[Show abstract][Hide abstract] ABSTRACT: A 41-year-old man was admitted in June 2007 with a 1-month history of headache and cerebellar ataxia. At the age of 5 years, in May 1971, he had presented with headache, vomiting, and gait disturbance. Cerebral angiographical study demonstrated vascular shift caused by a mass lesion in the cerebellar vermis. He had immediately undergone partial removal. Histological diagnosis was medulloblastoma (MB). Postoperatively he received a total of 40 Gy radiation to the whole brain and 30.5 Gy to the spine without chemotherapy. He was again seen 35 years later with a radiation-induced glioblastoma (GB) that arose in the region of the original MB. The tumor was surgically removed, and he received radiotherapy and chemotherapy with ACNU, procarbazine, and vincristine. Postoperative irradiation reduced the size of the second tumor.
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer is a highly aggressive malignancy due to elevated mitotic activities and epithelial-mesenchymal transition (EMT). Oncogenic RAS and transforming growth factor-beta signaling are implicated in these malignant features. The mechanisms that underlie EMT need to be addressed since it promotes tissue invasion and metastasis. The high-mobility group A protein 2 (HMGA2) is a non-histone chromatin factor that is primarily expressed in undifferentiated tissues and tumors of mesenchymal origin. However, its role in EMT in pancreatic cancer is largely unknown. Here we report that HMGA2 is involved in EMT maintenance in human pancreatic cancer cells. Specific knockdown of HMGA2 inhibited cell proliferation, leading to an epithelial-state transition that restores cell-cell contact due to E-cadherin up-regulation. Consistently, an inverse correlation between HMGA2-positive cells and E-cadherin-positive cells was found in cancer tissues. Inhibition of the RAS/MEK pathway also induced an epithelial transition, together with HMGA2 down-regulation. Transcriptional repressors of the E-cadherin gene, such as SNAIL, decreased after HMGA2 knockdown since HMGA2 directly activated the SNAlL gene promoter. The decrease of SNAIL after RAS/MEK inhibition was suppressed by HMGA2 overexpression. Further, let-7 microRNA-mediated HMGA2 down-regulation had no effect on the prevention of the transformed phenotype in these cells. These data shed light on the importance of HMGA2 in reversibly maintaining EMT, suggesting that HMGA2 is a potential therapeutic target for the treatment of pancreatic cancer.
American Journal Of Pathology 02/2009; 174(3):854-68. DOI:10.2353/ajpath.2009.080523 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Retinoblastoma protein (RB) acts as a tumor suppressor in many tissue types, by promoting cell arrest via E2F-mediated transcriptional repression. In addition to the aberrant forms of the RB gene found in different types of cancers, many viral oncoproteins including the simian virus 40 large T antigen target RB. However, cellular factors that inhibit RB function remain to be elucidated. Here, we report that RB interacts with the high mobility group protein A1 (HMGA1), a-non-histone architectural chromatin factor that is frequently overexpressed in cancer cells. HMGA1 binds the small pocket domain of RB, and competes with HDAC1. Subsequently, overexpression of HMGA1 abolishes the inhibitory effect of RB on E2F-activated transcription from the cyclin E promoter. Under serum starvation, T98G cells had been previously shown to be arrested in the G0 phase in an RB-mediated manner. The G0 phase was characterized by growth arrest and low levels of transcription, together with the hypophosphorylation of RB and the downregulation of HMGA1. In contrast, such serum-depleted G0 arrest was abrogated in T98G cells overexpressing HMGA1. The overexpressed HMGA1 was found to form complexes with cellular RB, suggesting that downregulation of HMGA1 is required for G0 arrest. There were no phenotypic changes in HMGA1-expressing T98G cells in the presence of serum, but the persistent expression of HMGA1 under serum starvation caused various nuclear abnormalities, which were similarly induced in T antigen-expressing T98G cells. Our present findings indicate that overexpression of HMGA1 disturbs RB-mediated cell arrest, suggesting a negative control of RB by HMGA1.
Cancer Science 01/2008; 98(12):1893-901. DOI:10.1111/j.1349-7006.2007.00608.x · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cancer cells possess both genetic and epigenetic alterations that dysregulate essential cellular processes, leading to disordered cell proliferation and differentiation. Oncogenes and tumor suppressor genes have been found to be activated and inactivated, respectively, in malignant cells. Epigenetic regulation of the genome is mediated by interactions between DNA methylation, chromatin, and modifications of histones and various transcriptional regulators. Recent studies have shown that some components of the epigenetic system as well as epigenetically mutated genes are diagnostic and therapeutic targets in cancer. We discuss the molecular basis of the epigenetic mechanism in association with the development of cancer.
International Journal of Hematology 09/2004; 80(2):103-7. DOI:10.1532/IJH97.04052 · 1.92 Impact Factor