GTF2IRD1 on chromosome 7 is a novel oncogene regulating the tumor-suppressor gene TGFßR2 in colorectal cancer.

Chromosome 7q (Ch.7q) is clonally amplified in colorectal cancer (CRC). We aimed to identify oncogenes on Ch.7q that are overexpressed through DNA copy number amplification and determine the biological and clinical significance of these oncogenes in CRC. We identified general transcription factor 2I repeat domain-containing protein 1 (GTF2IRD1) as a potential oncogene using a CRC dataset from The Cancer Genome Atlas with a bioinformatics approach. We measured the expression of GTF2IRD1 in 98 patients with CRC using immunohistochemistry and RT-quantitative PCR (RT-qPCR). The biological effects of GTF2IRD1 expression were explored by gene set enrichment analysis (GSEA). Next, we undertook in vitro cell proliferation and cell cycle assays using siGTF2IRD1-transfected CRC cells. We further investigated the oncogenic mechanisms through which GTF2IRD1 promoted CRC progression. Finally, we assessed the clinical significance of GTF2IRD1 expression by RT-qPCR. GTF2IRD1 was overexpressed in tumor cells and liver metastatic lesions. The GSEA revealed a positive correlation between GTF2IRD1 expression and cell cycle progression-related genes. GTF2IRD1 knockdown inhibited cell proliferation and induced cell cycle arrest in Smad4-mutated CRC. GTF2IRD1 downregulated the expression of the gene encoding transforming growth factor ß receptor 2 (TGFßR2), a tumor-suppressor gene in Smad4-mutated CRC. On multivariate analysis, high GTF2IRD1 expression was an independent poor prognostic factor. Clinicopathological analysis showed that GTF2IRD1 expression was positively correlated with liver metastasis. In conclusion, GTF2IRD1 promoted CRC progression by downregulating TGFßR2 and could be a prognostic biomarker on Ch.7q in CRC. GTF2IRD1 could also be a novel oncogene in CRC.

Oncogenic splicing abnormalities induced by DEAD-Box Helicase 56 amplification in colorectal cancer.

Alternative splicing, regulated by DEAD-Box Helicase (DDX) families, plays an important role in cancer. However, the relationship between the DDX family and cancer has not been fully elucidated. In the present study, we identified a candidate oncogene DDX56 on Ch.7p by a bioinformatics approach using The Cancer Genome Atlas (TCGA) dataset of colorectal cancer (CRC). DDX56 expression was measured by RT-qPCR and immunochemical staining in 108 CRC patients. Clinicopathological and survival analyses were carried out using three CRC datasets. Biological roles of DDX56 were explored by gene set enrichment analysis (GSEA), and cell proliferation in vitro and in vivo, cell cycle assays, and using DDX56-knockdown or overexpressed CRC cells. RNA sequencing was carried out to elucidate the effect of DDX56 on mRNA splicing. We found that DDX56 expression was positively correlated with the amplification of DDX56 and was upregulated in CRC cells. High DDX56 expression was associated with lymphatic invasion and distant metastasis and was an independent poor prognostic factor. In vitro analysis, in vivo analysis and GSEA showed that DDX56 promoted proliferation ability through regulating the cell cycle. DDX56 knockdown reduced intron retention and tumor suppressor WEE1 expression, which functions as a G2-M DNA damage checkpoint. We have identified DDX56 as a novel oncogene and prognostic biomarker of CRC that promotes alternative splicing of WEE1.

Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancer.

