Yao-Tsung Yeh

Altered p-STAT3 (tyr705) expression is associated with histological grading and intratumour microvessel density in hepatocellular carcinoma

Background: Constitutive activation of signal transducer and activator of transcription 3 at tyrosine residue 705 (p-STAT3 (tyr705)) has been associated with many types of human cancers. However, its potential roles and biological effects in hepatocellular carcinoma (HCC) are not well established. Aim: To explore whether an altered p-STAT3 (tyr705) expression is associated with angiogenesis or proliferation and thereby plays a part in HCC development. Methods: Paraffin-wax-embedded sections from 69 patients with HCC were collected in this study. Using a semiquantitative immunohistochemical staining method, the expression patterns of p-STAT3 (tyr705) in both HCC lesions and the adjacent non-tumorous liver parenchyma were analysed. The results obtained were further correlated with intratumour microvessel density (MVD), Ki-67 expression, clinicopathological parameters and overall survival. Results: A strong p-STAT3 (tyr705) nuclear staining was observed in 49.3% of HCC lesions, but was reported only in 5.8% of the adjacent non-tumorous liver parenchyma (p<0.001). The expression of p-STAT3 (tyr705) in HCC lesions was significantly and positively correlated with the intratumour MVD (p = 0.002), but not with Ki-67 expression. No significant correlation of p-STAT3 (tyr705) was found in addition to histological grading (p = 0.019). Multivariate Cox regression analysis showed that p-STAT3 (tyr705) expression was a significant predictor of overall survival for HCC (p = 0.036), although the Kaplan–Meier survival curves showed no significant difference between the high and low p-STAT3 (tyr705) expression subgroups. Conclusions: The results showed that p-STAT3 (tyr705) expression was closely correlated with histological grading and intratumour MVD in HCC. Thus, the potential role of p-STAT3 (tyr705) in HCC development may be through these correlations.

Potential role of leptin expression in hepatocellular carcinoma

Background: Obesity is associated with hepatocellular carcinoma (HCC). The association may result from the aberrant expression of adipokines. Aim: To explore the potential biological effect and prognostic value of leptin, one of the adipokines, in HCC. Methods: Immunohistochemistry was used to evaluate the expression of leptin in 68 patients with HCC. The expression of Ki-67 and microvessel density (MVD) of tumorous lesions in HCC were also analysed. The result of leptin expression was further correlated with Ki-67 expression, intratumour MVD, clinicopathological characteristics, overall survival and the postoperative use of medroxyprogesterone acetate (MPA). Results: High leptin expression was seen in 60.3% of patients with HCC and was significantly correlated with intratumour MVD (high v low; 59.2 (standard deviation 3.2) v 44.2 (19.5), p = 0.004), but not with Ki-67 expression. No marked correlation was seen between leptin expression and clinicopathological characteristics. However, using a multivariate Cox’s proportional hazards model, leptin expression was a predictor for improved overall survival of patients with HCC (odds ratio 0.16; 95% confidence interval 0.03 to 0.87; p = 0.033). In addition, the Kaplan–Meier survival curve showed that high leptin expression was associated with a better survival in patients with HCC, treated postoperatively with MPA (p = 0.008, log rank test). Conclusion: High leptin expression was associated with an increased intratumour MVD and thus may be associated with HCC development. In addition, high leptin expression was a predictor for improved survival of patients with HCC, treated postoperatively with MPA.

Potential prognostic value of leptin receptor in hepatocellular carcinoma

Background: Obesity is associated with several human malignancies, including hepatocellular carcinoma (HCC). This association may result from the deregulated expression of adipokines. Aims: To explore the potential role and the prognostic value of leptin receptor (Ob-R) in HCC. Methods: 66 patients with pathologically confirmed HCC were included in this study. Immunohistochemistry was used to evaluate the expression of Ob-R, microvessel density (MVD) and Ki-67 index in these patients. Eventually, the profiles of Ob-R expression, obtained by a semiquantitative scoring system, were further correlated with Ki-67 expression, intratumour MVD, clinicopathological characteristics and overall survival. Results: High Ob-R expression was seen in 53% of patients with HCC and was significantly correlated with intratumour MVD (high v low; 59.4 ?3.2) v 44.7 ?3.7); p = 0.004), but not with Ki-67 expression. In addition, Ob-R expression was inversely correlated with vascular invasion (p = 0.037), but not with other known clinicopathological characteristics. The Kaplan–Meier survival curve showed that high Ob-R expression was associated with a better overall survival (p = 0.027). Meanwhile, multivariate analysis showed that Ob-R expression was a significant determinant for HCC (odds ratio 0.02, 95% confidence interval 0.01 to 0.85; p = 0.041). Conclusion: Ob-R expression may have a potential role in the carcinogenesis of HCC. The positive association of Ob-R expression in the cancerous lesions of HCC with the survival outcome can be explained by its inverse correlation with vascular invasion, and may have prognostic value in HCC.

