Ack1 overexpression promotes metastasis and indicates poor prognosis of hepatocellular carcinoma.

Despite the substantial data supporting the oncogenic role of Ack1, the predictive value and biologic role of Ack1 in hepatocellular carcinoma (HCC) metastasis remains unknown. In this study, both correlations of Ack1 expression with prognosis of HCC, and the role of Ack1 in metastasis of HCC were investigated in vitro and in vivo. Our results showed that Ack1 was overexpressed in human HCC tissues and cell lines. High Ack1 expression was associated with HCC metastasis and determined as a significant and independent prognostic factor for HCC after liver resection. Ack1 promoted HCC invasion and metastasis in vitro and in vivo. Mechanistically, we confirmed that Ack1 enhanced invasion and metastasis of HCC via EMT by mediating AKT phosphorylation. In conclusion, our study shows Ack1 is a novel prognostic biomarker for HCC and promotes metastasis of HCC via EMT by activating AKT signaling.

Mesohepatectomy for centrally located large hepatocellular carcinoma: Indications, techniques, and outcomes.

BACKGROUND: Whether mesohepatectomy should be performed for large hepatocellular carcinoma (HCC) located in the central part of the liver is controversial, and the safety and long-term survival after this operation remain to be investigated. METHODS: Between January 2002 and December 2012, 696 patients with HCC located in the central part of the liver who received liver resection in our hospital were included in this study. These patients were divided into three groups: 158 patients with large HCC (tumor size >5.0 cm) and 192 patients with small HCC (tumor size ≤ 5.0 cm) who received mesohepatectomy were classified as the mesohepatectomy for large HCC (MHG-L) group and the mesohepatectomy for small HCC (MHG-S) groups, respectively, and 346 patients with large HCC who received hemihepatectomy or less were classified as the non-mesohepatectomy for large HCC (NMHG-L) group. The operative indications, techniques, and outcomes of the three groups were analyzed retrospectively. RESULTS: There were no substantial differences among the three groups in in-hospital mortality or postoperative complication rates. The overall survival and disease-free survival were not different between the MHG-L group and the NMHG-L group or between the MHG-L group and the MHG-S group. Univariable and multivariable analyses of the MHG-L mesohepatectomy group indicated that cirrhosis, tumor number, and vascular invasion were independent risk factors of poor long-term survival of mesohepatectomy. In the MHG-L and NMHG-L groups, solitary large hepatocellular carcinoma had better long-term survival than nodular large hepatocellular carcinoma. CONCLUSION: Mesohepatectomy is safe and efficacious for BCLC B/C patients who have centrally located large HCC, especially for solitary tumors, with good survival outcomes.

[Segmental resection of the liver by Glissonean pedicle transection for primary liver cancer].

OBJECTIVE: To study the clinical effect of segmental resection of the liver using Glissonean pedicle transection for primary liver cancer. METHODS: The clinical data of 55 primary liver cancer patients admitted from January 2006 to October 2008 were analyzed retrospectively. Twenty-five of the patients underwent segmental resection of the liver by Glissonean pedicle transection (group A), and 30 underwent routine hepatectomy (group B). The positivity rate of the resection margin, micrometastasis in the hepatic parenchyma surrounding the lesions and postoperative recurrence rates were investigated. RESULTS: The positivity rate of the resection margin was 4.0% in group A, significantly lower than that of group B. The number of histological micrometastasis was significantly higher in group A than in group B (16 vs 8). The median distance of histological micrometastasis was 6.8 mm (2.7-25.6 mm) in group A and 4.2 mm (2.4-9.0 mm) in group B. The one-year recurrence rate was significantly lower in group A than in group B (16% vs 26.7%). CONCLUSION: Glissonean pedicle transection for segmental liver resection is a simpler procedure than routine hepatectomy for primary liver cancer and can reduce the number of histological micrometastasis and recurrence rate.

Novel role for epidermal growth factor-like domain 7 in metastasis of human hepatocellular carcinoma.

UNLABELLED: Epidermal growth factor-like domain 7 (Egfl7) is a recently identified secreted protein that is believed to be primarily expressed in endothelial cells (ECs). Although its expression was reported elevated during tumorigenesis, whether and how Egfl7 contributes to human malignancies remains unknown. In the present study overexpression of Egfl7 was found predominantly in hepatocellular carcinoma (HCC) cells in HCC tissues and closely correlated with poor prognosis of HCC. The expression of Egfl7 in cancer cells was further verified with HCC cell lines including HepG2, MHCC97-L, and HCCLM3, and the Egfl7 expression levels positively correlated with metastatic potential of HCC cell lines was tested. To functionally characterize Egfl7 in HCC, we depleted its expression in HCCLM3 cells by using small interfering RNA. Interestingly, reduction of Egfl7 expression resulted in significant inhibition of migration but not growth of HCCLM3 cells. Biochemical analysis indicated that Egfl7 could facilitate the phosphorylation of focal adhesion kinase (FAK) and therefore promote the migration of HCCLM3 cells. In addition, this effect was almost completely blocked by inhibition of epidermal growth factor receptor (EGFR), indicating that the activation of FAK by Egfl7 is mediated through EGFR. Finally, we used a mouse model to demonstrate that down-regulation of Egfl7 was associated with suppression of intrahepatic and pulmonary metastases of HCC. Collectively, our study shows for the first time that overexpression of Egfl7 in HCC and Egfl7 promotes metastasis of HCC by enhancing cell motility through EGFR-dependent FAK phosphorylation. CONCLUSION: Our study suggests Egfl7 as a novel prognostic marker for metastasis of HCC and a potential therapeutic target.

