[Show abstract][Hide abstract] ABSTRACT: The expression of oxysterol binding protein-related protein (ORP) 5 is related to invasion and a poor prognosis in pancreatic cancer patients. ORP5 induced the expression of sterol response element binding protein (SREBP) 2 and activated the downstream gene of sterol response element. ChIP using SREBP2 antibody revealed that histone deacetylase 5 (HDAC5) was one of the downstream genes of SREBP2. The effect of HMG-CoA reductase inhibitors (statins) were analyzed according to the expression level of ORP5. The invasion rate and growth was suppressed in cells that strongly expressed ORP5 in a time- and dose-dependent manner, but had less effect in cells weakly expressing ORP5, suggesting that when the potential of invasion and growth relies on the cholesterol synthesis pathway, it becomes sensitive to HMG-CoA reductase inhibitor. Furthermore, HDAC inhibitor, tricostatin A, induced the expression of phosphatase and tensin homolog as well when ORP5 was suppressed or the cells were treated with statin. Treatment with both statin and tricostatin A showed a synergistic antitumor effect in cells that highly expressed ORP5. Therefore, in some pancreatic cancers, continuous ORP5 expression enhances the cholesterol synthesis pathway and this signal transduction regulates phosphatase and tensin homolog through HDAC5 expression. This is the first report to detail how the signal transduction of cholesterol synthesis is related to cancer invasion and why statins can suppress invasion and growth.
(Cancer Sci 2010; 101: 898–905)
Cancer Science 04/2010; 101(4):898-905. DOI:10.1111/j.1349-7006.2009.01475.x · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genetic instability is known as a cause of oncogenesis. Though Rad18 is reported to function in a post replication mismatch repair system, the relation between the status of Rad18 and human tumorigenesis has not been described so far.
Mutation analysis of 34 human cancer cell lines and 32 non small cell lung cancer (NSCLC) tissues were performed by RT-PCR SSCP. Expression level of Rad18 was measured by real time RT-PCR. Stable transfectant was constructed for in vitro study.
No mutation was found in both cancer cell lines and NSCLC tissues. A single nucleotide polymorphism (SNP) at codon 302 was detected in 51.5% of the cell lines and 62.5% of NSCLC tissues. Interestingly, Rad18 was homozygously deleted in a pulmonary adenocarcinoma cell line PC3. Furthermore, there was no difference in the expression level of wild type Rad18 and Rad18 with SNP. The growth, cell morphology, sensitivity to anti-cancer drugs and in vitro DNA repair activity between wild type Rad18 and Rad18 with SNP revealed to have no difference in vitro.
Though the frequency of SNP was tended to be higher in NSCLC patients than healthy volunteers (57.7%), as the difference was not significant, we have concluded that there is no relation between Rad18 SNP and lung cancer development.
Journal of Experimental & Clinical Cancer Research 08/2009; 28(1):106. DOI:10.1186/1756-9966-28-106 · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In previous studies, the gene expression profiles of two hamster pancreatic cancer cells with different potentials for invasion and metastasis were analyzed. In the present study, we identified that one of the genes expressed strongly in the highly metastatic cell line is hamster oxysterol binding protein-related protein (ORP)-5. The aim of the present study was to clarify the relationship between ORP5 and invasion and poor prognosis of human pancreatic cancer. Invasion assays were carried out in both hamster and human pancreatic cancer cells by suppressing the ORP5 gene with short interfering RNA or inducing its expression by introducing an expression vector. To evaluate the relationship between ORP5 and the characteristics of human pancreatic cancer, 56 pancreatic cancer tissue specimens were analyzed and the ORP5 expression in each pancreatic cancer tissue specimen was analyzed by immunohistochemistry. In both the hamster and human pancreatic cancer cells, suppression of ORP5 significantly reduced the invasion rate of the cells and induction of ORP5 significantly enhanced the invasion rate of the cells. In the clinical sample, the median survival times of the patients with ORP5-positive (n = 33) and ORP5-negative (n = 23) cancer were 8.3 and 17.2 months, respectively (P = 0.02). Also, the 1-year survival rates of patients with ORP5-positive and ORP5-negative cancer were 36.4 and 73.9%, respectively (P = 0.005). The ORP5 expression level was related to both invasion and poor prognosis in human pancreatic cancer. These findings suggest that the expression of ORP5 may induce cancer cell invasion, resulting in the poor prognosis of pancreatic cancer.
Cancer Science 12/2008; 99(12):2387-94. DOI:10.1111/j.1349-7006.2008.00987.x · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The muscularis propria of the stomach is histologically divided into three layers; namely, the innermost oblique, the inner circular, and the outer longitudinal layers. In patients with gastric cancer the depth of tumor invasion has been reported to correlate with lymph node metastasis and prognosis. However, it is unclear whether the depth of tumor invasion in the muscularis propria has an effect on lymph node metastasis and prognosis.
Fifty-nine gastric cancer patients with muscularis propria invasion were analyzed retrospectively. These patients were divided into two groups, the inner group, with invasion up to the inner circular layer; and the outer group, with invasion beyond the inner circular layer. The relationships between tumor invasion and clinicopathological factors and survival were evaluated.
Of the 59 patients, 34 were classified as the inner group, and 25 were classified as the outer group. The inner group had a significantly lower probability of lymph node metastasis (P = 0.0053) and a significantly better overall cancer-specific survival (P = 0.017) than the outer group.
Gastric cancers with muscularis propria invasion had heterogeneous prognoses according to the tumor depth in the muscularis propria layers.
Gastric Cancer 02/2008; 11(4):219-25. DOI:10.1007/s10120-008-0486-3 · 3.72 Impact Factor