BACKGROUNDHuman U three protein 14a (hUTP14a) promotes p53 degradation. Moreover, hUTP14a expression is upregulated in several types of tumors. However, the expression pattern of hUTP14a in hepatocellular carcinoma (HCC) remains unknown. The aim of this study was to investigate hUTP14a expression and its prognostic value in HCC.

METHODSThe hUTP14a expression was evaluated using immunohistochemistry (IHC) in HCC tissue specimens. The correlations between hUTP14a expression and clinicopathological variables were analyzed. The Kaplan-Meier method was used to analyze the association between hUTP14a expression and survival. Independent prognostic factors associated with overall survival (OS) and disease-free survival (DFS) were analyzed using the Cox proportional-hazards regression model.

RESULTSThe IHC data revealed that the hUTP14a positivity rate in HCC tissue specimens was significantly higher than that in nontumorous tissue specimens (89.9% vs. 72.7%, P < 0.05). The hUTP14a expression was detected in both the nucleolus and the cytoplasm. The positivity rate of nucleolar hUTP14a expression in HCC tissue specimens was higher than that in the nontumorous tissue specimens (29.3% vs. 10.1%, P < 0.05). No significant difference was found between HCC and nontumorous tissue specimens of cytoplasmic hUTP14a expression (60.6% vs. 62.6%, P > 0.05). In addition, no significant correlation was found between nucleolar hUTP14a expression and other clinicopathological variables. The 5-year OS and DFS rates in patients with positive nucleolar hUTP14a expression were significantly lower than those in patients with negative hUTP14a expression (P = 0.004 for OS, P = 0.003 for DFS). Multivariate analysis showed that nucleolar hUTP14a expression was an independent prognostic factor for OS (P = 0.004) and DFS (P < 0.001).

CONCLUSIONSThe positivity rate of hUTP14a expression was significantly higher in HCC specimens. Positive expression of nucleolar hUTP14a might act as a novel prognostic predictor for patients with HCC.

Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; genetics ; metabolism ; Carcinoma, Hepatocellular ; metabolism ; mortality ; pathology ; Disease-Free Survival ; Female ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Liver Neoplasms ; metabolism ; mortality ; pathology ; Male ; Middle Aged ; Multivariate Analysis ; Prognosis ; Proportional Hazards Models ; Ribonucleoproteins, Small Nucleolar ; genetics ; metabolism

OBJECTIVETo detect the expression of interleukin-17A(IL-17A) in hepatocellular carcinoma (HCCs) tissues, and to analyze its relationship with clinicopathological characteristics and epithelial-mesenchymal transition (EMT).

METHODSThe expression of IL-17A, E-cadherin, vimentin proteins and Snail mRNA were detected by immunohistochemistry and in situ hybridization histochemistry in the hepatocellular carcinoma (HCC) tissues of 74 patients.

RESULTSIL-17A staining was detected in 54.1% (40/74) specimens of human HCCs, but only 25.0% (5/20) in corresponding peritumoral tissues (P<0.05). The positive rate of IL-17A expression in HCC patients with grade III+IV and UICC stage III+IV tumors was significantly higher than those with grade I+II and UICC stage I+II tumors. The expression of IL-17A was positively correlated with portal vein tumor thrombus and microvascular invasion (all P<0.05). The 1- and 2-year recurrence-free survival rates were 27.6% and 17.2% in the patients with positive IL-17A expression, but 79.3% and 58.5% in IL-17A-negative HCCs. The 1- and 2-year overall survival rates were 69.0% and 27.8% in the cases with positive IL-17A expression, while 91.3% and 87.0% in IL-17A-negative cases. Patients with IL-17A-positive HCCs showed significantly shorter recurrence-free and overall survival compared with the patients with IL-17A-negative HCCs (P<0.05). Multivariate analysis indicated that IL-17A expression was an independent factor for recurrence-free and overall survival of HCCs. IL-17A-positive HCCs were characterized by increased expression of vimentin (r=0.492, P<0.01) or Snail (r=0.410, P<0.05) and loss of E-cadherin expression (r=-0.404, P<0.05).