BACKGROUND: Translational reprogramming through controlled initiation from non-AUG start codons is considered a crucial driving force in tumorigenesis and tumor progression. However, its clinical impact and underlying mechanism are not fully understood. METHODS: Using a bioinformatics approach, we identified translation initiation regulator 5MP1/BZW2 on chromosome 7p as a potential oncogenic driver gene in colorectal cancer (CRC), and explored the biological effect of 5MP1 in CRC in vitro or in vivo. Pathway analysis was performed to identify the downstream target of 5MP1, which was verified with transcriptomic and biochemical analyses. Finally, we assessed the clinical significance of 5MP1 expression in CRC patients. FINDINGS: 5MP1 was ubiquitously amplified and overexpressed in CRC. 5MP1 promoted tumor growth and induced cell cycle progression of CRC. c-Myc was identified as its potential downstream effector. c-Myc has two in-frame start codons, AUG and CUG (non-AUG) located upstream of the AUG. 5MP1 expression increased the AUG-initiated c-Myc isoform relative to the CUG-initiated isoform. The AUG-initiated c-Myc isoform displayed higher protein stability and a stronger transactivation activity for oncogenic pathways than the CUG-initiated isoform, accounting for 5MP1-driven cell cycle progression and tumor growth. Clinically, high 5MP1 expression predicts poor survival of CRC patients. INTERPRETATION: 5MP1 is a novel oncogene that reprograms c-Myc translation in CRC. 5MP1 could be a potential therapeutic target to overcome therapeutic resistance conferred by tumor heterogeneity of CRC. FUND: Japan Society for the Promotion of Science; Priority Issue on Post-K computer; National Institutes of Health; National Science Foundation; KSU Johnson Cancer Center.

Multiregion Genomic Analysis of Serially Transplanted Patient-derived Xenograft Tumors.

BACKGROUND: Intratumoral heterogeneity (ITH) is a major cause underlying therapeutic difficulty of cancer. Although an understanding of ITH is critically important in order to develop novel therapeutic strategies, experimental models that enable the examination of ITH in a time series are lacking. MATERIALS AND METHODS: We developed an experimental approach based on patient-derived xenograft (PDX) mice and a multiregional sequencing approach (MRA). The multiple regions of primary colorectal cancer (CRC) and serially transplanted PDX tumors were analyzed via whole-exome sequencing and bioinformatic analyses. RESULTS: Our PDX-MRA of CRC indicated the spatiotemporal genetic transition of ITH. It was found that the subclonal architecture of CRC dynamically changes during serial transplantation. Furthermore, our data suggest that environmental selective pressures drive the development of minor pre-existing subclones in PDX-MRA. CONCLUSION: PDX-MRA is a useful tool for understanding the spatiotemporal dynamics of ITH.

Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer.

Yes-associated protein 1 (YAP1) acts as an oncogene through dephosphorylation and nuclear translocation, and nuclear accumulation of YAP1 is associated with poor prognosis in gastric cancer (GC). We previously identified ivermectin, an antiparasitic drug, as a YAP1 inhibitor. Here, we aimed to clarify whether ivermectin had antitumor effects on GC through inhibition of YAP1. First, we evaluated the antiproliferative effects of ivermectin on human GC cells using in vitro proliferation assays and a xenograft mouse model. YAP1-knockdown assays were performed to assess whether the sensitivity to ivermectin depended on YAP1 expression. Next, we explored the mechanism through which ivermectin regulated YAP1 expression or localization by immunoblotting and reverse transcription-quantitative polymerase chain reaction for YAP1 and the downstream gene CTGF. Finally, the clinical significance of YAP1 expression was examined using three independent GC datasets. We found that MKN1 GC cells were most sensitive to ivermectin, whereas MKN7 cells were most resistant. In MKN1 xenografts, ivermectin suppressed tumor growth, and the sensitivity of MKN1 cells to ivermectin was decreased by YAP1 knockdown. Ivermectin inhibited YAP1 nuclear expression and CTGF expression in MKN1 cells but not MKN7 cells. Moreover, ivermectin decreased YAP1 mRNA expression, thereby inhibiting nuclear accumulation of YAP1 in MKN1 cells. In survival analysis, low YAP1 mRNA expression was associated with a better prognosis in three independent GC datasets. In conclusion, we identified ivermectin as a potential antitumor agent and found a promising novel therapeutic strategy for inhibition of GC progression by blocking YAP1 expression.

Interleukin-8 producing hepatocellular carcinoma with pyrexia.

We discuss a patient who had poorly differentiated HCC with pyrexia and high CRP in laboratory data, which are not commonly observed in the usual HCC. A 50-year-old man with a history of liver dysfunction was admitted with a chief complaint of a prolonged fever and general fatigue. Preoperative diagnosis was HCC with portal vein tumor thrombus. Posterior segmentectomy of the liver and thrombectomy was performed. Rapid tumor recurrence occurred after surgery, and he died 79 days after the operation. Immunohistochemical stain of HCC in this patient revealed the production of proinflammatory cytokine, interleukin-8 (IL-8). IL-8 production may have contributed to the high fever, high inflammatory reaction, and poor prognosis in this case.

