Prospero homeobox 1 mediates the progression of gastric cancer by inducing tumor cell proliferation and lymphangiogenesis.

BACKGROUND: Prospero homeobox 1 (PROX1) functions as a tumor suppressor gene or an oncogene in various cancer types. However, the distinct function of PROX1 in gastric cancer is unclear. We determined whether PROX1 affected the oncogenic behavior of gastric cancer cells and investigated its prognostic value in patients with gastric cancer. METHODS: A small interfering RNA against PROX1 was used to silence PROX1 expression in gastric cancer cell lines AGS and SNU638. Expression of PROX1 in gastric cancer tissues was investigated by performing immunohistochemistry. Apoptosis, proliferation, angiogenesis, and lymphangiogenesis were determined by performing the TUNEL assay and immunohistochemical staining for Ki-67, CD34, and D2-40. RESULTS: PROX1 knockdown induced apoptosis by activating cleaved caspase-3, caspase-7, caspase-9, and poly(ADP-ribose) polymerase, and by decreasing the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL. PROX1 knockdown also suppressed tumor cell proliferation. In addition, PROX1 knockdown decreased lymphatic endothelial cell invasion and tube formation and the expression of vascular endothelial growth factor (VEGF)-C and -D and cyclooxygenase (COX)-2. However, PROX1 knockdown only decreased umbilical vein endothelial cell invasion, not tube formation. The mean Ki-67 labeling index and lymphatic vessel density value of PROX1-positive tumors were significantly higher than those of PROX1-negative tumors. However, no significant difference was observed between PROX1 expression and apoptotic index or microvessel density. PROX1 expression was significantly associated with age, cell differentiation, lymph node metastasis, cancer stage, and poor survival. CONCLUSIONS: These results indicate that PROX1 mediates the progression of gastric cancer by inducing tumor cell proliferation and lymphangiogenesis.

Impact of KITENIN on tumor angiogenesis and lymphangiogenesis in colorectal cancer.

Angiogenesis and lymphangiogenesis are involved in the dissemination of tumor cells from solid tumors to regional lymph nodes and various distant sites. KAI1 COOH-terminal interacting tetraspanin (KITENIN) contributes to tumor progression and poor clinical outcomes in various cancers including colorectal cancer. The aim of the present study was to evaluate whether KITENIN affects tumor angiogenesis and lymphangiogenesis in colorectal cancer. A KITENIN small interfering RNA vector was used to silence KITENIN expression in colorectal cancer cell lines including DLD1 and SW480 cells. To evaluate the ability of KITENIN to induce angiogenesis and lymphangiogenesis in human umbilical vein endothelial cells (HUVECs) and lymphatic endothelial cells (HLECs), we performed Matrigel invasion and tube formation assays. Immunohistochemistry was used to determine the expression of KITENIN in colorectal cancer tissues. Angiogenesis and lymphangiogenesis were evaluated by immunostaining with CD34 and D2-40 antibodies. KITENIN silencing inhibited both HUVEC invasion and tube formation in the DLD1 and SW480 cells. KITENIN silencing led to decreased expression of the angiogenic inducers vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor-1α and increased expression of the angiogenic inhibitor angiostatin. KITENIN silencing did not inhibit either HLEC invasion or tube formation in all tested cells, but it resulted in decreased expression of the lymphangiogenic inducer VEGF-C. KITENIN expression was significantly associated with tumor stage, depth of invasion, lymph node and distant metastases and poor survival. The mean microvessel density was significantly higher in the KITENIN-positive tumors than that in the KITENIN-negative tumors. However, the mean lymphatic vessel density of KITENIN-positive tumors was not significantly higher than that of the KITENIN-negative tumors. These results suggest that KITENIN promotes tumor progression by enhancing angiogenesis in colorectal cancer.

A case of diaphragmatic hernia induced by radiofrequency ablation for hepatocellular carcinoma.

Because of its safety and treatment effectiveness, the popularity of radiofrequency ablation (RFA) for the treatment of hepatocellular carcinoma (HCC) has gradually increased. However, some serious complications of RFA such as hepatic infarction, bowel perforation, and tumor seeding have been reported. Recently, we experienced a case of diaphragmatic hernia after RFA for HCC. A 61-year-old man with alcoholic cirrhosis was diagnosed with a 1.0 cm sized HCC in segment (S) 5 and a 1.3 cm sized HCC in S 8 of the liver. He was treated by transarterial chemoembolization and RFA. After RFA, an abdominal CT revealed a diaphragmatic defect with herniating mesentery. Twenty-two months after the RFA, the chest CT showed the diaphragmatic defect with herniating colon and mesentery. Because he had no symptoms, and surgical repair for the diaphragmatic hernia would be a high risk operation for him, we decided to treat the patient conservatively. For its great rarity, we report this case with a review of the literature.

