Satoru Sekoguchi

Premature telomere shortening and impaired regenerative response in hepatocytes of individuals with NAFLD

Abstract: Aims: The risk factors associated with poor prognosis of nonalcoholic fatty liver disease (NAFLD) are not fully understood. Our aim was to assess the role of progressive hepatocellular telomere shortening in the clinical course of NAFLD.

Role of cell-cycle turnover and oxidative stress in telomere shortening and cellular senescence in patients with chronic hepatitis C.

Background:  In addition to the telomere shortening that occurs with cell division, oxidative stress can damage or shorten telomeres and induce a condition termed premature senescence, possibly before telomeres become critically short. We investigated the effects of cell‐cycle turnover and oxidative stress on cellular senescence in hepatitis C virus (HCV)‐related chronic liver injury.

Centrosome aberration accompanied with p53 mutation can induce genetic instability in hepatocellular carcinoma.

Centrosome duplication is controlled in a cell cycle-specific manner and occurs once every cell cycle, thereby ensuring the balanced segregation of chromosomes during the mitotic phase. Numerical or structural abnormalities can arise in the centrosomes of malignant cells. Under defective cell cycle checkpoint systems, cancer cells with abnormal centrosomes can survive and re-enter the cell cycle, promoting unbalanced chromosome segregation and genetic instability. We investigated the centrosome aberrations in 33 patients diagnosed with hepatocellular carcinoma (HCC), using fluorescent pericentrin immunostaining. We also studied the p53 mutation, proliferative activity, and DNA ploidy in these cases. In normal hepatocytes, one centrosome was identified per cell as a round dot, usually in the vicinity of the nuclear membrane. However, in cancer cells from HCC tissue, several patterns of centrosome abnormalities occurred, including supernumerary centrosomes and centrosomes with an abnormal shape and size. Although the frequency of abnormal centrosomes in each tissue was relatively low compared with previous reports in other cancers, nevertheless, centrosome aberration was found in 30 out of 33 HCC tissues. The percentage of tumor cells with abnormal centrosomes was significantly higher in the nondiploid tumors (15.8±15.9‰) than in the diploid tumors (5.4±5.1‰) (P<0.05), and tended to be higher in the tumors with p53 mutation (11.6±13.1‰) than in those with wild-type p53 (5.6±6.8‰). Furthermore, 82% of nondiploid tumors exhibited p53 mutation, whereas only 41% of diploid tumors showed p53 mutation. The percentage of tumor cells with centrosome abnormalities were not related to tumor stage, size or proliferative activity. Therefore, our results indicate that hepatic cancer cells, under centrosome aberration and a defective checkpoint system possibly caused by p53 mutation, have the potential for genetic instability and aggressive behavior. This potential effect occurs irrespective of the tumor size or stage.

In vivo expression patterns of survivin and its splicing variants in chronic liver disease and hepatocellular carcinoma.

Abstract: Aim: Our aim was to clarify the significance of expression levels and post‐transcriptional splicing patterns of survivin during multistep hepatocarcinogenesis and tumor progression.

Differentiation of follicular from mucosa-associated lymphoid tissue lymphoma by detection of t(14;18) on single-cell preparations and paraffin-embedded sections.

A 57‐year‐old woman was referred to the Kyoto Prefectural University of Medicine because of multiple polypoid lesions in the duodenum. On the basis of the histopathologic findings, mucosa‐associated lymphoid tissue lymphoma had been diagnosed. The polypoid lesions did not show any improvement in spite of antimicrobial therapy for elimination of Helicobacter pylori. Because the disease remained stable during the clinical course, no other specific treatment was administered. We performed fluorescence in situ hybridization (FISH) analysis on a single‐cell preparation obtained from the duodenal lesions, to assess the specific chromosome translocation. We identified BCL2/IGH fusion at a frequency of 83%. Two‐color FISH was also performed on paraffin‐embedded tissue sections, which demonstrated BCL2/IGH fusion–positive cells in neoplastic follicles. These findings, together with the CD10+ immunophenotyping of tumor cells, led to a diagnosis of primary follicular lymphoma of the duodenum. Interphase FISH with the IGH gene and oncogene probes is a rapid and powerful tool for assessing genomic changes in gastrointestinal lymphoma on single‐cell preparations and tissue sections. This technique is particularly useful in view of the increasingly small core biopsy samples and needle aspirations obtained for diagnostic purposes.