the long-term prognosis. RESULTS With a median follow-up of 49.1 months, patients with high viral load had lower median overall survival (78.3 months vs. 111.4 months, P<0.001) and RFS (44.6 months vs. 94.8 months, P<0.001) compared with those with low viral load. Multivariate analysis revealed that preoperative high viral load was an independent risk factor affecting both overall survival and recurrence-free survival (both P<0.001). The subgroup analysis revealed that postoperative antiviral therapy independently improved recurrence-free survival for patients with high viral load (P=0.001). CONCLUSIONS Hepatitis B virus-related HCC patients with preoperative high viral load led to poorer overall and recurrence-free survival than those with low viral load after curative resection. To prevent postoperative recurrence, antiviral therapy should be initiated in those patients with hepatitis B virus DNA ≥ 10,000 copies/ml.

Postoperative adjuvant transcatheter arterial chemoembolisation improves survival of intrahepatic cholangiocarcinoma patients with poor prognostic factors: Results of a large monocentric series

BACKGROUND The prognosis of patients with intrahepatic cholangiocarcinoma (ICC) is currently unsatisfactory. The aims of this study were to identify prognostic factors after curative ICC resection, and to evaluate the effects of postoperative transcatheter arterial chemoembolisation (TACE). METHODS A retrospective analysis was conducted of 114 ICC patients who underwent curative resection from January 2005 to December 2006. Relationships between survival and clinicopathological factors were evaluated using univariate and multivariate analyses. The benefits of adjuvant TACE were investigated separately. RESULTS The cumulative 1-, 3-, and 5-year survival rates were 63%, 26%, and 15%, respectively. Multivariate analysis revealed that tumour size ≥ 5 cm (hazard ratio [HR] 1.875, 95% CI 1.139-3.088, P=0.013) and advanced TNM stage (stage III or IV) (HR 1.681, 95% CI 1.035-2.732, P=0.036) were independently associated with poor prognosis. Fifty-seven patients underwent adjuvant TACE. In patients with poor prognostic factors, TACE improved the survival rate (P<0.001). However, in patients without poor prognostic factors, TACE did not significantly change the survival rate (P=0.724). CONCLUSIONS Postoperative adjuvant TACE can prolong survival in ICC patients with tumour size ≥ 5 cm or advanced TNM stage.

Sorafenib sensitizes hepatocellular carcinoma cell to cisplatin via suppression of Wnt/β-catenin signaling.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In this study, we found that nuclear accumulation of β-catenin was higher in cisplatin-resistant Huh7 cells than in Huh7 cells, indicating that Wnt signaling was activated in cisplatin-resistant cells. Wnt signaling inhibition increased cisplatin-induced growth inhibition in hepatoma cell. We further demonstrated that sorafenib could inhibit Wnt signaling in Huh7 cells and cisplatin-resistant Huh7 cells. Co-treatment with cisplatin and sorafenib was more effective in inhibiting cancer cell proliferation than cisplatin alone in vitro and in vivo, whereas Wnt3a (Wnt activator) treatment abrogated sorafenib-induced growth inhibition. These data demonstrated that sorafenib sensitizes human HCC cell to cisplatin via suppression of Wnt/β-catenin signaling, thus offering a new target for chemotherapy of HCC.

Risk factors for hilar cholangiocarcinoma: A case-control study in China

AIM To study the association between hilar cholangiocarcinoma (HC) and pre-existing medical conditions. METHODS Three hundred and thirteen HC patients admitted to the Eastern Hepatobiliary Surgery Hospital (Shanghai, China) in 2000-2005 and 608 healthy controls were enrolled in this study. Association between HC and pre-existing medical conditions was studied with their adjusted odds ratio (OR) calculated by logistic regression analysis. RESULTS The prevalence of choledocholithiasis (adjusted OR = 2.704, P = 0.039), hepatolithiasis (adjusted OR = 3.278, P = 0.018), cholecystolithiasis (adjusted OR = 4.499, P < 0.0001), cholecystectomy (adjusted OR = 7.012, P = 0.004), biliary ascariasis (adjusted OR = 7.188, P = 0.001), liver fluke (adjusted OR = 10.088, P = 0.042) and liver schistosomiasis (adjusted OR = 9.913, P = 0.001) was higher in HC patients than in healthy controls. CONCLUSION Biliary tract stone disease (choledocholithiasis, hepatolithiasis, cholecystolithiasis) and parasitic liver disease (biliary ascariasis, liver fluke, liver schistosomiasis) are the risk factors for HC in Chinese population.

