Paracarcinomatous Liver Tissues Research Articles

High expression of GP73 in primary hepatocellular carcinoma and its function in the assessment of transcatheter arterial chemoembolization.

Golgi glycoprotein 73 (GP73) is a type II Golgi transmembrane protein and a potential novel marker for the diagnosis of primary hepatocellular carcinoma (PHC). However, its reliability as a serum marker for the diagnosis of PHC following transcatheter arterial chemoembolization (TACE) remains unknown. The aim of the present study was to evaluate the diagnostic value of serum GP73 levels in patients with PHC, to determine its diagnostic accuracy in patients with PHC following TACE. Reverse transcription-quantitative polymerase chain reaction analysis was used to measure GP73 expression in PHC and adjacent para-carcinomatous liver tissue in 40 patients with PHC, and 15 normal liver samples from benign hepatic tumors. The associations between GP73 expression levels with clinicopathological characteristics of the patients were also analyzed. Serum GP73 levels were detected by ELISA in 68 patients with PHC following TACE and 29 healthy individuals. The levels of serum GP73 were tested 2 days prior to intervention, and 7 and 30 days following TACE. GP73 mRNA expression levels in PHC were significantly higher than in the corresponding para-carcinomatous liver and normal liver samples. High expression levels of GP73 mRNA were associated with tumor size, vascular invasion and tumor differentiation, suggesting augmented tumor invasion and metastasis. The expression levels of serum GP73 were markedly higher in the patients with PHC compared with healthy individuals. Serum GP73 levels in the 68 patients with PHC were higher compared with the 29 normal controls [152.5 (76.4-284.5) compared with 49.3 (12.6-26.7) µg/l], and the difference was statistically significant (P<0.01). High levels of serum GP73 were associated with tumor differentiation. The levels of Barcelona clinic liver cancer stage A, B and C were 92.12 (38.9-135.2), 122.9 (55.2-178.5), and 162.55 (110.8-232.9) µg/l, respectively (P<0.05). The serum GP73 levels 7 days following TACE [99.2 (66.7-150.8)] were significantly lower than prior to TACE, and the difference was statistically significant (P<0.05). In the group of 49 patients with serum α-fetoprotein (AFP) levels <400 µg/l, the serum GP73 levels were >132 µg/l. Serum GP73 levels may serve as a potential independent diagnostic marker for PHC, and the combined evaluation of serum GP73 and AFP may increase the diagnostic efficiency of PHC. Significant overexpression of GP73 mRNA was associated with aggressive PHC. However, further research is required to confirm the potential of GP73 as a diagnostic marker.

MiR-17-5p as a Novel Prognostic Marker for Hepatocellular Carcinoma

ABSTRACTObjectives: miRNAs are frequently deregulated in cancer and have shown promise as tissue-based markers for cancer classification and prognostication. Emerging evidence indicates that miR-17-5p plays an important role in carcinogenesis. However, the expression of miR-17-5p in HCC tissues and its clinical relevance has not been systematically studied yet, and whether miR-17-5p expression has influence on prognosis of HCC is still unknown. In this study, we investigate the expression and clinical significance of miR-17-5p in human HCC. Methods: The expression levels of miR-17-5p were measured in 120 paired hepatocellular carcinoma (HCC) and paracarcinomatous liver tissues (PCLTs) derived from patients who underwent hepatic resection by qRT-PCR. Furthermore, the correlation of miR-17-5p levels with clinicopathologic variables and prognosis was analyzed. Results: miR-17-5p was significantly upregulated in HCCs (p < .001). Furthermore, HCC with metastasis had higher miR-17-5p levels than that without metastasis (p < .001). Importantly, the elevated expression of miR-17-5p correlated with multiple tumor nodules (p = .046), worse Edmondson–Steiner grade (p = .024), vein invasion (p = .001), shortened overall survival (p = .012), and disease-free survival (p = .011) of HCC. Multivariable Cox regression analysis revealed that miR-17-5p was an independent risk factor for overall survival and disease-free survival (p = .002 and p = .042, respectively). Conclusion: miR-17-5p is highly elevated in HCC, especially in HCC with metastasis. miR-17-5p can serve as a novel prognostic marker for HCC.