A comprehensive analysis of immunohistochemical studies in intrahepatic cholangiocarcinoma using the survival tree model.

OBJECTIVE: Various immunohistochemical studies have been performed regarding intrahepatic cholangiocarcinoma (ICC), including the cell cycle-related proteins (p27, cyclin D1, 14-3-3sigma, p53, cyclin B1 and Ki-67), the proto-oncogenes (c-erbB-2 and c-Met), the extracellular matrix proteins (tenascin and laminin) and others (beta-catenin, epidermal growth factor receptor, osteopontin, aquaporin 1, MUC5AC and fascin). Nevertheless, none of these have been proven to be a predictive power of the prognosis with high specificity and sensitivity for ICC. METHODS: Sixty-one patients with ICC were selected and ICC specimens were immunohistochemically stained with the above 16 markers, as previously reported. RESULTS: The immunoreactivity of osteopontin, tenascin and Ki-67 divided the patients with ICC into 4 subgroups by the survival tree model. There was a significant relationship between the location of the tumor, TNM classification, histological differentiation, tumor size, lymphatic permeation, perineural invasion, lymph node metastasis, intrahepatic metastasis and viral infection among the 4 subgroups. In addition, there was a significant difference in survival among the 4 subgroups. CONCLUSION: In this study, the subgrouping by the survival tree model might be helpful for predicting the patients' prognosis in ICC.

Biliary phenotype of hepatocellular carcinoma after preoperative transcatheter arterial chemoembolization.

BACKGROUND AND AIM: Transcatheter arterial chemoembolization (TACE) is now the mainstay of treatment for non-curative hepatocellular carcinoma (HCC), and hoped to have chemotherapeutic and ischemic effects; however, the histopathological changes of HCC caused by TACE have not been sufficiently discussed so far. We aimed to assess the morphological and immunohistochemical features of HCC treated with TACE by immunostaining cytokeratin (CK) 7, CK14, CK19 and vimentin, and to correlate these data with observed clinicopathological characteristics. METHODS: Eighty cases of surgically resected HCC with preoperative TACE and 146 cases of HCC resected without TACE as a control were analyzed. RESULTS: The incidences of intrahepatic metastasis, poorly differentiated histology, multinucleated giant cells, mitotic figures and cytoplasmic inclusion bodies in the TACE group were significantly higher than those in the non-TACE group. The TACE group showed reactivity for CK7 in 56.3% (45/80) of patients, CK14 in 12.5% (10/80), CK19 in 23.8% (19/80) and vimentin in 6.3% (5/80) of patients. CK19 expression in the TACE group was significantly higher than in the non-TACE group (P = 0.0423). There was no correlation between immunoreactivity and the number of times TACE was carried out, but the expression of CK19 and vimentin in the massive necrotic group was higher than that in the mild necrotic group (P = 0.0197, P = 0.0229, respectively). Only TACE was an independent determinant of CK19 expression in all cases by multivariate analysis. CONCLUSIONS: These results suggest that preoperative TACE may have an impact on the biliary phenotype of HCC. Some post-therapeutic HCC patients might develop HCC with a biliary phenotype indicating more aggressive malignancies.

Noninvasive estimation of hepatic steatosis using plain CT vs. chemical-shift MR imaging: significance for living donors.

PURPOSE: To compare plain computed tomography (CT) and chemical-shift MR imaging (CSI) for establishing a noninvasive method to estimate the degree of steatosis. MATERIALS AND METHODS: A total of 58 patients who had histological proof of liver tissue and underwent CT and/or CSI within two weeks, were studied. They consisted of 38 living donor candidates and 20 liver surgery patients without hepatitis or cirrhosis. The CT index (CTI) and MR index (MRI) were defined and correlated to histological grades of steatosis. Correlation was also performed exclusively for mild steatosis (grades 0-2). RESULTS: Both plain CT (rho=0.74, P<0.0001) and CSI (rho=0.83, P<0.0001) had good correlation with histological grades of steatosis, showing no significant difference between them. For mild steatosis, CSI (rho=0.77, P<0.0001) had better correlation than CT (rho=0.49, P=0.001) (P=0.049). Accuracy in differentiation between grade 0-1 vs. grade 2-4 steatosis was 85% using a CTI>6, and 91% using an MRI<0.03 as criteria. That between grade 0-2 and grade 3-4 was 91% using a CTI>-8 and 88% using an MRI<0.25 as criteria. CONCLUSION: Both plain CT and CSI were useful in estimating the degree of steatosis but CSI was superior to CT in differentiating mild steatosis. These indices may at least partially replace percutaneous biopsy in evaluating grades of steatosis for living donors.

