Shengfu Huang

High expression of vanilloid receptor-1 is associated with better prognosis of patients with hepatocellular carcinoma

The vanilloid receptor-1 (VR1) is a ligand-gated, nonselective cation channel expressed predominantly by sensory neurons, but is also involved in carcinogenesis. To elucidate its role in hepatocarcinogenesis, we analyzed the expression of VR1 receptor in tumor and nontumor tissues from human hepatocellular carcinoma (HCC) samples. In situ hybridization analysis showed overexpression of VR1 mRNAs in 9/15 (60.0%) noncancer and 6/15 (40.0%) HCC samples. Immunohistochemistry of 62 HCC samples showed the expression of VR1 increased from normal liver or chronic hepatitis to cirrhosis. Marked expression of VR1 was noted in the majority [31/38 (81.6%)] of cirrhotic liver samples. In HCC, high expression of VR1 was observed in 30/62 (48.4%) cases. Clinicopathologic evaluation indicated a significant correlation between VR1 expression and histopathologic differentiation (P=0.001). Univariate analysis indicated that disease-free survival was significantly better in HCC patients with high versus those with low VR1 expression levels (P= 0.021). Our results indicate that VR1 has anti-HCC progression effects and can be potentially used as a prognostic indicator of HCC. The results suggest the potential beneficiary effects of VR1 expression on the prognosis of patients with HCC.

Anatomic resection of segment VIII of liver for hepatocellular carcinoma in cirrhotic patients based on an intrahepatic Glissonian approach

BACKGROUND Isolated segmentectomy VIII is a technically demanding operative procedure and is reported only rarely. To our knowledge, no reports on anatomic segmentectomy based on an intrahepatic approach have been described. For cirrhotic patients with hepatocellular carcinoma (HCC) limited to segment VIII, this is a parenchyma-preserving hepatectomy that can be tolerated. METHODS Eighteen patients with HCC underwent anatomic segment VIII segmentectomy from January 2005 to January 2008 in our institution. The operative techniques, postoperative, and oncologic outcomes were reviewed. RESULTS Anatomic segmentectomy VIII was feasible with the technology described herein in all patients. The perioperative and oncologic outcomes were comparable with those of other similar hepatic resections. The median follow-up time was 28 months. The 3-year survival rate was 65%. CONCLUSION Although complex and technically demanding, an intrahepatic Glissonian approach for anatomic segmentectomy of segment VIII is an oncologically radical but parenchyma-sparing hepatic resection. In terms of preserving greater functioning liver parenchyma, it may be a safe and effective alternative to extensive hepatectomy.

Clinical significance of transient receptor potential vanilloid 2 expression in human hepatocellular carcinoma

Transient receptor potential vanilloid 2 (TRPV2), one of the members of TRP (transient receptor potential) superfamily of ion channels, has been suggested to contribute to pain associated with inflammation or neuropathy. To investigate its role in hepatocarcinogenesis, we examined the expression of TRPV2 in human hepatocellular carcinoma (HCC) samples and analyzed the association of TRPV2 expression with its clinical significance. TRPV2 expression in 55 HCC patients was examined by immunohistochemistry, and the correlation between TRPV2 levels and clinicopathologic parameters was analyzed. Thirteen paired HCC specimens and their nontumor counterparts were investigated by quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. Quantitative RT-PCR and Western blotting analysis revealed that expression of TRPV2 at both the mRNA and protein levels were increased in cirrhotic livers compared with chronic hepatitis, whereas that also occurred in moderately and well-differentiated tumors compared with that of poorly differentiated tumors. Immunohistochemistry of the 55 HCC samples showed that the expression of TRPV2 increased when going from normal liver or chronic hepatitis to cirrhosis. Increased TRPV2 expression was observed in tissues of liver cirrhosis (31/37, 83.8%). In HCC, increased expression of TRPV2 was identified in 16/55 (29%) cases. Clinicopathologic assessment suggested a significant association between TRPV2 expression and portal vein invasion and histopathologic differentiation (P = 0.036 and 0.001, respectively). Our data suggest that TRPV2 plays a role in human hepatocarcinogenesis and might be a prognostic marker of patients with HCC.