Characteristics of intrahepatic cholangiocarcinoma in patients with hepatitis B virus infection: clinicopathologic study of resected tumours

Recent efforts suggest an aetiological role of hepatitis B virus (HBV) infection in intrahepatic cholangiocarcinoma (ICC). The purpose of this study was to clarify the clinicopathologic characteristics and surgical outcomes of patients with HBV‐associated ICC. All patients with chronic HBV infection were identified from a database of patients with ICC that underwent surgical resection between 1 January 2005 and 31 December 2006. Their clinicopathologic and survival characteristics were compared with ICC patients without chronic HBV infection. The age of the HBV‐associated ICC patients tend to be younger than that of ICC patients without chronic HBV infection. HBV‐associated ICC patients tend to have higher abnormal α‐fetoprotein levels and lower abnormal serum carbohydrate antigen19‐9 (CA19‐9), r‐glutamyltransferase (r‐GT) and alkaline phosphatase levels. The pathologic features of the resected specimens revealed that HBV‐associated ICC patients tended to be of the mass‐forming type have a lower prevalence of lymphatic involvement and poorer tumour differentiation, and a higher prevalence of capsule formation and liver cirrhosis. Patients with HBV‐associated ICC had a significantly better survival than patients without chronic HBV infection. The clinicopathological features of HBV‐associated ICC patients showed significant differences from ICC patients without HBV infection. These tumours are characterized by the mass‐forming growth pattern and appeared to have a more favourable prognosis.

Preoperative predictors of short-term survival after hepatectomy for multinodular hepatocellular carcinoma

AIM To investigate preoperative factors associated with poor short-term outcome after resection for multinodular hepatocellular carcinoma (HCC) and to assess the contraindication of patients for surgery. METHODS We retrospectively analyzed 162 multinodular HCC patients with Child-Pugh A liver function who underwent surgical resection. The prognostic significance of preoperative factors was investigated by univariate analysis using the log-rank test and by multivariate analysis using the Cox proportional hazards model. Each independent risk factor was then assigned points to construct a scoring model to evaluate the indication for surgical intervention. A receiver operating characteristics (ROC) curve was constructed to assess the predictive ability of this system. RESULTS The median overall survival was 38.3 mo (range: 3-80 mo), while the median disease-free survival was 18.6 mo (range: 1-79 mo). The 1-year mortality was 14%. Independent prognostic risk factors of 1-year death included prealbumin < 170 mg/L [hazard ratio (HR): 5.531, P < 0.001], alkaline phosphatase > 129 U/L (HR: 3.252, P = 0.005), α fetoprotein > 20 μg/L (HR: 7.477, P = 0.011), total tumor size > 8 cm (HR: 10.543; P < 0.001), platelet count < 100 × 10⁹/L (HR: 9.937, P < 0.001), and γ-glutamyl transpeptidase > 64 U/L (HR: 3.791, P < 0.001). The scoring model had a strong ability to predict 1-year survival (area under ROC: 0.925, P < 0.001). Patients with a score ≥ 5 had significantly poorer short-term outcome than those with a score < 5 (1-year mortality: 62% vs 5%, P < 0.001; 1-year recurrence rate: 86% vs 33%, P < 0.001). Patients with score ≥ 5 had greater possibility of microvascular invasion (P < 0.001), poor tumor differentiation (P = 0.003), liver cirrhosis with small nodules (P < 0.001), and intraoperative blood transfusion (P = 0.010). CONCLUSION A composite preoperative scoring model can be used as an indication of prognosis of HCC patients after surgical resection. Resection should be considered with caution in patients with a score ≥ 5, which indicates a contraindication for surgery.

LincRNA-p21 activates endoplasmic reticulum stress and inhibits hepatocellular carcinoma

LincRNA-p21 is a downstream long non-coding RNA (lncRNA) transcript of p53. LincRNA-p21 serves as a repressor in p53-dependent transcriptional responses and participates in diverse biological processes, including apoptosis, cell cycle, metabolism and pluripotency. However, the role of lincRNA-p21 in human hepatocellular carcinoma remains to be defined. Here in this work, we demonstrated that lincRNA-p21 acted as a tumor suppressive lncRNA in human hepatocellular carcinoma. We firstly found the downregulation of lincRNA-p21 level in human hepatocellular carcinoma tissues, and showed that low expression of lincRNA-p21 was associated with high disease stage and predicted poor survival. Further we showed that lincRNA-p21 knockdown promoted proliferation and colony formation of HepG2, Huh7 and Bel-7042 cells in vitro, while lincRNA-p21 overexpression obtained oppose results. Using tumor xenograft experiments, we also demonstrated that lincRNA-p21 inhibited HepG2 cell growth in vivo and lincRNA-p21 contributed to sorafenib-induced growth regression of HepG2 cell in vivo. Further mechanism analysis revealed that lincRNA-p21 promoted ER stress both in vitro and in vivo, which facilitated apoptosis of hepatocellular carcinoma cells. Finally, we demonstrated that ER stress accounted for lincRNA-p21 effects on apoptosis, proliferation and in vivo growth of hepatocellular carcinoma. These findings implicate that lincRNA-p21 is a potential prognostic factor and therapeutic target for human hepatocellular carcinoma.