Liver metastasis with intraductal invasion originating from rectal cancer: report of a case.

We report a case of liver metastasis with intraductal invasion from colorectal cancer. The patient underwent abdominoperineal resection of the rectum for rectal cancer, and a computed tomography (CT) scan, done 4 years later, revealed a low-density lobular mass in the left lobe of the liver, with a tumor embolus in the second branch of the left bile duct (B2). Because the preoperative imaging findings showed an intraductal growth pattern, we performed a left lobectomy of the liver for intrahepatic cholangiocarcinoma (IHCC). Immunohistochemically, the carcinoma cells, including the intraductal growth, were focally positive for Cytokeratin (CK) 20, but negative for CK 7. This CK staining pattern suggested that the liver tumor was a metastasis from the previously resected rectal cancer. Thus, metastases from colorectal cancer can involve intraductal growth.

Down-regulation of aquaporin-1 in intrahepatic cholangiocarcinoma is related to tumor progression and mucin expression.

Aquaporin-1 (AQP-1) has been found to be important in bile formation across cell membranes of the biliary epithelium, and thus it has been suggested that AQP-1 is involved in the pathogenesis of hepatobiliary disease. To clarify the role of AQP-1 in the development of intrahepatic cholangiocarcinoma, we determined AQP-1 expression in the normal bile duct, 21 cases of biliary dysplasia, and in 112 cases of intrahepatic cholangiocarcinoma by immunohistochemical analysis. Mucus core protein 5AC expression, a poor prognostic marker of intrahepatic cholangiocarcinoma, was also assessed in intrahepatic cholangiocarcinoma cases. High (>50%) expression of AQP-1 was detected in 16% (9/58) of the normal large bile ducts examined, and in 48% (10/21) of the biliary dysplasia samples originating from large bile ducts. High (>50%), low (40 mm) and poorly differentiated histology were significantly more prevalent in the negative AQP-1 group than in the high AQP-1 group. Low or negative AQP-1 expression was associated with positive lymph node metastasis (P=.0001). AQP-1 expression was found to inversely correlate with that of mucus core protein 5AC, and their distributions tended to be complementary. The low and negative AQP-1 expression was an independent prognostic factor by multivariate survival analysis. We concluded that AQP-1 is up-regulated in biliary dysplasia, as compared with in the normal large bile duct, and down-regulation of AQP-1 is associated with mucin production and aggressive progression of intrahepatic cholangiocarcinoma.

Proposal of progression model for intrahepatic cholangiocarcinoma: clinicopathologic differences between hilar type and peripheral type.

It is important to clarify the histologic progression of intrahepatic cholangiocarcinoma (ICC) in consideration of its origin from the intrahepatic large or small biliary ducts. On the basis of the gross and histologic assessment, we classified 87 cases of ICC smaller than 5 cm in diameter into hilar type (H-ICC, n=38) or peripheral type (P-ICC, n=49) to compare their clinical and histologic features. Biliary dysplasia was observed in 65.8% (25/38) of H-ICC cases, whereas hepatitis virus infection and liver cirrhosis were associated with 46.7% (21/45) and 28.6% (14/49) of P-ICC, respectively. The frequency of perineural invasion, lymph node metastasis, and extrahepatic recurrence of H-ICC was significantly higher than that of P-ICC (P<0.0001, 0.0106, and 0.0279, respectively). H-ICC cases showed frequent vascular invasion and intrahepatic metastasis even with small tumor size, compared with P-ICC cases. H-ICC showed large duct involvement within the tumor, and in the cases of large tumor size, intraductal spread was detected in the tumor periphery. P-ICC of small size contained preserved architecture of the portal tracts. The survival of patients with H-ICC was worse than that of patients with P-ICC (P=0.0121). The independent and best prognostic factor by multivariate analysis was intrahepatic metastasis for H-ICC and lymph node metastasis for P-ICC. Our results suggest that ICCs derived from a different level of biliary ducts were related to different premalignant conditions and different tumor progression. Some ICCs arising from the large biliary duct are likely to exhibit an aggressive course even in cases of small tumor size. The recognition of the above events induces the proper therapy.