The promoting effect of adiponectin in hepatocellular carcinoma

Adipokines may explain the newly established association of obesity with hepatocellular carcinoma (HCC). This study investigated if adiponectin levels in HCC patients differed from healthy controls and their potential effect in the development of HCC.

Phosphorylated p38 and JNK MAPK proteins in hepatocellular carcinoma

Eur J Clin Invest 2012; 42 (12): 1295–1301

Prolactin Promotes Hepatocellular Carcinoma through Janus Kinase 2

BackgroundHepatocelluar carcinoma (HCC) is one human cancer with obvious gender disparity. This study investigated the association of aberrant prolactin levels with HCC risk and the potential impacts on HCC of the prolactin receptor (PRLR)/Janus kinase 2 (JAK2) signaling.MethodsSerum prolactin of 63 HCC patients and 162 subjects without HCC was measured by radioimmunoassay. The expressions of PRLR and phosphorylated JAK2 (p-JAK2) in 82 retrospectively collected HCC specimens were evaluated by immunohistochemistry and further incorporated into the survival analysis. The immunoblotting and proliferation assays were used to analyze the effects of PRLR/JAK2 signaling on liver cancer cells with prolactin treatment.ResultsSerum prolactin level was significantly higher in HCC patients than in controls. Hepatocellular carcinoma patients with high p-JAK2 expression had a significantly higher postoperative risk than those with low p-JAK2 expression. Moreover, results from the multivariate analysis indicated the prognostic role of p-JAK2 expression with respect to overall survival in HCC patients. In addition, the Kaplan–Meier survival curve showed that high p-JAK2 expression was associated with poor survival in HCC patients with high PRLR expression. The immunoblotting assay showed that prolactin induced the expression of both p-JAK2 and cyclin D1 in Hep-G2 cells. Importantly, the proliferative effects induced by prolactin could be effectively attenuated by adding AG490, a JAK2 inhibitor.ConclusionsIncreased circulating prolactin was found in HCC patients and high p-JAK2 expression could predict poor overall survival in those patients expressing high PRLR. In addition, prolactin contributed to the proliferation of liver cancer cells through PRLR/JAK2 signaling.

Increased caveolin-1 expression associated with prolonged overall survival rate in hepatocellular carcinoma.

Aims: Recent study indicates that the binding of caveolin‐1 (CAV1), the essential constituent of caveolae, to endothelial nitric oxide synthase (eNOS) prevents nitric oxide (NO) production in cirrhotic human liver. However, their interplay in hepatocellular carcinoma (HCC) remains undetermined. Methods: Paraffin‐embedded sections from 73 HCC patients were included in this study. The expression patterns of CAV1 and eNOS determined by immunohistochemistry were correlated with the clinicopathological characteristics and overall survival. Results: Although CAV1 expression did not correlate with any clinicopathological characteristic, increased CAV1 expression was associated with prolonged overall survival (p = 0.021), even when using the multivariate Coxs regression model (OR = 0.25, 95%CI = 0.08–0.72, p = 0.011). eNOS expression was correlated with an increased histological grade (p = 0.002) and intriguingly, the patients had a decreased overall survival when their lesions presented with high eNOS but low CAV1 expression concomitantly (p = 0.003). Meanwhile, the increased CAV1/eNOS merged level determined by immunofluorescence was significantly associated with a decreased histological grade and better overall survival (p = 0.023 and 0.001, respectively). Conclusions: Our results suggest CAV1 may play a tumour‐suppressive role and can serve as a predictive biomarker in HCC. The impacts of CAV1 on hepatocarcinogenesis may occur partly through its modulation of eNOS.

