Expression and prognostic significance of MAP4K4 in lung adenocarcinoma.

Accumulating evidence indicates that mitogen-activated protein 4 kinase 4 (MAP4K4) is frequently overexpressed in many types of human cancers, and plays important roles in transformation, invasiveness, adhesion, and cell migration. The aim of the present study was to explore the expression and prognostic significance of MAP4K4 in lung adenocarcinoma. The results of real-time quantitative PCR and Western blotting analysis revealed an enhanced expression of MAP4K4 in lung adenocarcinomas relative to adjacent non-tumorous lung tissues at both transcriptional and translational levels. Immunohistochemistry showed that 130 of 309 (42%) lung adenocarcinomas had high expression of MAP4K4. MAP4K4 overexpression was significantly correlated with histological grade (p=0.027), pT status (p=0.048), pN status (p=0.006), and pleural invasion (p=0.024). Patients with high MAP4K4 expression had a shorter overall survival compared with those with low MAP4K4 expression, regardless of histological grade, pT status, pN status, or pleural invasion status. Multivariate analysis identified MAP4K4 as an independent prognostic factor for lung adenocarcinoma. In conclusion, our results demonstrate that elevated MAP4K4 expression is closely associated with lung adenocarcinoma progression and has an independent prognostic value in predicting overall survival for patients with lung adenocarcinoma.

Expression and prognostic significance of centromere protein A in human lung adenocarcinoma.

BACKGROUND: Centromere protein A (CENP-A), one of the fundamental components of the human active kinetochore, is frequently upregulated in many cancers and plays important roles in cell cycle regulation, cell survival, and genetic stability. The aim of the present study was to explore the expression and prognostic significance of CENP-A in lung adenocarcinoma. EXPERIMENTAL DESIGN: The expression of CENP-A was detected in 20 fresh human lung adenocarcinoma specimens and corresponding non-tumorous lung tissues by real-time polymerase chain reaction (RT-PCR) and Western blotting analysis. Using immunohistochemistry, we analyzed CENP-A protein expression in additional 309 lung adenocarcinomas. The clinicopathological and prognostic significance of CENP-A expression was analyzed. RESULTS: RT-PCR and Western blotting analysis revealed an enhanced expression of CENP-A in lung adenocarcinomas relative to adjacent non-tumorous lung tissues at both transcriptional and translational levels. Immunohistochemistry showed that 146 of 309 lung adenocarcinomas (47.3%) had high expression of CENP-A. CENP-A overexpression was significantly correlated with pathological grade (P=0.009), pT status (P=0.017), pN status (P=0.002), pleural invasion (P=0.013), high Ki-67 expression (P=0.003), and P53 positivity (P=0.001). Patients with high CENP-A expression had shorter overall survival time compared with those with low CENP-A expression. Multivariate analysis identified CENP-A as an independent prognostic factor for lung adenocarcinoma. CONCLUSION: Our results demonstrate that elevated CENP-A expression is closely associated with lung adenocarcinoma progression and has an independent prognostic value in predicting overall survival for patients with lung adenocarcinoma.

Intrahepatic cholangiocarcinoma arising in multiple bile duct hamartomas: report of two cases and review of the literature.

Multiple bile duct hamartomas (BDHs)/von Meyenburg complexes, are tumor-like lesions of the liver. Malignant transformation in BDHs has been previously reported in very rare instances, and the most common tumor arising in this clinical setting is cholangiocarcinoma. Herein, we report on clinicopathological findings in two cases of cholangiocarcinoma occurring in liver with multiple BDHs. Histopathologically, multiple BDHs showed morphologic transition from clearly benign to dysplasia or carcinoma in situ, then to invasive carcinoma sequence of the biliary epithelium. The neoplastic epithelium showed positivity for cytokeratin 19, CA 19-9, and epithelial membrane antigen. Staining for Hep Par 1, alpha-fetoprotein, cytokeratin 20, and alpha1-antitrypsin was negative. All sections from the non-neoplastic liver in each specimen showed multiple BDHs. Any other clinically detectable primary tumor was not found. These two neoplasms were interpreted as a cholangiocarcinoma arising in BDHs. This suggested BDHs might be a risk factor of development of cholangiocarcinoma.