Histologic characteristics and prognostic significance in small hepatocellular carcinoma with biliary differentiation: subdivision and comparison with ordinary hepatocellular carcinoma.

The morphologic characteristics and biologic behavior of small liver cancers with hepatic and biliary differentiation, and their histogenesis, remain unclear. In this study, 35 cases of hepatocellular carcinoma (HCC) smaller than 3 cm in diameter with biliary differentiation were divided into 3 groups, group 1 [cytokeratin (CK) 19-negative/mucin-negative], group 2 (CK 19-positive/mucin-negative), and group 3 (CK 19-positive/mucin-positive). Sixty-one HCCs without biliary differentiation were used as controls. We compared the histologic features of these tumors and the postoperative outcomes. Three morphologic features of HCCs with biliary differentiation were respectively observed in 40% (14/35), 60% (21/35), and 42.9% (15/35) as follows: (1) cancer cells with intermediate morphology, (2) prominent inflammatory cell infiltrate, (3) desmoplastic stroma; neural cell adhesion molecule and c-kit expression were noted in 25.7%(9/35) and 8.6%(3/35), respectively. Extrahepatic tumor recurrence after surgery occurred in 0% (0/16) of group 1, 33.3% (3/9) of group 2, 40.0% (4/10) of group 3, and 8.2% (5/61) of the ordinary HCCs. The tumor-related survival of group 3 patients was worse than that of patients with ordinary HCCs, but there were no differences between the survival of group 1, or group 2 patients and those with ordinary HCCs. Our results suggest that the biliary differentiation does occur even in small HCC, and a mucin-producing cancer cells indicates aggressive tumor behavior. The combination of intermediate cancer cells, inflammatory cell infiltrate, and desmoplastic stroma is likely to be related to the biliary differentiation of HCC.

14-3-3sigma negatively regulates the cell cycle, and its down-regulation is associated with poor outcome in intrahepatic cholangiocarcinoma.

The 14-3-3sigma gene has been implicated in G2/M cell cycle arrest by p53, and the loss of 14-3-3sigma protein expression has been reported in diverse human cancers. However, the role of 14-3-3sigma in the signaling pathway of the cell cycle in the progression of intrahepatic cholangiocarcinoma has not been well understood. To clarify the role of 14-3-3sigma, we examined the protein expressions of 14-3-3sigma, cyclin B1, and p53 in 93 cases of intrahepatic cholangiocarcinoma by immunohistochemical staining. We also examined the correlation between these expressions and survival rate and clinicopathologic factors such as sex, age, tumor grade (ie, pathologic differentiation, tumor size, lymphatic permeation, vascular invasion, perineural invasion, lymph node metastasis), and tumor stage. Positive 14-3-3sigma protein expression (>30% of tumor cells) was observed in 67.7% (63/93) of cases of intrahepatic cholangiocarcinoma and was inversely correlated with cyclin B1 expression. No correlation was found between 14-3-3sigma expression and p53 expression or clinicopathologic factors; however, decreased 14-3-3sigma expression was an independent prognostic factor by multivariate survival analysis (P = .0282). Extensive methylation of 14-3-3sigma was found by methylation-specific polymerase chain reaction and sequence; however, no significant correlation was detected between methylation states and protein expression. These results indicate that depressed 14-3-3sigma protein is involved in the uncontrolled cell cycle in intrahepatic cholangiocarcinoma and that the decreased expression of 14-3-3sigma protein is a significant indicator of poor prognosis for patients with intrahepatic cholangiocarcinoma.

High expression of insulin-like growth factor binding protein-3 is correlated with lower portal invasion and better prognosis in human hepatocellular carcinoma.