SOCS-3 is associated with vascular invasion and overall survival in hepatocellular carcinoma

Aims: Alteration of the suppressor of cytokine signalling‐3 (SOCS‐3) has been observed in certain human cancers. However, the clinical role of this short‐lived protein in hepatocellular carcinoma (HCC) is not well established. Therefore, we aimed to explore the potential role of SOCS‐3 proteins in HCC. Methods: Paraffin embedded sections from 87 HCC patients were included in this study. The expression patterns of SOCS‐3 proteins were analysed using immunohistochemistry and the results were correlated with clinicopathological characteristics and overall survival of the HCC patients. Results: The SOCS‐3 expression of HCC lesions and the adjacent non‐tumourous liver tissues was significantly correlated (p = 0.035), while the SOCS‐3 expression in HCC lesions was significantly and positively correlated with vascular invasion and histological grading (p = 0.034 and 0.032, respectively). The Kaplan–Meier survival curve showed that the HCC patients with high SOCS‐3 expression were associated with a poor overall survival rate in the HCC subgroup with positive vascular invasion (p = 0.014). Furthermore, a multivariate Cox regression model showed that SOCS‐3 expression was also a significant determinant of the overall survival for HCC (p = 0.006). Conclusions: Our results indicate that altered SOCS‐3 expression is associated with the overall survival in a subset of HCC patients with positive vascular invasion. Constitutive and altered SOCS‐3 expression may have potential roles in a subset of HCC patients.

Crosstalk between Activated and Inactivated c-Src in Hepatocellular Carcinoma

C-Src activity is regulated by tyrosine phosphorylation at two distinct sites, Tyr416 and Tyr527, with opposite effects. However, the clinical roles of these sites in human cancers are not well defined. This study aims to determine whether the alterations and crosstalk of these two sites may contribute to hepatocellular carcinoma (HCC). Specimens from 85 patients who had undergone curative hepatectomy were collected for this study. The patterns of p-Tyr416-Src and p-Tyr527-Src, as well as the non-phosphorylated status for each site, were determined using immunohistochemistry and statistically correlated with clinicopathological characteristics and overall survival rate. The active state of c-Src, p-Tyr416-c-Src, was positively correlated with tumour grade (P = 0.062) but inversely correlated with vascular invasion (P = 0.071). Its non-phosphorylated status, non-p-Tyr416-c-Src, was positively correlated with tumour stage and grade (P = 0.041 and 0.020). The inactive state of c-Src, p-Tyr527-c-Src, was decreased in male patients but increased HCV-infected patients (P = 0.044 and 0.033). The Kaplan-Meier survival curve further showed that increased p-Tyr416-c-Src and decreased non-p-Tyr527-c-Src expression were associated with a poor patient survival rate (P = 0.004 and 0.025). Interestingly, the expression of non-p-Tyr416-c-Src was positively correlated with that of p-Tyr527-c-Src in the HCC lesions (P = 0.040). In addition, the patients with concomitantly low p-Tyr416-c-Src and non-p-Tyr527-c-Src expression had a prolonged overall survival rate (P = 0.030). A multivariable COX regression model showed that p-Tyr416-c-Src expression was an effective predictor for patient survival in HCC [OR = 3.78, 95%CI = 1.46–9.76; P = 0.006]. Our results suggest that the active state of c-Src, p-Tyr416-c-Src, may serve as an independent prognostic marker of patient survival in HCC. Relative levels of other phosphorylated or non-phosphorylated c-Src kinases may also present different statuses during HCC development and require further investigation.

Positive Association between STAT3 and Ki-67 in Cervical Intraepithelial Neoplasia

Signal transducer and activator of transcription 3 (STAT3) has been regarded as an oncogene in many types of cancers. However, its role in cervical carcinogenesis is not well determined. The purpose of this study was to evaluate the expression patterns of STAT3 in cervical intraepithelial neoplasia (CIN), normal cervix (NC), and squamous cell carcinoma (SCC) to explore its possible role in cervical carcinogenesis. Paraffin‐embedded sections from 83 patients including 20 CIN 1, 10 CIN 2, 26 CIN 3, and 27 comparative cases of 10 NC and 17 stage Ib SCC were collected in this study. Immunohistochemistry was performed to analyze the expression patterns of STAT3, and the results obtained were categorized by a semiquantitative method and were further correlated with the CIN histopathologic grade and the proliferation marker, Ki‐67, using the c2 test. Our results showed that nuclear STAT3 expression was predominantly in the squamous epithelial cells, and that high‐grade CIN and stage Ib SCC lesions had a higher nuclear STAT3 expression when compared with NC and CIN 1. Furthermore, the nuclear STAT3 expression in CIN was significantly correlated with Ki‐67 expression (p= 0.025), but not CIN lesion grade. In summary, our results indicate that an altered STAT3 expression in CIN is correlated with cell proliferation but may not have a direct contribution to cervical carcinogenesis.