Clinicopathologic significance of mitotic arrest defective protein 2 overexpression in hepatocellular carcinoma.

Mitotic arrest defective protein 2 (MAD2) gene plays a central role in the mitotic checkpoint. Elevated MAD2 expression was observed in a number of human malignancies; its role in the development of hepatocellular carcinoma is still not understood and is controversial. The purpose of this study was to investigate the clinicopathologic significance of MAD2 expression in hepatocellular carcinoma. The MAD2 protein and its messenger RNA levels were measured in hepatocellular carcinomas, high-grade dysplastic nodules, and their paired nontumorous liver tissues by quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry. The results showed that MAD2 at both messenger RNA and protein levels was overexpressed in 8 of 9 high-grade dysplastic nodules and in 51 of 58 hepatocellular carcinomas, including 12 of 14 unifocal small hepatocellular carcinomas. There was a tendency for MAD2 expression to increase in the process of this multistep carcinogenesis. A significantly high tumor MAD2 immunostaining was associated with the progression of histologic grade and the overall low survival. In conclusion, MAD2 is overexpressed frequently in hepatocellular carcinoma, including high-grade dysplastic nodules and early-stage small hepatocellular carcinoma, indicating that overexpression of MAD2 plays a role in the development and progression of hepatocellular carcinoma. It may be an early event in hepatocarcinogenesis and could be used as a potential prognostic indicator.

Malignant angiomyolipoma in the liver: a case report with pathological and molecular analysis.

Malignant angiomyolipoma (AML) of the liver is rare. We report a case of AML with malignant transformation and metastases. A 30-year-old man had developed giant hepatic masses. Microscopically, the periphery of the tumor showed components of classic hepatic AML, but the central region contained atypical epithelioid components with extremely pleomorphic and hyperchromatic nuclei with frequent mitotic figures. Immunohistochemical analysis revealed that the epithelioid cells were positive for HMB-45 and smooth muscle actin. Furthermore, the atypical epithelioid cells displayed P53 immunoreactivity and mutation at exon 7 for p53. The tumor showed a typical monoclonal pattern but no loss of heterozygosity or microsatellite instability. Markedly atypical epithelioid cells with vascular invasion, distant metastasis, and fatal outcome were interpreted as malignant characteristics of hepatic AML. It is suggested that large tumor size, pleomorphic nuclei with high proliferation activity, and P53 immunoreactivity may predict the existence of malignant transformation of hepatic AML.

Downregulated expression of metallothionein and its clinicopathological significance in hepatocellular carcinoma.

AIM: Metallothionein (MT) protein is related to different stages of development and progression of various tumors in humans. The aim of the present study was to investigate expression and localization of MT and their association with clinicopathological characteristics in hepatocellular carcinoma (HCC). METHODS: Histological specimens of 400 HCC with corresponding non-cancerous liver tissues were stained for MT (E9), P53 and Ki-67 by immunohistochemical staining using tissue microarrays. RNA expression of MT-1X and MT-2A isoforms was determined by real-time reverse transcription-polymerase chain reaction in a set of independent samples of 161 HCC. RESULTS: Downregulated expression of MT at both mRNA and protein levels was detected in HCC, compared with non-cancerous liver tissues. The frequencies of MT positivity were significantly lower in cases with positive hepatitis B surface antigen than in those with negative hepatitis B surfaceantigen (P = 0.042). The positive rate of MT expression was more frequent in tumors 2 cm in diameter (P = 0.007). There was a tendency for MT expression to decrease with the progression of histological grade. Mainly nuclear expression of MT correlated with poorly differentiated HCC. No statistical correlation was found between P53, Ki-67 and MT expression. CONCLUSIONS: Downregulated expression of MT in HCC may play a role in hepatocarcinogenesis and be a marker of hepatocellular differentiation. Hepatitis B virus infection may be correlated to downregulated expression of MT. The mainly nuclear MT immunostaining may reflect an aggressive behavior in poorly differentiated HCC.