Solitary large hepatocellular carcinoma: a specific subtype of hepatocellular carcinoma with good outcome after hepatic resection.

OBJECTIVE: To evaluate and compare the clinical and pathologic characteristics and outcomes after hepatic resection of large hepatocellular carcinoma (SLHCC), small HCC (SHCC), and nodular HCC (NHCC). SUMMARY BACKGROUND DATA: Traditional viewpoint insists that the classification and prognosis of HCC are determined by the size of HCC. As a result, large HCC is often considered as advanced and unresectable. However, we have observed a unique type of HCC-SLHCC, which is large in size but exhibits good clinical, pathologic, and molecular biologic characteristics as well as prognosis. METHODS: From January 1992 to December 2002, a total of 481 consecutive patients were diagnosed with HCC and received hepatic resection. In this series of patients, the clinical and pathologic data, surgical outcome, and long-term survival of patients with SLHCC (group A, n = 260) were analyzed retrospectively and compared with patients who had SHCC (group B, n = 135) or NHCC (group C, n = 86). Postresection prognostic factors of HCC were also evaluated by univariate and multivariate analysis using Cox's proportional hazards model. RESULTS: The clinical and pathologic characteristics of SLHCC and SHCC were similar except for tumor necrosis and tumor size. Patients of SLHCC had significantly longer operative time, higher intraoperative blood loss, higher intraoperative blood transfusion, and higher postoperative morbidity than SHCC. However, the 2 groups were similar in duration of hospital stay and overall morbidity. Overall survival and disease-free survival in group A and group B were similar and significantly better than those in group C. Multivariate analysis revealed that large amount of intraoperative blood transfusion and vein invasion were independently significant factors for overall survival of patients with HCC. CONCLUSION: The clinical and pathologic characteristics and the outcome after hepatic resection of SLHCC are similar to that of SHCC, but significantly better than NHCC. We propose SLHCC as a specific subtype of HCC and hepatic resection as its choice of standard treatment.

Decreased expression of methyl methansulfonate and ultraviolet-sensitive gene clone 81 (Mus81) is correlated with a poor prognosis in patients with hepatocellular carcinoma.

BACKGROUND: Recent work has demonstrated that methyl methansulfonate and ultraviolet-sensitive gene clone 81 (Mus81) is critical in the maintenance of chromosome stability and tumor suppression in mice. To investigate its role in human hepatocellular carcinoma (HCC), which currently is unknown, the authors examined the correlation between Mus81 expression and prognosis in patients with HCC. METHODS: Reverse transcriptase-polymersase chain reaction and Western blot analyses were used to determine Mus81 expression levels in 41 paired HCC and paracarcinomatous liver tissue (PCLT) specimens. Immunohistochemistry analysis was also performed on 104 HCC specimens from patients with follow-up information. RESULTS: Both Mus81 messenger RNA and protein expression levels were decreased significantly in HCC specimens. Moreover, lower Mus81 expression levels were detected in nodular HCC (NHCC) than in solitary large HCC (SLHCC) specimens. Among 104 specimens of HCC, the positive rate of Mus81 was significantly lower than the rate in PCLT (P = .017), and the decreased Mus81expression was correlated significantly with high Edmondson-Steiner grade, multiple tumor nodes, and venous invasion. Patients with HCC who had low Mus81 expression had either poorer disease-free survival or poorer overall survival than patients who had with high Mus81 expression (P = .0027 and P = .0001, respectively). Multivariate Cox regression analysis revealed that low Mus81 expression was an independent prognostic factor for patients with HCC (risk ratio, 5.74; P = .012). CONCLUSIONS: Mus81 expression levels were decreased significantly in HCC specimens, and the decreased levels were correlated with a poor prognosis in patients with HCC, implicating Mus81 as a candidate prognostic marker in HCC.

The hepatitis B virus X protein promotes hepatocellular carcinoma metastasis by upregulation of matrix metalloproteinases.

