Inhibition of mesothelin as a novel strategy for targeting cancer cells

Our plain-English summary of Inhibition of mesothelin as a novel strategy for targeting cancer cells, by K. Wang, V. Bodempudi, Z. Liu, et al (PloS One, 2012).

The study

• Authors: K. Wang, V. Bodempudi, Z. Liu, E. Borrego-Diaz, F. Yamoutpoor, A. Meyer, R.A. Woo, W. Pan, A.Z. Dudek, M.S. Olyaee, T. Esfandyari, F. Farassati
• Journal: PloS One
• Published: 2012;7(4):e33214
• Cited by: 45 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelin, a differentiation antigen present in a series of malignancies such as mesothelioma, ovarian, lung and pancreatic cancer, has been studied as a marker for diagnosis and a target for immunotherapy. We, however, were interested in evaluating the effects of direct targeting of Mesothelin on the viability of cancer cells as the first step towards developing a novel therapeutic strategy. We report here that gene specific silencing for Mesothelin by distinct methods (siRNA and microRNA) decreased viability of cancer cells from different origins such as mesothelioma (H2373), ovarian cancer (Skov3 and Ovcar-5) and pancreatic cancer (Miapaca2 and Panc-1). Additionally, the invasiveness of cancer cells was also significantly decreased upon such treatment. We then investigated pro-oncogenic signaling characteristics of cells upon mesothelin-silencing which revealed a significant decrease in phospho-ERK1 and PI3K/AKT activity. The molecular mechanism of reduced invasiveness was connected to the reduced expression of β-Catenin, an important marker of EMT (epithelial-mesenchymal transition). Ero1, a protein involved in clearing unfolded proteins and a member of the ER-Stress (endoplasmic reticulum-stress) pathway was also markedly reduced. Furthermore, Mesothelin silencing caused a significant increase in fraction of cancer cells in S-phase. In next step, treatment of ovarian cancer cells (OVca429) with a lentivirus expressing anti-mesothelin microRNA resulted in significant loss of viability, invasiveness, and morphological alterations. Therefore, we propose the inhibition of Mesothelin as a potential novel strategy for targeting human malignancies.

In plain English

This was a laboratory study of human cancer cell lines. It did not study asbestos exposure or people. The authors used two gene-silencing methods, siRNA and microRNA, to reduce, but not eliminate, mesothelin, a protein found on mesothelioma and some other cancer cells. In H2373 mesothelioma cells, silencing mesothelin cut the cells' growth rate to 40% of that of control-treated cells at 48 hours. Growth later rebounded, which the authors attributed to the siRNA wearing off. Mouse NIH3T3 cells, which lack mesothelin, showed no statistically significant change. Growth also fell in ovarian and pancreatic cancer cell lines. The cells' ability to invade through a gel layer fell in mesothelioma, ovarian and pancreatic cells. In mesothelioma cells, the growth-signaling proteins phospho-ERK1 and phospho-AKT, along with beta-catenin and Ero1, decreased. In Ovca429 ovarian cancer cells, a virus carrying anti-mesothelin microRNA lowered viability by about 50% at day 16 and 60% at day 22, and lowered invasion by close to 40%. The authors proposed inhibiting mesothelin as a potential new strategy for targeting cancer cells.

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 (in vitro) experiments on cultured cancer cell lines
• Who was studied: Human cell lines grown in culture: H2373 mesothelioma cells (obtained from the National Cancer Institute; the article does not say whether pleural or peritoneal); ovarian cancer lines Skov3, Ovcar3, Ovcar5 and Ovca429; and pancreatic cancer lines Miapaca2, Bxpc3 and Panc1. Mouse NIH3T3 cells and Huvec cells, which lack mesothelin, served as comparisons.
• Exposure: No asbestos exposure was studied. Cells were treated to silence the mesothelin gene, either with anti-mesothelin siRNA delivered by electroporation or with anti-mesothelin microRNA (by plasmid or by a lentivirus called MSLNmiR3). Controls received negative-control or scrambled sequences.
• Main results:
  • In H2373 mesothelioma cells, the proliferation rate fell to 40% of that of negative-control-treated cells at 48 hours after anti-mesothelin siRNA. Growth rebounded at later time points.
  • In mouse NIH3T3 cells, which lack mesothelin, the same treatment caused no statistically significant change in viability.
  • In Skov3 ovarian cancer cells, proliferation fell to about 50% of the negative control at day 3 after anti-mesothelin siRNA.
  • Invasiveness in the Boyden chamber test was significantly reduced in H2373 mesothelioma cells. In Skov3 and Bxpc3 cells it fell to less than 20% of the negative control (p less than 0.05).
  • In H2373 mesothelioma cells, silencing mesothelin decreased phospho-ERK1 and phospho-AKT, while phospho-p38 was unchanged. Beta-catenin and Ero1 were also reduced.
  • Silencing mesothelin significantly increased the fraction of cells in S-phase of the cell cycle, by roughly 50%. A symbol before this number was lost in conversion.
  • In Ovca429 ovarian cancer cells, the share of mesothelin-expressing cells was 18% after the anti-mesothelin lentivirus, compared with roughly 77% after the negative control virus. A symbol before the 77% figure was lost in conversion.
  • In Ovca429 cells given the anti-mesothelin lentivirus, viability fell by about 15% at day 6, about 50% at day 16 and 60% at day 22. Invasiveness fell by close to 40%.
• The authors' conclusion: The authors proposed inhibiting mesothelin as a potential novel strategy for targeting human cancers. They reported that animal experiments with the lentivirus were under way.
• Limitations the authors state:
  • The siRNA effect was temporary: growth rebounded as the siRNA cleared from the cells, which the authors attributed to the transient nature of electroporation.
  • The authors said a possible role of mesothelin in cell shape and invasiveness needs more study.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Mesothelioma, Immunotherapy, Ovarian Cancer.

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