Insulin-like growth factor binding protein-3 (IGFBP-3) modulates cell proliferation of various cancer cell types. However, it remains unclear how IGF-IGFBP-3-signaling is involved in growth and progression of hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the role of IGFBP-3 in HCC. Type 1 receptor for IGF (IGF-1R) was expressed at various levels in the seven lines examined, but IGF-2R was not expressed. Of the seven lines, the growth of HAK-1B, KIM-1, KYN-2 and HepG2 cells was stimulated in a dose-dependent manner by the exogenous addition of IGF-I or IGF-II, but the HAK-1A, KYN-1 and KYN-3 cell lines showed no growth. Exogenous addition of IGFBP-3 markedly blocked IGF-I and IGF-II-stimulated cell growth of KYN-2 and HepG2 cells, and moderately stimulated that of KIM-1 and HAK-1B cells, but no growth of the KYN-1, KYN-3 and HAK-1A cell lines was observed. IGF-I enhanced the phosphorylation of IGF-1R, Akt and Erk1/2 in KYN-2 cells, and coadministration of IGFBP-3 blocked all types of activation by IGF-I investigated here. In contrast, no such activation by IGF-I was detected in KYN-3 cells. IGFBP-3 also suppressed IGF-I-induced cell invasion by KYN-2 cells. Moreover, we were able to observe the apparent expression of IGFBP-3 in KYN-3 cells, but not in the other six cell lines. Furthermore reduced expression of IGFBP-3, but not that of IGF-1R, was significantly correlated with tumor size, histological differentiation, capsular invasion and portal venous invasion. Low expression of IGFBP-3 was independently associated with poor survival. IGFBP-3 could be a molecular target of intrinsic importance for further development of novel therapeutic strategy against HCC.

Characteristic differences according to the cirrhotic pattern of advanced primary biliary cirrhosis: Macronodular cirrhosis indicates slow progression.

It is important to evaluate advanced primary biliary cirrhosis (PBC) clinicopathologically to clarify its progressive mechanism. According to the cirrhotic pattern, 26 cases of explanted PBC were classified into non-cirrhotic (n=4), macronodular (n=4), mixed nodular (n=6), and micronodular cirrhosis (n=12), to compare their clinical and morphological features. In addition, the degree of preserved intrahepatic bile ducts and other histologic features were analyzed. Patients at living donor liver transplantation (LDLT) in the macronodular cirrhosis were significantly older than those in the micronodular cirrhosis. The mean duration between clinical presentation and LDLT in the macronodular cirrhosis was significantly longer than in the micronodular cirrhosis. The non-cirrhotic group showed a short duration between clinical presentation and LDLT. The ratio of explanted liver volume to standard liver volume (ELV/SLV) indicates that macronodular cirrhosis revealed more atrophic change than that in the other three types. The density of remnant intrahepatic bile ducts of less than 50mum per group in cases of macronodular cirrhosis was significantly higher than that in cases of micronodular cirrhosis. Therefore, different cirrhotic patterns of advanced PBC were correlated with the disease progression and the degree of bile duct disappearance. The macronodular cirrhotic patients were older, had a longer disease course, yet had less bile duct loss. We suggest that macronodular cirrhosis and micronodular cirrhosis of PBC are different type of PBC.

Prognostic impact of cholangiocellular and sarcomatous components in combined hepatocellular and cholangiocarcinoma.

Combined hepatocellular and cholangiocarcinoma (cHC-CC) is a rare type of liver cancer displaying both hepatocellular and cholangiocellular components. The cholangiocellular carcinoma (CC) in these tumors ranges from focal to prominent. Those cHC-CCs with sarcomatous features are reported to have a poor prognosis. To clarify whether the CC and sarcomatous component affects the prognosis, we classified 40 patients with cHC-CCs into 4 groups according to the presence of a sarcomatous component and the extent of the CC component. Seven (17.5%) tumors showed areas with a sarcomatous component. The remaining tumors were divided into a low-CC group (CC occupying <30% of the tumor, n = 12), a middle-CC group (30%-60%, n = 15), and a high-CC group (>60%, n = 6). Vascular invasion was more frequently present in the high-CC and sarcomatous group than in the other groups (P = .0007). No lymph node metastasis occurred in either the low- or the middle-CC groups, but it was detected in 3 (50%) cases of the high-CC group and in 2 (29%) cases of the sarcomatous group (P < .0001). There was a tendency for tumor size to increase from the low- to the middle- to the high-CC group. The Ki-67 labeling index values for the hepatocellular carcinoma, CC, and sarcomatous components were 11.4% +/- 12.9%, 25.4% +/- 18.3%, and 46.0% +/- 23.6%, respectively. The overall survival of patients in the high-CC and sarcomatous group was significantly poorer than that of patients in the low- and middle-CC groups (P = .0048). By multivariate analysis of overall survival, lymph node metastasis, histological subgroup, and vascular invasion were significant independent prognostic factors. A cHC-CC with a large CC component is as aggressive as cHC-CC with sarcomatous features.