Impact of serum C-reactive protein level on the prognosis of patients with hepatocellular carcinoma undergoing TACE.

BACKGROUND/AIMS: The aim of this study was to determine the relationship between serum CRP levels and the prognosis of hepatocellular carcinoma (HCC) patients. METHODS: HCC patients who underwent the first session of transcatheter arterial chemoembolization (TACE) between January 2005 and December 2009 (n=211) were analyzed retrospectively. The patients were divided into two groups: high C-reactive protein (CRP; ≥1 mg/dL, n=51) and low CRP (<1 mg/dL, n=160). They were followed for a mean of 22.44 months and their clinicoradiological variables and overall survival were compared. RESULTS: There were significant differences between the two groups in regard to tumor type, tumor-progression-free survival, 10-month mortality, white blood cell (WBC) count, tumor size, and TNM stage. Multivariate analysis revealed that a high serum CRP level was independently associated with tumor size and tumor type. Subgroup analysis of CRP groups according to tumor size demonstrated that a high serum level of CRP was significantly associated with poorly defined (diffuse) tumor type in the tumor size <5 cm group [hazard ratio (HR)=4.81, P=0.018]. A Lipiodol dose exceeding 7 mL (HR=5.55, P=0.046) and the 10-month mortality (HR=7.693, P=0.004) were significantly associated with high serum CRP level in the group of patients with a tumor size of ≥5 cm. In addition, subgroup analysis of matched CRP according to TNM stage revealed that elevated serum CRP was independently associated with tumor type, WBC count, and tumorprogression-free survival. CONCLUSIONS: A high serum CRP level is associated with large tumors and a poorly defined tumor type, and is significantly associated with 10-month mortality in patients with large HCC (size ≥5 cm) who undergo TACE.

Clinical significance and risk factors of postembolization fever in patients with hepatocellular carcinoma.

AIM: To investigate tumor response and survival in patients with postembolization fever (PEF) and to determine the risk factors for PEF. METHODS: Four hundred forty-three hepatocellular carcinoma (HCC) patients who underwent the first session of transcatheter arterial chemoembolization (TACE) between January 2005 and December 2009 were analyzed retrospectively. PEF was defined as a body temperature greater than 38.0 °C that developed within 3 d of TACE without evidence of infection. The tumor progression-free interval was defined as the interval from the first TACE to the second TACE based on mRECIST criteria. Clinical staging was based on the American Joint Committee on Cancer tumor, node, metastases (TNM) classification of malignant tumors. All patients were admitted before their 1(st) TACE treatment, and blood samples were obtained from all patients before and after treatment. Clinicoradiological variables and host-related variables were compared between two groups: patients with PEF vs patients without PEF. Additionally, variables related to 20-mo mortality and tumor progression-free survival were analyzed. RESULTS: The study population comprised 370 (85.4%) men and 73 (14.6%) women with a mean age of 62.29 ± 10.35 years. A total of 1836 TACE sessions were conducted in 443 patients, and each patient received between 1 and 27 (mean: 4.14 ± 3.57) TACE sessions. The mean follow-up duration was 22.23 ± 19.6 mo (range: 0-81 mo). PEF developed in 117 patients (26.41%) at the time of the first TACE session. PEF was not associated with 20-mo survival (P = 0.524) or computed tomography (CT) response (P = 0.413) in a univariate analysis. A univariate analysis further indicated that diffuse-type HCC (P = 0.021), large tumor size (≥ 5 cm) (P = 0.046), lipiodol dose (≥ 7 mL, P = 0.001), poor blood glucose control (P = 0.034), alanine aminotransferase (ALT) value after TACE (P = 0.004) and C-reactive protein (CRP) value after TACE (P = 0.036) served as possible risk factors correlated with PEF. The ALT value after TACE (P = 0.021) and lipiodol dose over 7 mL (P = 0.011) were independent risk factors for PEF in the multivariate analysis. For the 20-mo survival, poor blood sugar control (P < 0.001), portal vein thrombosis (P = 0.001), favorable CT response after TACE (P < 0.001), initial aspartate aminotransferase (P = 0.02), initial CRP (P = 0.042), tumor size (P < 0.001), TNM stage (P < 0.001) and lipiodol dose (P < 0.001) were possible risk factors in the univariate analysis. Tumor size (P = 0.03), poor blood sugar control (P = 0.043), and portal vein thrombosis (P = 0.031) were significant predictors of survival in the multivariate analysis. Furthermore, the tumor progression-free interval was closely associated with CRP > 1 mg/dL (P = 0.003), tumor size > 5 cm (P < 0.001), tumor type (poorly defined) (P < 0.001), and lipiodol dose (> 7 mL, P < 0.001). CONCLUSION: PEF has no impact on survival at 20 mo or radiologic response. However, the ALT level after TACE and the lipiodol dose represent significant risk factors for PEF.

