Biomedical subjects

Tetsuhiro Nakano

Publications and source records attributed to Tetsuhiro Nakano.

7 recordsLinked to original sources

PubMed2005

Genetic and epigenetic alterations of the candidate tumor-suppressor gene MYO18B, on chromosome arm 22q, in colorectal cancer.

Allelic imbalance (AI) on chromosome arm 22q has been detected in 20%-40% of colorectal cancers, suggesting that this chromosome arm has a tumor-suppressor gene involved in colorectal carcinogenesis. Recently, we isolated a candidate tumor-suppressor gene, MYO18B, at 22q12.1, that is deleted, mutated, and hypermethylated in more than 50% of lung cancers. In the present study, we analyzed genetic and epigenetic alterations of the MYO18B gene in colorectal cancers. AI at the MYO18B locus was detected in 16 of 43 (40%) informative cases. Mutations of the MYO18B gene were detected in 2 of 11 (18%) cell lines and 1 of 47 (2%) surgical specimens. Nine of 11 (82%) cell lines showed reduced MYO18B expression, which was restored in all 9 by treatment with 5-aza-2'-deoxycytidine and/or trichostatin A (TSA). Although hypermethylation of the promoter CpG island for MYO18B was not detected, a significant correlation was observed between the level of MYO18B expression and the level of acetylation of histones H3 and H4 in 6 cell lines with and without TSA treatment. Thus, it was suggested that MYO18B is inactivated in a considerable fraction of colorectal cancers by several mechanisms, especially silencing by histone deacetylation and/or AI. Furthermore, restoration of MYO18B expression in colorectal cancer cell lines HT29 and DLD-1 suppressed anchorage-independent growth, whereas it did not affect the growth rate in vitro. These results suggest that genetic and epigenetic inactivation of the MYO18B gene play an important role in colorectal carcinogenesis.

Acetylation↗

PubMed2005

Pulmonary pleomorphic liposarcoma.

Pulmonary liposarcoma is extremely rare with 6 cases previously reported in the English literature. The following is a report of a 36-year-old man with pulmonary liposarcoma. The patient had chest pain and a mass shadow in the right lower lung field was revealed on a chest X-ray film. A computed tomography and magnetic resonance imaging showed a heterogeneous tumor, compressing the right lower lobe of the lung. Because of the fatty tissue component in the tumor on the chest computed tomography, and the appearance as an extrapulmonary mass, preoperative diagnosis was posterior mediastinal liposarcoma. But thoracotomy revealed that the tumor originated from the lung. Right lower lobectomy and lymph node dissection was carried out with no additional therapy. The pathological diagnosis was pleomorphic liposarcoma originated from the lung. Two months after the operation, the patient died of respiratory failure due to local recurrence.

Adult↗

PubMed2004

Role of a BCL9-related beta-catenin-binding protein, B9L, in tumorigenesis induced by aberrant activation of Wnt signaling.

Wnt signaling plays a crucial role in a number of developmental processes and in tumorigenesis. beta-Catenin is stabilized by Wnt signaling and associates with the TCF/LEF family of transcription factors, thereby activating transcription of Wnt target genes. Constitutive activation of beta-catenin-TCF-mediated transcription resulting from mutations in adenomatous polyposis coli (APC), beta-catenin, or Axin is believed to be a critical step in tumorigenesis among divergent types of cancers. Here we show that the transactivation potential of the beta-catenin-TCF complex is enhanced by its interaction with a BCL9-like protein, B9L, in addition to BCL9. We found that B9L is required for enhanced beta-catenin-TCF-mediated transcription in colorectal tumor cells and for beta-catenin-induced transformation of RK3E cells. Furthermore, expression of B9L was aberrantly elevated in about 43% of colorectal tumors, relative to the corresponding noncancerous tissues. These results suggest that B9L plays an important role in tumorigenesis induced by aberrant activation of Wnt signaling.

Amino Acid Sequence↗

PubMed2004

Mutational analysis of the BAK gene in 192 advanced gastric and colorectal cancers.

The evasion of apoptosis has been linked to the development of cancer. A recent study of a small number of gastric and colorectal cancers found that the BAK gene, which encodes a pro-apoptotic protein, contained somatic mutations in approximately 17% of the samples analyzed. To investigate the precise frequency of BAK mutations, we examined the entire coding sequence of the BAK gene in gastric and colorectal cancers, using polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) analysis and direct sequencing. We could not detect any somatic mutations of the BAK gene in 192 colorectal and gastric cancers. We found only four single-nucleotide substitutions in the coding sequences, which were also found in corresponding normal samples. We conclude that somatic alterations of the BAK gene are rare in colorectal and gastric cancers.

