SORORIN and PLK1 as potential therapeutic targets in malignant pleural mesothelioma

Our plain-English summary of SORORIN and PLK1 as potential therapeutic targets in malignant pleural mesothelioma, by T. Kato, D. Lee, L. Wu, et al (International Journal of Oncology, 2016).

The study

• Authors: T. Kato, D. Lee, L. Wu, P. Patel, A.J. Young, H. Wada, H.P. Hu, H. Ujiie, M. Kaji, S. Kano, S. Matsuge, H. Domen, H. Kanno, Y. Hatanaka, K.C. Hatanaka, K. Kaga, Y. Matsui, Y. Matsuno, M. De Perrot, K. Yasufuku
• Journal: International Journal of Oncology
• Published: 2016;49(6):2411-2420
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive type of cancer of the thoracic cavity commonly associated with asbestos exposure and a high mortality rate. There is a need for new molecular targets for the development of more effective therapies for MPM. Using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and an RNA interference-based screening, we examined the SORORIN gene as potential therapeutic targets for MPM in addition to the PLK1 gene, which is known for kinase of SORORIN. Following in vitro investigation of the effects of target silencing on MPM cells, cell cycle analyses were performed. SORORIN expression was analyzed immunohistochemically using a total of 53 MPM samples on tissue microarray. SORORIN was found to be overexpressed in the majority of clinical MPM samples and human MPM cell lines as determined by qRT-PCR. Gene suppression of each SORORIN and PLK1 led to growth inhibition in MPM cell lines. Knockdown of SORORIN showed an increased number of G2M-phase population and a larger nuclear size, suggesting mitotic arrest. High expression of SORORIN (SORORIN-H) was found in 50.9% of all the MPM cases, and there is a tendency towards poorer prognosis for the SORORIN-H group but the difference is not significant. Suppression of SORORIN with PLK1 inhibitor BI 6727 showed a combinational growth suppressive effect on MPM cell growth. Given high-dose PLK1 inhibitor induced drug-related adverse effects in several clinical trials, our results suggest inhibition SORORIN-PLK1 axis may hold promise for the treatment of MPMs.

In plain English

This laboratory study examined two genes, SORORIN and PLK1, as possible treatment targets in malignant pleural mesothelioma. It did not study asbestos exposure. The authors measured gene activity in nine tumor samples from Toronto General Hospital and in four mesothelioma cell lines. They reported that both genes were overexpressed in a majority of the tumor samples, and highly expressed in the cell lines but low in a normal mesothelial cell line. Silencing either gene significantly slowed the growth of two mesothelioma cell lines. Silencing SORORIN raised the share of cells in the G2/M phase of the cell cycle, which the authors read as cells stalling during division. In tumor tissue from 53 patients operated on in Hokkaido, Japan, between 1990 and 2012, 27 (50.9%) showed high SORORIN levels. Among 21 patients who had curative surgery, those with high SORORIN tended toward shorter 5-year survival, but the difference was not statistically significant (P=0.1664). Combining SORORIN silencing with the PLK1-blocking drug BI 6727 significantly reduced cell growth. The authors concluded that combination therapy targeting these genes could be a potential new treatment strategy, and they recommended testing in xenograft models.

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: Laboratory study: gene expression measurement (qRT-PCR) in tumor samples and cell lines, gene silencing (RNA interference) and drug experiments in cell lines, and staining of tumor tissue on a tissue microarray with survival analysis
• Who was studied: Nine malignant pleural mesothelioma samples from Toronto General Hospital (4 epithelioid, 4 biphasic, 1 sarcomatoid). A further 53 mesothelioma samples (49 male, 4 female patients) came from surgery at Hokkaido University Hospital and affiliated hospitals between February 1990 and April 2012. The study also used four human mesothelioma cell lines (NCI-H28, -H226, -H2052, -H2452) and one normal mesothelial cell line (MES-F).
• Exposure: Asbestos exposure was not studied. The experimental treatments were siRNAs silencing SORORIN or PLK1 (10 nM) and the PLK1 inhibitor drug BI 6727, applied to mesothelioma cell lines.
• Main results:
  • SORORIN and PLK1 were overexpressed in a majority of the mesothelioma clinical samples tested by qRT-PCR
  • Both genes were highly expressed in four mesothelioma cell lines and showed low expression in the normal mesothelial cell line MES-F
  • Silencing SORORIN or PLK1 significantly suppressed proliferation of H28 and H2052 mesothelioma cells compared with controls at 4 days
  • Silencing SORORIN increased the proportion of cells in the G2/M phase, which the authors interpreted as mitotic arrest
  • High SORORIN expression was found in 27 of 53 mesothelioma cases (50.9%): 17 of 34 epithelioid (50.0%), 8 of 13 biphasic (61.5%) and 2 of 5 sarcomatoid (40.0%)
  • In curative surgical cases (n=21), patients with high SORORIN showed a tendency toward shorter overall 5-year survival than those with low SORORIN, but this was not statistically significant (P=0.1664)
  • In these 21 curative surgical cases, no significant association was found between SORORIN expression and age, gender, pathological stage or histological type
  • BI 6727 significantly reduced growth of NCI-H28 and H2052 cells at concentrations above 10 nM
  • Silencing SORORIN combined with BI 6727 significantly suppressed mesothelioma cell proliferation
• The authors' conclusion: The authors concluded that SORORIN and PLK1 are highly expressed in malignant pleural mesothelioma. They suggested that combination therapy targeting these genes can be a potential new therapeutic strategy for patients with this disease.
• Limitations the authors state:
  • The authors stated that further investigation is needed and recommended evaluating these approaches in xenograft models

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: Pleural Mesothelioma, Asbestos Exposure, Prognosis, Clinical Trial.

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