Numb downregulation suppresses cell growth and is associated with a poor prognosis of human hepatocellular carcinoma

Numb, an endocytic adaptor, is a known cell fate determinant that participates in asymmetric cell division. The present study aimed to explore the potential roles of Numb in hepatocarcinogenesis. Numb expression was investigated in hepatocellular carcinomas (HCC) with reverse transcription-quantitative polymerase chain reaction and immunohistochemical examination; its association with the prognosis of HCC patients was analyzed. In addition, the effects of Numb deletion on proliferation of HCC cells and its relevant molecules were evaluated in Huh7 and HepG2 cells. Numb overexpression was observed in 62% of adjacent non-tumor tissues and 46% of tumor tissues. Overexpression of Numb in HCC was associated with histological grade, portal vein invasion and the number of tumors (P=0.001, 0.022 and 0.034 respectively). Multivariate analysis revealed that Numb expression was an independent prognostic indicator of HCC patients. Methylation of the Numb promoter contributed to hepatocarcinogenesis. In vitro assays demonstrated that Numb silencing resulted in inhibition of cell proliferation, induction of apoptosis, down-regulation of cyclin-dependent protein kinase 4 (CDK4) and S-phase kinase-associated protein 2 (SKP2), and upregulation of Bcl-2 homologous antagonist/killer (BAK) and cyclin-dependent kinase inhibitor 1 (p21). The present study suggests that downregulation of Numb inhibits colony formation and cell proliferation, induces apoptosis of HCC cells and independently predicts the poor prognosis of HCC patients. Thus, Numb has a potential role in the development and progression of HCC.

Prothymosin-α and parathymosin expression predicts poor prognosis in squamous and adenosquamous carcinomas of the gallbladder

The present study aimed to investigate the expression patterns of prothymosin-α (PTMA) and parathymosin (PTMS) in patients with squamous cell carcinoma (SCC), adenosquamous cell carcinoma (ASC) and adenocarcinoma (AC) of the gallbladder, and to assess their association with the clinicopathological characteristics and prognosis of the patients. A retrospective analysis of data pertaining to patients with SCC/ASC (n=46) and AC (n=80) of the gallbladder, who were treated with surgical resection, was conducted. Kaplan-Meier survival analysis was also performed to assess the correlation of the expression pattern with survival. The results revealed a higher percentage of patients with a large tumor diameter (>3 cm) in the SCC/ASC group as compared with those in the AC group (P<0.05). No significant differences were observed between patients with SCC/ASC and those with AC with respect to the patient sex, presence of gallstones, TNM stage, lymph node metastasis, invasive growth into anatomically contiguous structures, surgical methods used, survival rate, and the expression levels of PTMA and PTMA (P>0.05). However, positive expression of PTMA and PTMA was associated with tumor size, TNM stage, lymph node metastasis, locally invasive growth, and treatment with radical resection in patients with SCC/ASC and AC (P<0.05). In addition, positive expression of PTMA and PTMA was observed in a significantly lower number of patients with advanced AC as compared with those in early AC (P<0.05), while these expression levels were also associated with shorter survival in the SCC/ASC group and AC group (P<0.05). Cox multivariate analysis also demonstrated a negative correlation between PTMA and PTMA levels, and the postoperative survival rate in the two groups. In conclusion, the present study indicated that the expression levels of PTMA and PTMA were closely associated with the tumorigenesis and progression of SCC, ASC and AC of the gallbladder. Positive expression of PTMA and PTMA may serve as a valuable prognostic factor in these patients.

Pharmacological inhibition of TRPV4 channel suppresses malignant biological behavior of hepatocellular carcinoma via modulation of ERK signaling pathway

TRPV4 (transient receptor potential vanilloid 4), a member of the TRP superfamily, has been reported to correlate with several different forms of cancers. However, the role of TRPV4 in human hepatocellular carcinoma (HCC) remains unclear. The present study demonstrated that elevated expression of TRPV4 was shown in HCC tumor tissues when compared with paired non-tumoral livers both in protein and mRNA levels. Furthermore, the enhanced expression of TRPV4 was highly associated with histological grade (P = 0.036) and the number of tumors (P = 0.045). Pharmacological inhibition of TRPV4 channels in HCC cells with the specific antagonist HC-067047 suppressed cell proliferation, induced apoptosis and decreased the migration capability by attenuating the epithelial-mesenchymal transition (EMT) process in vitro. The p-ERK expression was apparently repressed after treatment with the TRPV4 antagonist, further blockade of the ERK pathway with U0126 could significantly aggravate HCC cells apoptosis. In NOD-SCID mouse xenograft models, intraperitoneal injection of HC-067047 could obviously suppress tumor growth and induce apoptosis in vivo. Together, our studies showed that the antitumor effects caused by TRPV4 channel inhibition in HCC cell lines might be attributed to the suppression of EMT process and inactivation of p-ERK which induced subsequent cell apoptosis. Thus, pharmacological inhibition of TRPV4 channel may be an option for HCC treatment.