Apoptosis↗

PubMed2003

Pathogenetic and biologic significance of TP14ARF alterations in nonsmall cell lung carcinoma.

The INK4a/ARF locus on human chromosome band 9p21 carries two tumor suppressor genes, TP14ARF and TP16INK4a, and both are frequently inactivated in nonsmall cell lung carcinoma (NSCLC. TP14ARF and TP16INK4a play important roles in the TP53 and RB tumor suppressor pathways, respectively. To elucidate the genetic and epigenetic status of the TP14ARF and TP16INK4a genes in NSCLC, we comprehensively analyzed mutations, homozygous deletions, methylations in the CpG regions, and expression of the TP14ARF and TP16INK4a genes in 31 NSCLC cell lines. TP16INK4a (84%) was inactivated more frequently than TP14ARF (55%). Moreover, p16INK4a was inactivated in all 17 cell lines with TP14ARF inactivation. Three cell lines with base substitutions in exon 2 resulted in missense mutations of TP16INK4a but silent mutations of TP14ARF. There was a case of mutation in exon 1alpha unique to TP16INK4a, but not a mutation in exon 1beta unique to TP14ARF. The TP16INK4a gene was methylated in 6 cell lines, but the TP14ARF gene was not methylated in any cell line. Unlike a mutually exclusive relationship for inactivation between TP16INK4a and RB, TP14ARF and TP53 did not show such a relationship (P = 0.61, Fisher exact test). Thus, the present results indicate the TP16INK4a gene to be the primary target of INK4a/ARF locus alterations. Transient TP14ARF expression induced G1 arrest in the cells with wild-type TP53, but not in the cells with mutated TP53. Thus, the pathogenetic and biologic significance of TP14ARF inactivation is different between NSCLC cells with wild-type TP53 and those with mutated TP53.

Blotting, Western↗

PubMed2003

Biological properties and gene expression associated with metastatic potential of human osteosarcoma.

Lung metastasis has a great influence on the prognosis of patients with osteosarcoma. We previously established two high-metastatic sublines, M112 and M132, from the HuO9 human osteosarcoma cell line by in vivo selection. In this study, we newly isolated a high-metastatic subline, H3, and three low-metastatic sublines, L6, L12 and L13, from HuO9 by the dilution plating method. Three high-metastatic sublines produced more than 200 metastatic nodules in the lung, while three low-metastatic sublines produced no or few nodules after injection of 2 x 10(6) cells into the tail vein of nude mice. There were significant differences in the motility and invasiveness between high- and low-metastatic sublines, whereas the growth rates in vitro and the tumorigenicity in vivo showed no correlation with their metastatic abilities. Early adherence to culture plates was significantly lower in two of three low-metastatic sublines, which occupied smaller surface areas on the culture plates than other sublines did. Comparison of the expression of 637 cancer-related genes by cDNA microarray revealed that seven genes were differentially expressed between high- and low-metastatic sublines. Among them, five genes (AXL, TGFA, COLL7A1, WNT5A, and MKK6) were associated with adherence, motility, and/or invasiveness. These results suggest that the differences in motility/invasiveness and adhesive abilities are key determinants of lung metastasis in osteosarcoma.

Animals↗

PubMed2002

Establishment of human osteosarcoma cell lines with high metastatic potential to lungs and their utilities for therapeutic studies on metastatic osteosarcoma.

Relevant animal models for metastasis of osteosarcoma is needed to understand the biology and to develop the treatment modality of metastasis of human osteosarcoma. Therefore, we screened six human osteosarcoma cell lines for metastatic ability in nude mice. The HuO9 cell line was identified as being metastatic to the lung after intravenous injection. We established two sublines, HuO9-M112 and HuO9-M132, with high metastatic potential to the lung from the parental HuO9 cells by in vivo selection. There were no differences between these two sublines and the parental cells in the growth rate in vitro and the tumorigenicity after subcutaneous injection in nude mice, however, mice injected with the metastatic sublines became moribund earlier than mice injected with the parental HuO9 cells did. Thus, adriamycin (ADR) and recombinant interleukin-12 (IL-12) were administered to mice injected with the HuO9-M112 subline to suppress experimental lung metastases. Production of lung colonies was significantly suppressed and the prognoses of mice were significantly improved by both ADR and IL-12 treatments. These results indicate that both ADR and IL-12 are effective agents against pulmonary metastatic osteosarcoma, and that these sublines are useful for studies on the biological behavior and treatment of pulmonary metastatic osteosarcoma.

Animals↗