CONCLUSIONSOur results suggest that IL-17A is closely related to epithelial-mesenchymal transition in hepatocellular carcinoma. IL-17A-positive hepatocellular carcinoma demonstrates more aggressive biological behavior, and IL-17A may serve as a potential prognostic marker for this cancer.

Cadherins ; genetics ; metabolism ; Carcinoma, Hepatocellular ; metabolism ; mortality ; pathology ; physiopathology ; Disease-Free Survival ; Epithelial-Mesenchymal Transition ; Humans ; Immunohistochemistry ; Interleukin-17 ; metabolism ; Liver Neoplasms ; metabolism ; mortality ; pathology ; physiopathology ; Neoplasm Invasiveness ; Neoplasm Proteins ; genetics ; metabolism ; Neoplasm Recurrence, Local ; Prognosis ; RNA, Messenger ; metabolism ; Snail Family Transcription Factors ; Survival Rate ; Transcription Factors ; genetics ; metabolism ; Vimentin ; genetics ; metabolism

BACKGROUND/AIMS: Fibroblast growth factor signaling is involved in hepatocarcinogenesis. The aim of this study was to determine the fibroblast growth factor receptor (FGFR) isotype expression in hepatocellular carcinoma (HCC) and neighboring nonneoplastic liver tissue, and elucidate its prognostic implications. METHODS: Immunohistochemical staining of FGFR1, -2, -3, and -4 was performed in the HCCs and paired neighboring nonneoplastic liver tissue of 870 HCC patients who underwent hepatic resection. Of these, clinical data for 153 patients who underwent curative resection as a primary therapy were reviewed, and the relationship between FGFR isotype expression and overall survival was evaluated (development set). This association was also validated in 73 independent samples (validation set) by Western blot analysis. RESULTS: FGFR1, -2, -3, and -4 were expressed in 5.3%, 11.1%, 3.8%, and 52.7% of HCCs, respectively. Among the development set of 153 patients, FGFR2 positivity in HCC was associated with a significantly shorter overall survival (5-year survival rate, 35.3% vs. 61.8%; P=0.02). FGFR2 expression in HCC was an independent predictor of a poor postsurgical prognosis (hazard ratio, 2.10; P=0.02) in the development set. However, the corresponding findings were not statistically significant in the validation set. CONCLUSIONS: FGFR2 expression in HCC could be a prognostic indicator of postsurgical survival.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Blotting, Western ; Carcinoma, Hepatocellular/metabolism/mortality/*pathology ; Female ; Hepatectomy ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Liver Neoplasms/metabolism/mortality/*pathology ; Male ; Middle Aged ; Prognosis ; Proportional Hazards Models ; Protein Isoforms/metabolism ; Receptors, Fibroblast Growth Factor/*metabolism ; Young Adult