Downregulation of MAGI1 Associates with Poor Prognosis of Hepatocellular Carcinoma

ABSTRACTObjective: MAGI1 (membrane-associated guanylate kinase, WW and PDZ domain containing 1) plays an important role in stabilization of adherens junctions and suppression of invasiveness and metastasis. However, its expression and clinical revelance in hepatocellular carcinoma (HCC) are still unknown. So, this study was performed to detect the expression and clinical significance of MAGI1 in human HCC. Methods: The mRNA and protein expression levels were examined by using reverse transcription-PCR (RT-PCR) and Western blotting in 31 paired HCC and paracarcinomatous liver tissues (PCLT). Furthermore, samples of 104 HCC patients were determined immunohistochemically for MAGI1 expression and the correlation of MAGI1 levels with prognosis was analyzed. Results: The expression levels of MAGI1 were significantly downregulated in HCCs than those in PCLTs (p < .01). Importantly, the decreased expression of MAGI1 correlated with multiple tumor nodules (p < .05), absence of capsular formation (p < .05), worse Edmondson–Steiner grade (p < .05), vein invasion (p < .01), shortened median overall survival time (25 versus 42 months; p = .013), and disease-free survival time (20 versus 40 months; p = .018) of HCC. Multivariable Cox regression analysis revealed that MAGI1 expression level was an independent factor for prognosis (p = .038). Conclusions: MAGI1 expression is decreased in HCC, which correlates with poor prognosis, suggesting MAGI1 as a novel prognostic marker for HCC.

Increased expression of Abi1 in hepatocellular carcinoma and its correlation with poor prognosis of hepatocellular carcinoma

To investigate the expression of Abi1 in hepatocellular carcinoma (HCC) and the correlation between its expression level and clinical pathological characteristics as well as prognosis of HCC. Abi1 expression was determined at both mRNA and protein levels in 40 HCC tissues and their corresponding para carcinomatous liver tissues by RT-PCR and immunohistochemistry. The correlations between Abi1 expression levels and pathological characteristics as well as prognosis were also analyzed. The expression level of Abi1 mRNA in HCC tissues were significantly higher than those in corresponding para carcinomatous liver tissue (P < 0.05), and the expression level of Abi1 mRNA in nodular HCC tissues were also significantly higher than those in solitary large HCC tissues. Immunohistochemistry results showed that Abi1 protein located in cytoplasm of HCC cells and the expression level of Abi1 protein were significant positive correlated with the number of HCC, capsular formation, venous invasion and Edmondson-Steiner grade (P < 0.05). Combined with follow-up data, the results also showed that HCC patients with high Abi1 protein expression had a higher risk of invasion/metastasis and a shorter survival than those with low Abi1 protein expression (P < 0.05). Expression level of Abi1 is up-regulated in HCC tissues compared with corresponding para carcinomatous liver tissue and the expression level of Abi1 is significantly correlated with the number of tumor, capsular formation, venous invasion, Edmondson-Steiner grade and prognosis of HCC.

P53‐induced RING‐H2 protein, a novel marker for poor survival in hepatocellular carcinoma after hepatic resection

Currently, the role of p53-induced RING-H2 protein (PIRH2) in the development of hepatocellular carcinoma (HCC) remains unknown. The objective of this retrospective study was to investigate the expression of PIRH2 and its relation to prognosis in patients with HCC after hepatic resection. Reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative real-time RT-PCR, and Western blot analyses were used to detect expression levels of PIRH2 in 30 samples of HCC tissue and paracarcinomatous liver tissue (PCLT) and in 5 samples of normal liver tissue (NL). In addition, immunohistochemical analysis was performed on 122 HCC specimens and follow-up information data from those patients were reviewed. Both messenger RNA and protein expression levels of PIRH2 were elevated significantly in HCC tissues compared with PCLT and NL tissues. The increased PIRH2 expression was correlated with vein invasion, Edmondson-Steiner grade, TNM stage, and multiple tumor nodes (P<.05). It is noteworthy that the patients with HCC who had high PIRH2 expression had shorter overall survival and disease-free survival than the patients who had low PIRH2 expression (median survival, 280 days vs 372 days; P = .0002; median disease-free survival, 220 days vs 310 days; P = .0016). Multivariate Cox regression analysis revealed that high PIRH2 expression was an independent prognostic factor for patients with HCC (relative risk, 1.792; P = .009). The current data revealed that increased expression of PIRH2 was correlated with poor survival in patients with HCC, indicating that PIRH2 is a novel prognostic marker for HCC.

