Hyaluronic acid enhances cell migration and invasion via the YAP1/TAZ-RHAMM axis in malignant pleural mesothelioma

Our plain-English summary of Hyaluronic acid enhances cell migration and invasion via the YAP1/TAZ-RHAMM axis in malignant pleural mesothelioma, by W. Shigeeda, M. Shibazaki, S. Yasuhira, et al (Oncotarget, 2017).

The study

• Authors: W. Shigeeda, M. Shibazaki, S. Yasuhira, T. Masuda, T. Tanita, Y. Kaneko, T. Sato, Y. Sekido, C. Maesawa
• Journal: Oncotarget
• Published: 2017;8(55):93729-93740
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Most malignant mesotheliomas (MPMs) frequently show activated forms of Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ), which transcriptionally regulates the receptor for hyaluronic acid-mediated motility (RHAMM). As RHAMM is involved in cell migration and invasion in various tumors, we speculated that hyaluronic acid (HA) in pleural fluid might affect the progression of mesothelioma by stimulating cell migration and invasion through RHAMM. The level of RHAMM expression was decreased by YAP1/TAZ knockdown, and conversely increased by forced expression of the active form of YAP1, suggesting that RHAMM was regulated by YAP1/TAZ in MPM cells. Cell migration and invasion were also decreased by YAP1/TAZ or RHAMM knockdown. Notably, HA treatment increased cell motility and invasion, and this was abolished by RHAMM knockdown, suggesting that HA may augment local progression of MPM cells via RHAMM. Furthermore, treatment with fluvastatin, which regulates RHAMM transcription by modulating YAP1/TAZ activity, decreased the motility and invasion of MPM cells. Collectively, these data suggest that HA is an "unfavorable" factor because it promotes malignancy in mesothelioma and that the YAP1/TAZ-RHAMM axis may have potential value as a therapeutic target for inhibition of disease progression in MPM.

In plain English

This was a laboratory study of human malignant pleural mesothelioma (MPM) cell lines in Japan. Its experiments did not examine asbestos exposure, which appears only as background in the introduction. The authors tested whether hyaluronic acid (HA), found at high levels in MPM patients' pleural fluid, affects how mesothelioma cells move (migration) and invade surrounding material. After profiling five cell lines, they focused on three. Lowering YAP1 and TAZ together cut levels of RHAMM, an HA receptor, by over 90%. Lowering YAP1, TAZ or RHAMM reduced cell migration, and invasion tended to fall. RHAMM knockdown also suppressed invasion, most clearly in Y-MESO-27 (a 74% decrease). Adding HA to the cells increased migration in all three lines and invasion in two. Blocking RHAMM reduced the HA-driven rise in migration. The cholesterol drug fluvastatin reduced migration in all three lines and invasion in two. The discussion also reports, from a supplementary figure not included here, that MPM patients with higher RHAMM expression had significantly worse prognosis. The authors concluded that their results support the possibility that inhibiting YAP1/TAZ or RHAMM may offer a new way to slow MPM progression.

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) study of human malignant pleural mesothelioma cell lines grown in culture. Experiments were repeated three independent times. The discussion also cites a patient-prognosis analysis shown only in a supplementary figure.
• Who was studied: Five human MPM cell lines (ACC-MESO-4, NCI-H28, Y-MESO-12, Y-MESO-27, Y-MESO-30) were profiled. Three were selected for most experiments: ACC-MESO-4 and NCI-H28 (normal LATS2 gene) and Y-MESO-27 (LATS2 deletion).
• Exposure: No asbestos exposure was studied. Cells were treated with hyaluronic acid (100 μg/ml) and with fluvastatin (up to 0.6 μM). YAP1, TAZ and RHAMM were reduced using small interfering RNA (siRNA) knockdown.
• Main results:
  • In all of the cell lines tested, knocking down YAP1 and TAZ together decreased RHAMM protein by over 90%.
  • Forcing expression of a hyperactive form of YAP1 (YAP1-5SA) increased RHAMM mRNA in the MPM cell lines.
  • Knocking down YAP1 or TAZ alone significantly decreased cell migration in all cell lines tested.
  • Invasion tended to decrease with YAP1, TAZ or combined knockdown. RHAMM knockdown also suppressed invasion, with the most apparent effect in Y-MESO-27 (a 74% decrease).
  • Added HA significantly increased cell migration in all three cell lines. It significantly increased invasion in ACC-MESO-4 and Y-MESO-27.
  • RHAMM knockdown significantly reduced the HA-induced increase in migration in all cell lines tested. The same trend was seen for invasion in Y-MESO-27.
  • Fluvastatin at 0.6 μM significantly decreased cell migration in all three cell lines. It reduced invasion in all except NCI-H28.
  • In HA-treated cells, fluvastatin significantly decreased migration in all three cell lines and decreased invasion in Y-MESO-27.
  • In the discussion, citing a supplementary figure, the authors report that MPM patients with higher RHAMM expression had a significantly worse prognosis than patients with low expression.
• The authors' conclusion: The authors concluded that their results and available data support the possibility that reducing or inhibiting YAP1/TAZ or RHAMM may provide a new avenue of treatment to inhibit progression of MPM. They also suggested that HA in the pleural effusion of MPM patients may promote malignancy through RHAMM.

Topics

Medical terms in this study, explained in our Lexicon: Hyaluronic Acid, Pleural Mesothelioma, Mesothelioma, Disease Progression.

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