Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model

Our plain-English summary of Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model, by D. Minami, N. Takigawa, Y. Kato, et al (Cancer Science, 2015).

The study

• Authors: D. Minami, N. Takigawa, Y. Kato, K. Kudo, H. Isozaki, S. Hashida, D. Harada, N. Ochi, M. Fujii, T. Kubo, K. Ohashi, A. Sato, T. Tanaka, K. Hotta, M. Tabata, S. Toyooka, M. Tanimoto, K. Kiura
• Journal: Cancer Science
• Published: 2015;106(10):1296-302
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is an aggressive and therapy-resistant neoplasm arising from mesothelial cells. Evidence suggests that the major pathology associated with asbestos-induced mesothelioma is local iron overload. In the present study, we induced iron-induced mesothelioma in rats based on previous reports. Ten Wistar rats were given ferric saccharate and nitrilotriacetate i.p. for 5 days a week. Five of the ten rats exhibited widespread mesotheliomas in the peritoneum and tunica vaginalis. The tumor cells showed positive immunostaining for calretinin, wilms tumor-1, podoplanin and the oxidative DNA marker 8-hydroxy-2'-deoxyguanosine. In three of the five rats with mesothelioma, array-based comparative genomic hybridization analysis identified a common chromosomal deletion mapped to the chromosomal 4q31 locus, which encompasses the TBXAS1 gene. Downregulation of the TBXAS1 gene was confirmed using quantitative PCR. TBXAS1 gene expression was also reduced in three of four human malignant pleural mesothelioma cell lines compared with normal bronchial epithelial cells. Immunohistochemistry revealed that TBXAS1 expression was weakly positive and positive in five and three out of eight human malignant mesothelioma samples, respectively. In conclusion, TBXAS1 gene expression was downregulated in rats with iron-induced mesothelioma. The relationship between iron overload and TBXAS1 downregulation should be pursued further.

© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

In plain English

This animal experiment, with added tests on human cells and tissue, used iron, not asbestos. The authors gave 10 male Wistar rats abdominal injections of an iron compound (ferric saccharate) plus nitrilotriacetic acid (NTA). Four control rats received saline or NTA alone. All animals were killed 2 years later. Five of the 10 iron-treated rats developed widespread peritoneal mesothelioma, with tumors also in the tunica vaginalis. No control rat did. In three of those five rats, a genome test found a shared deletion in a chromosome region containing the TBXAS1 gene, and a second test confirmed lower TBXAS1. TBXAS1 was slightly but significantly reduced in three of four human mesothelioma cell lines compared with normal cells. In tissue from eight mesothelioma patients, TBXAS1 staining was weakly positive in five and positive in three. The authors concluded that TBXAS1 was downregulated in rats with iron-induced mesothelioma and that its link to iron overload should be clarified. They stated they could not address any relationship between asbestos and TBXAS1.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (rat model of iron-induced mesothelioma with whole-genome analysis), followed by laboratory tests on human mesothelioma cell lines and surgical tumor samples
• Who was studied: 14 male Wistar rats: 2 saline controls, 2 NTA-only controls and 10 given NTA plus ferric saccharate. Also tested were four human malignant mesothelioma cell lines (H2052, H28, MSTO-211H, H290) compared with a cell line (Met5A) the authors describe as normal bronchial epithelial cells. Further samples came from eight patients with malignant mesothelioma (seven men, one woman, mean age 65; two epithelioid, three biphasic, three sarcomatoid tumors) and one patient with non-malignant pleural thickening, all operated on at Okayama University Hospital, Japan.
• Exposure: No asbestos was used. The experimental rats received NTA at 83.5 mg per kg per day by injection into the abdomen, 5 days a week for 5 months. They also received ferric saccharate at 5 mg iron per kg bodyweight per day, 5 days a week for 3 months. Control rats received saline (0.5 mL, 5 days a week for 3 months) or NTA alone.
• Main results:
  • Mesothelioma appeared only in the iron plus NTA group. Five of the 10 rats in that group had widespread peritoneal mesotheliomas. None of the 2 saline or 2 NTA-only rats did.
  • The five rats with mesothelioma also had mesothelial tumors in the tunica vaginalis. Tumor cells stained positive for calretinin, Wilms tumor-1 and podoplanin, and negative for CEA and Ep-CAM. Mesothelioma cell nuclei stained for the oxidative DNA damage marker 8-OH-dG.
  • In three of the five rats with mesothelioma (M1, M3, M5), whole-genome analysis found a shared chromosomal deletion at the 4q31 locus, which contains the TBXAS1 gene. Other genomic changes were not consistent among tumors. Quantitative PCR confirmed TBXAS1 downregulation.
  • One rat with mesothelioma (M2) had a deletion at the chromosome 5q32 locus, which contains the Cdkn2a/b gene.
  • In the human cell lines, TBXAS1 gene expression was slightly but significantly reduced in three of four mesothelioma cell lines (H2052, H28, H290) compared with normal cells (Met5A). MSTO-211H showed no decrease.
  • In the eight human mesothelioma samples, TBXAS1 protein staining was weakly positive in five (10 to 30% of tumor cells) and positive in three (70 to 100% of cells).
  • TBXAS1 gene expression was lower in five human mesothelioma tissue samples (H3, H4, H6, H7, H8) than in the control cells. The difference was statistically significant only for H4.
• The authors' conclusion: The authors concluded that TBXAS1 gene expression was downregulated in rats with iron-induced mesothelioma. They said the relationship between iron overload and this downregulation should be clarified further.
• Limitations the authors state:
  • The study could not address any relationship between asbestos and TBXAS1 downregulation. The authors said a study using asbestos-induced rat mesothelioma should be done.
  • Because there were few patients, the relationship between TBXAS1 expression and clinical features or survival could not be determined.
  • It was unclear whether differences in TBXAS1 between cell lines depended on tumor histology. More cell lines are needed.
  • The authors noted that iron-NTA and asbestos may differ in how they cause mesothelioma in rats, and that further investigation is needed.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Neoplasm, Mesothelial Cells, Pathology, Peritoneum, Tunica Vaginalis, Calretinin, Podoplanin (D2-40).

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