Expression of RON in colorectal cancer and its relationships with tumor cell behavior and prognosis.

AIMS AND BACKGROUND: The aims of the current study were to evaluate whether recepteur d'origine nantais (RON) affects tumor cell behavior and oncogenic signaling pathways in colorectal cancer, and to examine the relationship of its expression with various clinicopathological parameters and patient survival. METHODS: Immunohistochemistry, Western blot and RT-PCR were used to detect the expression of the RON gene in human colorectal cancer tissue. To study the biological role of RON in tumor cell behavior and cellular signaling pathways, we used small interfering RNA (siRNA) to knock down RON gene expression in human colorectal cancer cell lines. RESULTS: Knockdown of RON inhibited the induction of the invasive growth phenotype and the activation of oncogenic signaling pathways including Akt, MAPK and ß-catenin. RON overexpression was associated with tumor size, lymphovascular invasion, depth of invasion, lymph node metastasis, distant metastasis, tumor stage and poor survival. CONCLUSIONS: These results suggest that RON overexpression may help in predicting poor clinical outcomes in colorectal cancer.

AIDS-related gastrointestinal kaposi sarcoma in Korea: a case report and review of the literature.

Kaposi sarcoma (KS) is a vascular neoplasm, which is fairly prevalent in acquired immunodeficiency syndrome (AIDS) patients. Mucocutaneous and lymph node involvements are characteristic features of KS in AIDS patients. The involvement of gastrointestinal tract occurs in 40% of KS patients and leads to significant morbidity and mortality. In the highly active antiretroviral therapy (HAART) era, the rate of AIDS related KS has fallen with control of human immunodeficiency virus (HIV) viremia. However, it is still recognized as the primary AIDS-defining illness, and the proportion of AIDS diagnoses made due to KS ranged from 4.1% to 7.5%. In Korea, AIDS-related KS has been report in low rate incidence. Its gastrointestinal involvements are rarely reported. To date, five cases have been recorded in Korea. Herein, we present an additional case of gastrointestinal KS as the AIDS-defining illness and review of the Korean medical literature.

Association between single nucleotide polymorphisms of the transient receptor potential vanilloid 1 (TRPV-1) gene and patients with irritable bowel syndrome in Korean populations.

BACKGROUND AND STUDY AIMS: Transient receptor potential vanilloid type 1 (TRPV1) plays a crucial role in pain perception and its expression is up-regulated in patients with irritable bowel syndrome (IBS). The aim of this study was to investigate the potential association between Single nucleotide polymorphism (SNPs) of the TRPV-1 gene and patients with IBS. PATIENTS AND METHODS: We chose to focus on three SNPs in the human TRPV1 coding region (rs222749, rs9894618 and rs222747) in 80 healthy controls and 103 IBS patients. We developed the high resolution melting (HRM) method to determine the genotyping of rs222747 and rs9894618 and the genotyping of rs222749 was also determined by direct sequencing method. RESULTS: The CG genotype of rs222747 was 58.8% in controls and 45.6% in the IBS group. The GG genotype of rs222747 was 15.0% in controls and 20.4% in the IBS group. The CT genotype of rs222749 was 313% in controls and 32.0% in the IBS group. The CC genotype of rs9894618 was 98.8% in controls and 100.0% in the IBS group. There was no significant difference in allele frequency of these three SNPs of the TRPV1 gene between controls and the IBS group. Also, no significant difference was observed between the IBS subtypes. CONCLUSIONS: These results suggest that the SNPs of the TRPV1 gene may not be associated with IBS in Korean populations. Further studies with large cases are needed to validate the results of the present study.

