Koji Ikejiri

IDENTIFICATION AND INITIAL CHARACTERIZATION OF A FOURTH LEADER EXON AND PROMOTER OF THE HUMAN IGF-II GENE

Transcription of the human insulin-like growth factor II (IGF-II) gene is regulated by activation of multiple promoters which act in a tissue-specific and development-dependent manner. Previously, we have identified three different promoters, one of which is active in adult liver tissue only, whereas the other two are active in many fetal tissues and adult non-hepatic tissues. Here we report the identification of a fourth leader exon of the human IGF-II gene indicating the presence of a fourth promoter. Transcription from this promoter yields a 5.0 kb IGF-II mRNA species, which is detected in fetal liver and leiomyosarcoma tissue.

FUNCTIONAL ANALYSIS OF MULTIPLE PROMOTERS OF THE RAT INSULIN-LIKE GROWTH FACTOR II GENE

We have characterized the multiple promoters of the rat insulin-like growth factor II (rIGFII) gene by in vivo transient expression assay using a series of deletion mutant templates. Among the four promoters (P1, P2, P3 and P6), two (P2 and P3) showed relatively strong promoter activities compared with the other two. One of the four promoters, P2, was further characterized by gel band-shift and footprinting analysis using HeLa cell nuclear extract, showing two retarded bands and at least one protected sequence stretch. The results indicated that P2 has a very simple structure like P3, and consists of no more than 141 base-pairs (bp) including a TATA box and two GC core hexanucleotides. Promoter strength shown by in vivo transient expression in different cell types failed to explain the differential employment of P2 and P3 in these cells, suggesting the involvement of other regulatory mechanisms that might operate only in the native state.

An insulin-like growth factor II-producing histiocytoma associated with hypoglycemia: Analysis of the peptide, its gene expression, and glucose transporter isoforms☆

An insulin-like growth factor II (IGF-II)-producing histiocytoma was detected in a patient presenting with the classical findings of tumor-related hypoglycemia (low serum insulin and IGF-I concentrations, glucose intolerance, and only modestly increased serum IGF-II levels). Acid-gel filtration of serum extracts showed a single peak of IGF-II immunoreactivity that emerged at the same site as the 125I-labeled human IGF-II standard. High-performance liquid chromatography (HPLC) analysis of the tumor IGF-II demonstrated that it had an identical retention time to that of recombinant human IGF-II. The tumor IGF-II content was extremely high, messenger RNA (mRNA) for IGF-II showed a 100-fold increase in expression compared with normal human liver tissue. Of special interest, a newly identified exon (hE1) was shown to be predominantly expressed in the tumor by Northern blot analysis using leader exon-specific rat IGF-II complementary DNA (cDNA) probes. Although the significance of this finding remains uncertain, this is the first evidence of a new transcription unit in the human IGF-II gene. In addition, immunoblotting showed that the levels of the glucose transporters, GLUT1 and GLUT4, in the tumor were low and undetectable, respectively. This finding makes it unlikely that increased glucose consumption by the tumor accounted for the hypoglycemia in this patient. This case report provides an interesting insight into the pathophysiology of tumor-induced hypoglycemia and new evidence of the abnormal regulation of IGF-II gene expression in human tumors.

Leptomeningeal Carcinomatosis Originating from Advanced Gastric Cancer : A Report of Three Cases and Review of the Literatures

BACKGROUND Leptomeningeal carcinomatosis (LMC) is a rare complication of gastric cancer. Case 1. A 57-year-old female was diagnosed with gastric cancer and underwent distal gastrectomy with D2 lymph node dissection. Two years later, the patient suffered from para-aortic lymph node metastases and provided chemotherapy. During the chemotherapy, the patient emergently visited our hospital with chief complaints of a severe headache and dizziness. The above symptoms promptly abated by meningeal drainage, with a high value of the cerebrospinal fluid (CSF) pressure. Despite the administration of subsequent chemotherapy, the patients clinical state rapidly worsened, including gradual progression of both blindness and hearing loss. Case 2. A 42-year-old male was diagnosed with Stage IV gastric cancer due to both distant lymph node metastases and an ascites. Chemotherapy with S-1 plus docetaxel was initiated. Upon finishing the fifth course of treatment, the patient complained of a severe headache. The magnetic resonance imaging (MRI) findings were suggestive of LMC. Under suspicion of carcinomatous meningitis, the patient underwent both cerebrospinal drainage with a high pressure value of 180 mmH2O and a cytological examination with a diagnosis of Class V. Immediately following the cerebrospinal drainage, the patients symptoms promptly diminished. Case 3. A 66-year-old female was diagnosed with gastric cancer and underwent total gastrectomy with D2 dissection. About a year later, the patient suffered from the peritoneal dissemination, and provided serial chemotherapy regimens for 13 months. Thereafter the patient suffered from mildly stiff shoulders followed by serial severe headaches, and meningeal drainage was performed. The CSF showed pleocytosis and the presence of neoplastic cells, leading a diagnosis of LMC. After the placement of an Ommaya reservoir, the intrathecal chemotherapy was performed. Within two weeks of treatment, the patients condition improved significantly, and the cell counts in the CSF obtained from the Ommaya reservoir remained low for six months after the first diagnosis of LMC. CONCLUSIONS Although gastric LMC-affected patients often exhibit a fatal clinical course, the administration of intrathecal chemotherapy may improve survival. Systemic chemotherapy may be also administered in a limited number of patients with a superior performance status. At present, each case requires the individual making treatment decisions. Further accumulation of clinical cases and improving the overall understanding of the pathogenesis of this disease is needed in order to advance in the treatment of gastric LMC.