OBJECTIVE: To evaluate the safety and clinical outcomes of chemoembolization in Child-Pugh class C patients with hepatocellular carcinomas (HCC). MATERIALS AND METHODS: The study comprised 55 patients with HCC who were classified as Child-Pugh class C and who underwent initial chemoembolization between January 2003 and December 2012. Selective chemoembolization was performed in all technically feasible cases to minimize procedure-related complications. All adverse events within 30 days were recorded using the Common Terminology Criteria for Adverse Events (CTCAE). The tumor response to chemoembolization was evaluated using the modified Response Evaluation Criteria In Solid Tumors. RESULTS: Thirty (54.5%) patients were within the Milan criteria, and 25 (45.5%) were beyond. The mortality of study subjects at 30 days was 5.5%. Major complications were observed in five (9.1%) patients who were all beyond the Milan criteria: two hepatic failures, one hepatic encephalopathy, and two CTCAE grade 3 increases in aspartate aminotransferase/alanine aminotransferase abnormality. The mean length of hospitalization was 6.3 ± 8.3 days (standard deviation), and 18 (32.7%) patients were discharged on the next day after chemoembolization. The tumor responses of the patients who met the Milan criteria were significantly higher (p = 0.014) than those of the patients who did not. The overall median survival was 7.1 months (95% confidence interval: 4.4-9.8 months). CONCLUSION: Even in patients with Child-Pugh class C, chemoembolization can be performed safely with a selective technique in selected cases with a small tumor burden.
Adult ; Aged ; Alanine Transaminase/metabolism ; Aspartate Aminotransferases/metabolism ; Carcinoma, Hepatocellular/mortality/*pathology/therapy ; Chemoembolization, Therapeutic/adverse effects ; Female ; Hepatic Encephalopathy/etiology ; Humans ; Length of Stay ; Liver Neoplasms/mortality/*pathology/therapy ; Liver Transplantation ; Male ; Middle Aged ; Proportional Hazards Models ; Severity of Illness Index ; Survival Rate ; Treatment Outcome ; Tumor Burden

Bi-phenotypic neoplasm refers to tumors derived from a common cancer stem cell with unique capability to differentiate histologically into two distinct tumor types. Bi-phenotypic hepatocellular carcinoma-cholangiocarcinoma (HCC-CC), although a rare tumor, is important for clinicians to recognize, since treatment options targeting both elements of the tumor are crucial. Imaging findings of bi-phenotypic HCC-CC are not specific and include features of both HCC and CC. A combination of imaging and immuno-histochemical analysis is usually needed to make the diagnosis.
CA-19-9 Antigen/metabolism ; Carcinoma, Hepatocellular/mortality/pathology/radiography ; Cholangiocarcinoma/mortality/pathology/radiography ; Humans ; Liver Neoplasms/mortality/pathology/*radiography ; Magnetic Resonance Imaging ; Phenotype ; Risk Factors ; Survival Analysis ; Tomography, X-Ray Computed ; alpha-Fetoproteins/analysis

BACKGROUND/AIMS: The role of prostaglandin E2 (PGE2) in the modulation of cell growth is well established in colorectal cancer. The aim of this study was to elucidate the significance of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) down-regulation on the prognosis of hepatocellular carcinoma (HCC) patients. METHODS: The expression of 15-PGDH in HCC cell lines and resected HCC tissues was investigated, and the correlation between 15-PGDH expression and HCC cell-line proliferation and patient survival was explored. RESULTS: The interleukin-1-beta-induced suppression of 15-PGDH did not change the proliferation of PLC and Huh-7 cells in the MTS [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The induction of 15-PGDH by transfection in HepG2 cells without baseline 15-PGDH expression was suppressed at day 2 of proliferation compared with empty-vector transfection, but there was no difference at day 3. Among the 153 patients who received curative HCC resection between 2003 and 2004 at our institution, 15-PGDH expression was observed in resected HCC tissues in 56 (36.6%), but the 5-year survival rate did not differ from that of the remaining 97 non-15-PGDH-expressing patients (57.1% vs 59.8%; P=0.93). Among 50 patients who exhibited baseline 15-PGDH expression in adjacent nontumor liver tissues, 28 (56%) exhibited a reduction in 15-PGDH expression score in HCC tissues, and there was a trend toward fewer long-term survivors compared with the remaining 22 with the same or increment in their 15-PGDH expression score in HCC tissues. CONCLUSIONS: The prognostic significance of 15-PGDH down-regulation in HCC was not established in this study. However, maintenance of 15-PGDH expression could be a potential therapeutic target for a subgroup of HCC patients with baseline 15-PGDH expression in adjacent nontumor liver tissue.
Adolescent ; Adult ; Aged ; Carcinoma, Hepatocellular/*diagnosis/mortality/pathology ; Down-Regulation ; Female ; Hep G2 Cells ; Humans ; Hydroxyprostaglandin Dehydrogenases/*metabolism ; Immunohistochemistry ; Kaplan-Meier Estimate ; Liver Neoplasms/*diagnosis/mortality/pathology ; Male ; Middle Aged ; Prognosis ; Young Adult