Epigallocatechin-3-gallate Inhibits LPS-Induced NF-κB and MAPK Signaling Pathways in Bone Marrow-Derived Macrophages.

BACKGROUND/AIMS: Epigallocatechin-3-gallate (EGCG), the primary catechin in green tea, has anti-inflammatory and anti-oxidative properties. The aim of the current study was to characterize the impact of EGCG on lipopolysaccharide (LPS)-induced innate signaling in bone marrow-derived macrophages (BMMs) isolated from ICR mice. METHODS: The effect of EGCG on LPS-induced pro-inflammatory gene expression and nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling was examined using reverse transcription-polymerase chain reaction, Western blotting, immunofluorescence, and the electrophoretic mobility shift assay. RESULTS: EGCG inhibited accumulation of LPS-induced IL-12p40, IL-6, MCP-1, ICAM-1, and VCAM-1 mRNA in BMMs. EGCG blocked LPS-induced IκBα degradation and RelA nuclear translocation. EGCG blocked the DNA-binding activity of NF-κB. LPS-induced phosphorylation of ERK1/2, JNK, and p38 was inhibited by EGCG. U0126 (an inhibitor of MEK-1/2) suppressed the LPS-induced IL-12p40, IL-6, MCP-1, ICAM-1, and VCAM-1 mRNA accumulation in BMMs. CONCLUSIONS: These results indicate that EGCG may prevent LPS-induced pro-inflammatory gene expression through blocking NF-κB and MAPK signaling pathways in BMMs.

Knockdown of RON inhibits AP-1 activity and induces apoptosis and cell cycle arrest through the modulation of Akt/FoxO signaling in human colorectal cancer cells.

BACKGROUND/AIMS: Altered Recepteur d'Origine nantais (RON) expression transduces signals inducting invasive growth phenotype that includes cell proliferation, migration, matrix invasion, and protection of apoptosis in human cancer cells. The aims of the current study were to evaluate whether RON affects tumor cell behavior and cellular signaling pathways including activator protein-1 (AP-1) and Akt/forkhead box O (FoxO) in human colorectal cancer cells. METHODS: To study the biological role of RON on tumor cell behavior and cellular signaling pathways in human colorectal cancer, we used small interfering RNA (siRNA) to knockdown RON gene expression in human colorectal cancer cell line, DKO-1. RESULTS: Knockdown of RON diminished migration, invasion, and proliferation of human colorectal cancer cells. Knockdown of RON decreased AP-1 transcriptional activity and expression of AP-1 target genes. Knockdown of RON activated cleaved caspase-3, -7, -9, and PARP, and down-regulated the expression of Mcl-1, survivin and XIAP, leading to induction of apoptosis. Knockdown of RON induced cell cycle arrest in the G2/M phase of cancer cells by an increase of p27 and a decrease of cyclin D3. Knockdown of RON inhibited the phosphorylation of Akt/FoxO signaling proteins such as Ser473 and Thr308 of Akt and FoxO1/3a. CONCLUSIONS: These results indicate that knockdown of RON inhibits AP-1 activity and induces apoptosis and cell cycle arrest through the modulation of Akt/FoxO signaling in human colorectal cancer cells.

Black tea extract prevents lipopolysaccharide-induced NF-κB signaling and attenuates dextran sulfate sodium-induced experimental colitis.

BACKGROUND: Black tea has been shown to elicit anti-oxidant, anti-carcinogenic, anti-inflammatory and anti-mutagenic properties. In this study, we investigated the impact of black tea extract (BTE) on lipopolysaccharide (LPS)-induced NF-κB signaling in bone marrow derived-macrophages (BMM) and determined the therapeutic efficacy of this extract on colon inflammation. METHODS: The effect of BTE on LPS-induced NF-κB signaling and pro-inflammatory gene expression was evaluated by RT-PCR, Western blotting, immunofluorescence and electrophoretic mobility shift assay (EMSA). The in vivo efficacy of BTE was assessed in mice with 3% dextran sulfate sodium (DSS)-induced colitis. The severity of colitis was measured by weight loss, colon length and histologic scores. RESULTS: LPS-induced IL-12p40, IL-23p19, IL-6 and IL-1ß mRNA expressions were inhibited by BTE. LPS-induced IκBα phosphorylation/degradation and nuclear translocation of NF-κB/p65 were blocked by BTE. BTE treatment blocked LPS-induced DNA-binding activity of NF-κB. BTE-fed, DSS-exposed mice showed the less weight loss, longer colon length and lower histologic score compared to control diet-fed, DSS-exposed mice. DSS-induced IκBα phosphorylation/degradation and phosphorylation of NF-κB/p65 were blocked by BTE. An increase of cleaved caspase-3 and poly (ADP-ribose) polymerase (PARP) in DSS-exposed mice was blocked by BTE. CONCLUSIONS: These results indicate that BTE attenuates colon inflammation through the blockage of NF-κB signaling and apoptosis in DSS-induced experimental colitis model.

