Biomedical subjects

Takashi Sakatani

Publications and source records attributed to Takashi Sakatani.

5 recordsLinked to original sources

PubMed2005

Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice.

Loss of imprinting (LOI) of the insulin-like growth factor II gene (IGF2) is an epigenetic alteration that results in a modest increase in IGF2 expression, and it is present in the normal colonic mucosa of about 30% of patients with colorectal cancer. To investigate its role in intestinal tumorigenesis, we created a mouse model of Igf2 LOI by crossing female H19+/- mice with male Apc+/Min mice. Mice with LOI developed twice as many intestinal tumors as did control littermates. Notably, these mice also showed a shift toward a less differentiated normal intestinal epithelium, reflected by an increase in crypt length and increased staining with progenitor cell markers. A similar shift in differentiation was seen in the normal colonic mucosa of humans with LOI. Thus, altered maturation of nonneoplastic tissue may be one mechanism by which epigenetic changes affect cancer risk.

Adenoma↗

PubMed2003

Oncogenomics: prospects for the future.

Genomics has generated a wealth of data that is now being used to identify additional molecular alterations associated with cancer development. Mapping these alterations in the cancer genome is a critical first step in dissecting oncological pathways. There are two ways in which cancer research has changed in recent years. The first is the progressive elucidation of the genomic basis of cancer. This has been accomplished by the generation of detailed information using procedures such as global expression profiling. The second is a renewed emphasis on the role of epigenetic modifications in the etiology of cancer. Changes in DNA methylation and chromatin modification patterns are some of the epigenetic factors that cause gene deregulation in cancer. In this article, current and evolving genomic applications and the hypotheses underlying the modality for cancer therapy will be reviewed.

Animals↗

PubMed2002

Expression of heavy subunit of gamma-glutamylcysteine synthetase (gamma-GCSh) in human colorectal carcinoma.

Gamma-glutamylcysteine synthetase (gamma-GCS) is a heterodimer consisting of heavy (gamma-GCSh) and light (gamma-GCSl) subunits. gamma-GCS catalyzes the rate-limiting de novo biosynthesis of glutathione (GSH), an abundant physiological antioxidant that plays important roles for regulating oxidative stress. Expression of gamma-GCSh and gamma-GCSl are sensitive to oxidative stress. To investigate whether expression of gamma-GCS is correlated with tumor progression, we used immunohistochemical approaches to examine 16 human colorectal adenomas and resected 57 carcinomas from untreated patients. In adjacent normal colorectal epithelium, levels of gamma-GCSh expression were low. Strong cytoplasmic staining for gamma-GCSh was detected in 3 (18.8%) adenoma and 48 (84.2%) carcinomas. The frequency of gamma-GCSh expression in carcinoma was significantly higher than in adenoma (p<0.0001). We used RNase protation assay and Western blot to determine levels of gamma-GCSh mRNA and protein from 10 pairs of matched carcinomas with adjacent normal controls. Elevated expression of both gamma-GCSh mRNA and protein were found in 6 cases, suggesting that transcriptional and/or posttranscriptional regulation play an important role in the upregulation of gamma-GCS during colorectal carcinogenesis. We also examined the expression of another redox-regulated gene, multidrug resistance protein 1 (MRP1). Strong staining for MRP1 was detected in 1 (6.3%) adenoma and 40 (70.2%) carcinomas. The frequency of MRP1 expression in carcinoma was significantly higher than in adenoma ( p<0.0001). Nuclear p53 expression was detected in 30 (52.6%) of carcinomas. There is a significant correlation between gamma-GCSh and MRP1 expression (p=0.013) but not between gamma-GCSh and p53. Since gamma-GCS is a sensor of oxidative stress, these results are consistent with the notion that oxidative stress is associated with colorectal tumor progression.

Adenoma↗

PubMed2002

Expression of survivin messenger RNA correlates with poor prognosis in patients with hepatocellular carcinoma.

Suppression of apoptosis is important for carcinogenesis and tumor growth. Recent studies revealed that survivin not only inhibited apoptosis but also accelerated cancer cell proliferative activity. To investigate the prognostic role of expression of the antiapoptosis gene, survivin, in hepatocellular carcinoma (HCC), the authors analyzed the correlation between the expression pattern of survivin messenger RNA (mRNA) and clinicopathologic findings of patients. Tissues were obtained by surgical resection of livers from 51 patients with HCC and 6 patients without HCC. Expression of survivin mRNA was evaluated using reverse transcription-polymerase chain reaction in 51 tumors, 51 adjacent histologically noncancerous livers, and 6 normal livers. Survivin protein expression was evaluated using Western blotting, and apoptotic cancer cells were detected by immunostaining with polyclonal rabbit anti-single-stranded DNA. Survivin mRNA expression was detected in 21 of 51 (41%) tumors, 2 of 51 (4%) noncancerous livers, and none of the 6 normal livers. Survivin mRNA expression did not correlate with tumor size or stage of HCC. Percentage of apoptotic cancer cells of 30 survivin mRNA-negative tumors (5.2 +/- 3.4%) was significantly higher than that of 21 survivin mRNA-positive tumors (2.2 +/- 2.3%, P = 0.0019). The disease-free 5-year survival rate of 21 patients positive for survivin mRNA (19%) was significantly poorer than that of 30 patients negative for survivin mRNA (39%, P = 0.0148). Survivin mRNA was detected in 57% (17/30) patients with HCC recurrence but in only 19% (4/21) of patients without recurrence (P = 0.0072). These results indicated that survivin mRNA expression could be used as an independent prognostic factor for patients with HCC after hepatectomy.

Apoptosis↗

PubMed1999

Clinicopathological value of immunohistochemical detection of occult involvement in pT3N0 gastric cancer.

BACKGROUND: In cases of pT3 gastric cancer, even when standard histological staining reveals no evidence of metastases in the regional lymph nodes, patients still may die of postoperative recurrence of the tumor. An attempt was made in the present study to explain the unfavorable outcome of such patients by investigating the presence of occult cancer cells in lymph nodes by immunostaining of cytokeratin.METHODS: We examined 2310 lymph nodes that had been removed from 83 patients with stage II gastric cancer (pT3, N0, M0). Two consecutive sections of 4 &mgr;m thick were prepared for simultaneous staining with hematoxylin and eosin and immunostaining with the CAM 5.2 monoclonal antibody against cytokeratin, respectively.RESULTS: Evidence of occult involvement was found in 299 of 2310 (13%) lymph nodes and in 54 of 83 (65%) patients with pT3 gastric cancer. An analysis of survival demonstrated the limited 5-year survival of patients with occult involvement in their resected lymph nodes, as compared with that of patients without involvement ( P < 0.01). Moreover, the patients in whom group 2 lymph nodes had occult cancer cells had a significantly poorer prognosis than those in whom occult involvement was limited to group 1 lymph nodes ( P < 0.05).CONCLUSIONS: The accuracy of predictions of prognosis of patients with pT3 gastric cancer should be greatly enhanced if cytokeratin-specific immunostaining is performed in conjunction with routine histopathological examination of lymph nodes.

Journal Article↗