Decreased Expression of Inhibitor of Growth 4 Correlated with Poor Prognosis of Hepatocellular Carcinoma

Inhibitor of growth 4 (ING4) is a candidate tumor suppressor that plays an important role in tumor growth and angiogenesis. Here, we examined the expression of ING4 in hepatocellular carcinoma (HCC) tissues and analyzed its correlation with the progression of HCC. Specimens from 136 HCC patients were determined immunohistochemically for ING4 expression. The correlation of ING4 levels with clinicopathologic variables, prognosis, and metastatic potential was analyzed. Among the 136 cases, 36 paired HCC and paracarcinomatous liver tissue specimens were analyzed for ING4 expression levels by real-time quantitative reverse transcription-PCR and Western blotting. MVD was determined by CD34 immunostaining to test whether it correlated with ING4 protein expression level. The ING4 mRNA and protein levels were significantly lower in HCC than paracarcinomatous liver tissue from both real-time quantitative reverse transcription-PCR and Western blotting (P = 0.039 and 0.012, respectively). Importantly, the ING4 protein level correlated with the Edmondson-Steiner grade (P = 0.035), vein invasion (P = 0.015), and microvessel density (P = 0.005). Survival and metastasis analysis indicated that HCC patients with lower ING4 expression had poorer overall survival and disease-free survival than those with high expression (P = 0.0001 and 0.0065; respectively). Multivariable Cox regression analysis revealed that the ING4 expression level was an independent factor for prognosis (hazard risk, 9.63; P = 0.001). ING4 expression is down-regulated in HCC tissues. ING4 expression level correlates with prognosis and metastatic potential, which suggests that ING4 is a candidate prognostic marker of HCC.

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

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. 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. 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). 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.

Increased Expression of Wiskott-Aldrich Syndrome Protein Family Verprolin-Homologous Protein 2 Correlated with Poor Prognosis of Hepatocellular Carcinoma

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. 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. 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). WAVE2 expression is elevated in HCC tissues, which correlates with a poor prognosis, suggesting WAVE2 as a candidate prognostic marker of HCC.

Correlation between CD105 expression and postoperative recurrence and metastasis of hepatocellular carcinoma

BackgroundAngiogenesis is one of the mechanisms most critical to the postoperative recurrence and metastasis of hepatocellular carcinoma (HCC). Thus, finding the molecular markers associated with angiogenesis may help identify patients at increased risk for recurrence and metastasis of HCC. This study was designed to investigate whether CD105 or CD34 could serve as a valid prognostic marker in patients with HCC by determining if there is a correlation between CD105 or CD34 expression and postoperative recurrence or metastasis.MethodsImmunohistochemical staining for the CD105, CD34 and vascular endothelial growth factor (VEGF) antibodies was performed in 113 HCC tissue specimens containing paracarcinomatous tissue and in 14 normal liver tissue specimens. The quantitation of microvessels identified by anti-CD105 and anti-CD34 monoclonal antibodies and the semiquantitation of VEGF expression identified by anti-VEGF monoclonal antibody were analyzed in conjunction with the clinicopathological characteristics of the HCC and any available follow-up information about the patients from whom the specimens were obtained.ResultsCD105 was not expressed in the vascular endothelial cells of any normal liver tissue or paracarcinomatous liver tissue but was expressed in the vascular endothelial cells of all HCC tissue. In contrast, CD34 was expressed in the vascular endothelial cells of normal liver tissue, paracarcinomatous tissue, and HCC tissue in the following proportions of specimens: 86.7%, 93.8%, and 100%, respectively. The microvascular densities (MVDs) of HCC determined by using an anti-CD105 mAb (CD105-MVD) and an anti-CD34 mAb (CD34-MVD), were 71.7 ± 8.3 (SD) and 106.3 ± 10.4 (SD), respectively. There was a significant correlation between CD105-MVD and CD34-MVD (r = 0.248, P = 0.021). Although CD34-MVD was significantly correlated with VEGF expression (r = 0.243, P = 0.024), CD105-MVD was more closely correlated (r = 0.300, P= 0.005). The correlation between microscopic venous invasion and CD105-MVD, but not CD34-MVD, was also statistically significant (r = 0.254, P = 0.018). Univariate analysis showed that CD105-MVD was significantly correlated with the 2-year overall survival rate (P = 0.014); CD34-MVD was not (P = 0.601). Multivariate analysis confirmed that CD105-MVD was an independent prognostic factor and that CD34-MVD was not.ConclusionThe anti-CD105 mAb is an ideal instrument to quantify new microvessels in HCC as compared with anti-CD34 mAb. CD105-MVD as compared with CD34-MVD is relevant a significant and independent prognostic indicator for recurrence and metastasis in HCC patients.