Suppressed MKP-1 is an independent predictor of outcome in patients with hepatocellular carcinoma.

OBJECTIVE: An increase in the activity of mitogen-activated protein kinases (MAPKs) has been correlated with a more malignant phenotype in several tumor models in vivo. This study was designed to clarify the expression of MKP-1 in surgically resected hepatocellular carcinoma (HCC). METHODS: We reviewed the cases of 77 patients who had undergone initial liver resection for HCC without preoperative treatment. Immunohistochemical analysis of MKP-1 was performed on paraffin-embedded tissues. The correlation between MKP-1 expression and clinical outcome was investigated. RESULTS: Tumor cells were immunohistochemically stained for MKP-1 expression, and the same levels as in normal hepatocytes were detected in 66 (85%) of 77 HCC patients, being decreased in 11 (15%) HCCs. Decreased MKP-1 expression significantly correlated with serum alpha-fetoprotein levels and tumor size (p<0.05). The disease-free survival rates in MKP-1-negative and -positive patients were 0 and 31.0% at 5 years, respectively (p<0.01). The survival rates after a surgical resection in MKP-1-negative and -positive patients were 18.2 and 65.5% at 5 years, respectively (p<0.01). CONCLUSIONS: The MKP-1 expression in HCC was an independent prognostic factor for outcome in HCC patients. In the future, it will be useful to explore whether the phosphatase expression might account for the response to HCC treatments targeting at MAPK activation.

The newly established human hepatocyte cell line: application for the bioartificial liver.

BACKGROUND/AIMS: Human hepatocyte cell lines are reported to lose many of their biochemical functions in a hybrid artificial liver support system (HALSS). Differentiation therapy is useful to up-regulate liver function. METHODS: The human hepatoblastoma cell line HepG2 was transfected with HSV/tk gene. Albumin synthesis and ammonia removal activity were evaluated when HepG2/tk was cultured with histone deacetylase inhibitor (FR228) and peroxisome proliferator activated receptor-gamma ligand (pioglitazone). To investigate the function of HepG2/tk in vivo, cell transplantation for 90% hepatectonized rats was conducted. RESULTS: We established stable cell lines which expressed HSV/tk and were sensitive to gancyclovir in vitro and in vivo. Both albumin synthesis rate and ammonia removal rate improved for HepG2/tk incubated with FR228 and pioglitazone for 3 days, which induced nuclear transport of p21. Rats with intrasplenic injection of HepG2/tk precultured for 3 days with FR228 and pioglitazone survived significantly longer than the control rats. The ammonia and total bilirubin concentrations were significantly lower in the test group than in the control group. The injection of gancyclovir inhibited the prolonged survival of the rats with precultured HepG2/tk. CONCLUSIONS: HepG2/tk is safe as well as enhancing high levels of liver function. It will be a potential cell source for HALLS in the future.

[Gastrointestinal stromal tumor of the omentum: report of a case].

A 69-year old man was found a mass becoming larger in abdominal computed tomography. The mass consisted of intermingling solid and cystic component was located below the liver. Abdominal angiography showed tumor staining supplied from right gastroepiploic artery. We considered the mass cystadenoma, lymphangioma, cystic mesothelioma, or gastrointestinal stromal tumor (GIST) preoperatively, and then surgical resection was performed. The tumor was found localized in the greater omentum. Pathological examination showed the tumor composed of proliferation of atypical sort spindle cells and tumor cells were immunohistochemically positive for C-KIT and CD34, identifying the tumor as a primary GIST of the greater omentum.