Small interfering RNA-directed targeting of RON alters invasive and oncogenic phenotypes of human hepatocellular carcinoma cells.

The recepteur d'origine nantais (RON) receptor tyrosine kinase is highly expressed in various cancers including human hepatocellular carcinoma (HCC) and involved in tumor progression. The aims of the current study were to evaluate whether RON affects tumor cell behavior and oncogenic signaling cascades in HCC cells. We investigated the biologic role of RON on tumor cell behavior and oncogenic signaling cascades including Akt, c-Raf and extracellular signal-regulated kinase (ERK) by using the small interfering RNA (siRNA) in HCC cell lines, chang, HepG2 and Huh7. Knockdown of RON suppressed tumor cell migration and invasion in all tested HCC cell lines. The proportion of apoptotic cells induced by knockdown of RON was greater than that induced by transfection of the scramble siRNA in all tested HCC cell lines. Knockdown of RON resulted in cell cycle arrest in the G2/M phase of chang and Huh7 cells, and sub G1 phase of HepG2 cells. Knockdown of RON activated cleaved caspase-3 and PARP, and down-regulated the expression of Bcl-2, Bcl-xL and survivin, leading to induction of apoptosis in all tested cell lines. Knockdown of RON negatively regulates the progression of the cell cycle by decreasing cyclin D1 and D3, and increasing p21 and p27 in all tested cell lines. The phosphorylation of Akt, c-Raf and ERK1/2 signal proteins was significantly blocked by knockdown of RON in all tested cell lines. These results suggest that RON is associated with invasive and oncogenic phenotypes such as tumor cell migration, invasion, resistance to apoptosis and cell cycle arrest through the modulation of Akt, c-Raf and ERK signaling cascades in HCC cells.

[Comparison of terlipressin and octreotide with variceal ligation for controlling acute esophageal variceal bleeding--a randomized prospective study].

BACKGROUND/AIMS: Terlipressin and octreotide had been used to control acute variceal bleeding and to prevent early rebleeding after endoscopic hemostasis. We compared the efficacy and safety of terlipressin and octreotide combined with endoscopic variceal ligation (EVL) for the treatment of acute esophageal variceal bleeding and we evaluated their clinical significance as related to rebleeding. METHODS: The eighty eight cirrhotic patients were randomized to the terlipressin group (n=43; 2 mg i.v. initially and 1 mg i.v. at every 4 hours for 3 days) or the octreotide group (n=45; continuous infusion of 25 microgram/h for 5 days) combined with EVL for the treatment of acute esophageal variceal bleeding. RESULTS: The initial hemostasis rates were 98% (42/43 cases) in the terlipressin group and 96% (43/45 cases) in the octreotide group. The 5-day and 42-day rebleeding rates were 12% (5/43 cases) and 28% (12/43 cases), respectively, in the terlipressin group and 9% (4/45 cases) and 24% (11/45 cases), respectively, in the octreotide group. No significant difference was demonstrated between the terlipressin and octreotide groups. The mortality at 42 days was similar in both group, but a high mortality rate (48%) was shown to be related to 42-day rebleeding. The risk factors related to 42-day rebleeding were Child-Pugh class C (aOR=30.2, 95% CI=7.7-117.9), ascites above grade II (aOR=6.6, 95% CI=2.2-19.2) and advanced hepatocellular carcinoma (aOR=4.6, 95% CI=1.1-18.9). CONCLUSIONS: Comparing terlipressin and octreotide combined with EVL showed them to be equally safe and effective therapeutic agents in patients with acute esophageal variceal bleeding. The high risk factors related to early rebleeding were poor liver function and advanced hepatocellular carcinoma.