BACKGROUND/AIMS: Several studies reported a subgroup of gastric cancer patients showing elevated serum alpha-fetoprotein (AFP) at the time of diagnosis. We investigated the clinicopathological characteristics and prognostic factors of AFP producing gastric cancer (AFPPGC) by comparing with AFP non-producing gastric cancer (AFPNPGC). METHODS: A total of 909 patients were diagnosed with gastric cancer from January 2005 to March 2013 at Gyeongsang National University Hospital and their AFP levels were measured at the time of diagnosis. After excluding 138 patients with underlying liver diseases, 34 patients with elevated serum AFP level over 10 mg/mL were assigned to AFPPGC group and the remaining 737 patients with serum level of AFP below 10 ng/mL were assigned to AFPNPGC group. RESULTS: The median survival length was shorter in AFPPGC group than AFPNPGC group (18.3+/-25.5 months vs. 30.0+/-22.0 months, p=0.004). The incidence of liver metastasis (47.1% vs. 3.3%, p<0.001) and lymph node metastasis (91.2% vs. 31.6%, p<0.001) was significantly higher in AFPPGC group. The probability of encountering metachronous liver metastasis after the operation was higher in AFPPGC group (44.4% vs. 2.0%, p<0.001). Multivariate analysis revealed that patients in the AFPPGC group who received chemotherapy (p=0.037) or underwent operation (p=0.001) had a better survival rate. CONCLUSIONS: AFPPGC behaves more aggressively and shows a worse prognosis. Therefore, serum AFP level should be routinely checked in all patients diagnosed with gastric cancer.
Aged ; Aged, 80 and over ; Female ; Humans ; Liver Neoplasms/secondary ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Proportional Hazards Models ; Smoking ; Stomach Neoplasms/*diagnosis/mortality/pathology ; Survival Rate ; Treatment Outcome ; alpha-Fetoproteins/*metabolism

BACKGROUND/AIMS: Several studies reported a subgroup of gastric cancer patients showing elevated serum alpha-fetoprotein (AFP) at the time of diagnosis. We investigated the clinicopathological characteristics and prognostic factors of AFP producing gastric cancer (AFPPGC) by comparing with AFP non-producing gastric cancer (AFPNPGC). METHODS: A total of 909 patients were diagnosed with gastric cancer from January 2005 to March 2013 at Gyeongsang National University Hospital and their AFP levels were measured at the time of diagnosis. After excluding 138 patients with underlying liver diseases, 34 patients with elevated serum AFP level over 10 mg/mL were assigned to AFPPGC group and the remaining 737 patients with serum level of AFP below 10 ng/mL were assigned to AFPNPGC group. RESULTS: The median survival length was shorter in AFPPGC group than AFPNPGC group (18.3+/-25.5 months vs. 30.0+/-22.0 months, p=0.004). The incidence of liver metastasis (47.1% vs. 3.3%, p<0.001) and lymph node metastasis (91.2% vs. 31.6%, p<0.001) was significantly higher in AFPPGC group. The probability of encountering metachronous liver metastasis after the operation was higher in AFPPGC group (44.4% vs. 2.0%, p<0.001). Multivariate analysis revealed that patients in the AFPPGC group who received chemotherapy (p=0.037) or underwent operation (p=0.001) had a better survival rate. CONCLUSIONS: AFPPGC behaves more aggressively and shows a worse prognosis. Therefore, serum AFP level should be routinely checked in all patients diagnosed with gastric cancer.
Aged ; Aged, 80 and over ; Female ; Humans ; Liver Neoplasms/secondary ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Proportional Hazards Models ; Smoking ; Stomach Neoplasms/*diagnosis/mortality/pathology ; Survival Rate ; Treatment Outcome ; alpha-Fetoproteins/*metabolism