The hepatitis B virus (HBV) is a major cause of human hepatocellular carcinoma (HCC) which has a very high mortality rate due to high incidence of metastasis. It is unknown whether HBV contributes to HCC metastasis. In this report, we present clinical data obtained from HCC patients indicating that the expression of hepatitis B virus X protein (HBx) in HCC is associated with an increased expression of membrane-type 1 matrix metalloproteinase (MT1-MMP), and matrix metalloproteinase-2(MMP-2), which correlates with a poor prognosis. We further demonstrate experimentally that HBx upregulates MT1-MMP, which in turn induces MMP-2. Significantly, HBx-mediated MMP activation is associated with a marked increase of cell migration, as revealed by both wound-healing and transwell migration assays, suggesting that HBx may facilitate tumor cell invasion by upregulation of MMPs and subsequent destruction of the extracellular matrix. Together, our results support a model in which HBx contributes to HCC metastasis by upregulation of MMPs.

Increased expression of Wiskott-Aldrich syndrome protein family verprolin-homologous protein 2 correlated with poor prognosis of hepatocellular carcinoma.

PURPOSE: Because of its role in cell migration, the Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE) 2 has been implicated in cancer metastasis. Evidence to support such a role of WAVE2 in human cancer, however, is lacking. We thus examined the expression of WAVE2 in hepatocellular carcinoma (HCC) tissues to test whether the levels of WAVE2 expression correlated to the progression of HCC. EXPERIMENTAL DESIGN: Samples of 112 HCC patients were determined immunohistochemically for WAVE2 expression and the correlation of WAVE2 levels with prognosis was analyzed. Among the 112 cases, 31 paired HCC and paracarcinomatous liver tissue specimens were analyzed for WAVE2 levels by reverse transcription-PCR and Western blotting, respectively. RESULTS: Among 112 cases of HCCs, the immunohistochemistry data indicated significant increase of WAVE2 expression levels in 71 cases. Importantly, the increased WAVE2 expression correlated with the multiple tumor nodules (P = 0.008), the absence of capsular formation (P = 0.035), Edmondson-Steiner grade (P = 0.009), vein invasion (P = 0.023), and a shortened median survival time (326 versus 512 days; P = 0.003). Multivariable Cox regression analysis revealed the WAVE2 expression level was an independent factor for prognosis. The immunohistochemistry data were further confirmed by results of reverse transcription-PCR and Western analysis of 31 HCC cases, in which the WAVE2 mRNA and protein in HCC tissues were significantly elevated when compared with paracarcinomatous liver tissue (P < 0.001). CONCLUSIONS: WAVE2 expression is elevated in HCC tissues, which correlates with a poor prognosis, suggesting WAVE2 as a candidate prognostic marker of HCC.

[Risk factors for metastasis and recurrence of hepatocellular carcinoma at different stages].

OBJECTIVE: To analyze the risk factors for metastasis and recurrence of hepatocellular carcinoma (HCC) postoperatively. METHODS: Data of 270 cases of postoperative HCC were analyzed by SPSS software retrospectively. RESULTS: Out of the 270 cases, 162 got follow-up study and 136 showed metastasis and recurrence. Lots of risk factors induced the recurrence of HCC, such as AFP, tumor form, venous blood invasion, HBV infection, resection dimension and perioperative transfusion. There were different risk factors at different stages. CONCLUSION: The early recurrence of HCC may be mediated by macro- or micro-vessel blood invasion and metastasis, the late recurrence by multicentric carcinogenesis or introhepatic cacinoma de novo.

Clinical analysis of the risk factors for recurrence of HCC and its relationship with HBV.

AIM: To comprehend the risk factors of recurrence of hepatocellular carcinoma (HCC) and its relationship with the infection patterns of hepatitis B virus (HBV). METHODS: All materials of 270 cases of postoperative HCC were statistically analyzed by SPSS software. Recurrence and metastasis were classified into early (< or =2 years) and late phase (>2 years). Risk factors for recurrence and metastasis after surgery in each group were analyzed. RESULTS: Out of 270 cases of HCC, 162 cases were followed up in which recurrence and metastasis occurred in 136 cases. There were a lot of risk factors related to recurrence and metastasis of HCC; risk factors contributing to early phase recurrence were serum AFP level, vascular invasion, incisal margin and operative transfusion, gross tumor classification and number of intrahepatic node to late phase recurrence. The HBV infective rate of recurrent HCC was 94.1%, in which "HBsAg, HBeAb, HbcAb" positive pattern reached 45.6%. The proportion of HBV infection in solitary large hepatocellular carcinoma (SLHCC) evidently decreased compared to nodular hepatocellular carcinoma (NHCC) (P<0.05). CONCLUSION: The early and late recurrence and metastasis after hepatectomy of HCC were associated with different risk factors. The early recurrence may be mediated by vascular invasion and remnant lesion, the late recurrence by tumor's clinical pathology propert, as multicentric carcinogenesis or intrahepatic carcinoma de novo. HBV replication takes a great role in this process. From this study, we found that SLHCC has more satisfactory neoplasm biological behavior than NHCC.