BACKGROUND/AIMS: Cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) are up-regulated in hepatocellular carcinoma (HCC). To investigate the levels of COX-2 and VEGF expression in chronic hepatitis (CH), cirrhosis, and HCC. METHODS: The immunohistochemical expressions of COX-2 and VEGF were evaluated in tissues from patients with CH (n=95), cirrhosis (n=38), low-grade HCC (LG-HCC; n=6), and high-grade HCC (HG-HCC; n=29). RESULTS: The COX-2 expression scores in CH, cirrhosis, LG-HCC, and HG-HCC were 3.3+/-1.9 (mean+/-SD), 4.2+/-1.7, 5.5+/-1.0, and 3.4+/-2.4, respectively (CH vs. cirrhosis, P=0.016; CH vs. LG-HCC, P=0.008; LG-HCC vs. HG-HCC, P=0.004), and the corresponding VEGF expression scores were 0.9+/-0.8, 1.5+/-0.7, 1.8+/-0.9, and 1.6+/-1.1 (CH vs. cirrhosis, P<0.001; CH vs. LG-HCC, P=0.011; LG-HCC vs. HG-HCC, P=0.075). Both factors were correlated with the fibrosis stage in CH and cirrhosis (COX-2: r=0.427, P<0.001; VEGF: r=0.491, P<0.001). There was a significant correlation between COX-2 and VEGF in all of the tissue samples (r=0.648, P<0.001), and between high COX-2 and VEGF expression scores and survival (COX-2: P=0.001; VEGF: P<0.001). CONCLUSIONS: The expressions of both COX-2 and VEGF are significantly higher in cirrhosis and LG-HCC than in CH. High COX-2 and high VEGF expressions are associated with a high survival rate.
Adult ; Aged ; Carcinoma, Hepatocellular/*metabolism/mortality/pathology ; Cyclooxygenase 2/*metabolism ; Female ; Hepatitis, Chronic/*metabolism/mortality/pathology ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Liver Cirrhosis/*metabolism/mortality/pathology ; Liver Neoplasms/*metabolism/mortality/pathology ; Male ; Middle Aged ; Vascular Endothelial Growth Factor A/*metabolism

KITENIN (KAI1 C-terminal interacting tetraspanin) promotes invasion and metastasis in mouse colon cancer models. In the present study, we evaluated the effects of KITENIN knockdown by intravenous administration of short hairpin RNAs (shRNAs) in an orthotopic mouse colon cancer model, simulating a primary or adjuvant treatment setting. We established orthotopic models for colon cancer using BALB/c mice and firefly luciferase-expressing CT-26 (CT26/Fluc) cells. Tumor progression and response to therapy were monitored by bioluminescence imaging (BLI). In the primary therapy model, treatment with KITENIN shRNA substantially delayed tumor growth (P = 0.028) and reduced the incidence of hepatic metastasis (P = 0.046). In the adjuvant therapy model, KITENIN shRNA significantly reduced the extent of tumor recurrence (P = 0.044). Mice treated with KITENIN shRNA showed a better survival tendency than the control mice (P = 0.074). Our results suggest that shRNA targeting KITENIN has the potential to be an effective tool for the treatment of colon cancer in both adjuvant and metastatic setting.
Animals ; Carrier Proteins/*genetics/metabolism ; Cell Line, Tumor ; Colonic Neoplasms/genetics/mortality/pathology/*therapy ; Disease Progression ; Liver Neoplasms/prevention & control/*secondary ; Membrane Proteins/*genetics/metabolism ; Mice ; Mice, Inbred BALB C ; Neoplasm Metastasis/*prevention & control ; Neoplasm Recurrence, Local/genetics/*prevention & control ; RNA Interference ; RNA, Small Interfering/*therapeutic use ; Tumor Markers, Biological/genetics