PBK Expression Promotes the Aggressive Phenotypes of Mesothelioma

Our plain-English summary of PBK Expression Promotes the Aggressive Phenotypes of Mesothelioma, by K. Hori, I. Tanaka, T. Sato, et al (Cancer Science, 2025).

The study

• Authors: K. Hori, I. Tanaka, T. Sato, M. Sato, Y. Kodama, H. Itoigawa, Y. Abe, T. Kato, A. Taguchi, M. Sato, Y. Sekido, T.F. Chen-Yoshikawa, M. Ishii
• Journal: Cancer Science
• Published: 2025;116(9):2413-2426
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is one of the most aggressive neoplasms worldwide that has a particularly poor prognosis. We have previously discovered that oxytocin receptors (OXTR) are highly expressed in mesothelioma and that OXTR knockdown significantly decreases the proliferation of mesothelioma cells with high OXTR expression. In this study, we performed quantitative proteomic profiling of two mesothelioma cell lines with high OXTR expression using mass spectrometry to investigate the downstream signals of OXTR in mesothelioma cells. We found that OXTR knockdown significantly downregulated PDZ-binding kinase (PBK)-a serine/threonine protein kinase belonging to the bispecific MAPKK family. PBK knockdown significantly suppressed proliferation, migration, and colony formation in mesothelioma cells with high PBK expression and decreased Akt and MAPK phosphorylation levels. Furthermore, immunohistochemical analysis of PBK in surgical specimens obtained from patients with mesothelioma showed that high PBK expression was strongly associated with poor overall survival (log-rank test p = 0.0031; hazard ratio 3.339 and 95% confidence interval 1.12-10.00) and recurrence-free survival (log-rank test p = 0.0024; hazard ratio 3.355 and 95% confidence interval 1.25-9.04). In addition, the clinical significance of PBK expression was validated in mesothelioma using datasets from TCGA. Multivariable Cox regression analysis, incorporating stage and OXTR mRNA expression, demonstrated that PBK mRNA expression was the strongest independent predictor of OS. Our findings indicate that PBK plays a crucial role in the aggressiveness of mesothelioma, making it a promising therapeutic target and potential prognostic biomarker for mesothelioma.

© 2025 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This laboratory study of mesothelioma cell lines, combined with a retrospective review of patient tumors, examined a protein called PBK. It did not study asbestos exposure. In cell lines, reducing the oxytocin receptor (OXTR) lowered PBK. Reducing PBK slowed growth and colony formation more in two high-PBK lines than in one low-PBK line, and a PBK-blocking drug, OTS-514, showed a similar pattern. Among 23 patients operated on for mesothelioma at Nagoya University Hospital between 2005 and 2019, the 11 with strong PBK staining had a median overall survival of 24.4 months, versus 71.1 months for the 12 with weak staining (hazard ratio 3.339, 95% confidence interval 1.12 to 10.00). The authors also analyzed 85 cases from The Cancer Genome Atlas, adjusting for sex, age, tumor type, stage and OXTR. In these cases, each one-unit increase in PBK mRNA on a log10 scale (a tenfold increase) was associated with a hazard ratio for death of 4.65 (95% confidence interval 1.978 to 10.94). The authors noted the small number of patients. They concluded that PBK is a promising therapeutic target and a potential prognostic biomarker.

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 (cell line) experiments combined with a retrospective analysis of surgical tumor specimens and of a public gene-expression dataset (The Cancer Genome Atlas)
• Who was studied: Three commercial mesothelioma cell lines (NCI-H2052, NCI-H2373, NCI-H2452). Tumor specimens from 23 patients who had extrapleural pneumonectomy or pleurectomy/decortication for mesothelioma at Nagoya University Hospital, Japan, between April 2005 and November 2019 (19 male; mean age 61; 18 epithelioid, 5 biphasic). 87 mesothelioma cases from The Cancer Genome Atlas, 85 of them with survival information.
• Exposure: Not studied. The article does not report asbestos or other exposures of the patients. It studied levels of the proteins PBK and OXTR in mesothelioma cells and tumors.
• Main results:
  • In the two high-OXTR mesothelioma cell lines, reducing OXTR lowered PBK mRNA levels.
  • Reducing PBK inhibited cell growth more in the high-PBK cell lines (NCI-H2052, NCI-H2373) than in the low-PBK line (NCI-H2452).
  • Reducing PBK lowered Akt phosphorylation. The authors did not see a consistent decrease in p38 or ERK phosphorylation in the same cells.
  • The PBK inhibitor OTS-514 inhibited growth at lower concentrations in the high-PBK cell lines, but not in the low-PBK cell line.
  • In the 23 Nagoya surgical patients, median overall survival was 24.4 months in the PBK-strong group (n = 11) versus 71.1 months in the PBK-weak group (n = 12). The log-rank p value was 0.0031 and the hazard ratio was 3.339 (95% CI 1.12 to 10.00).
  • In the same patients, recurrence-free survival was shorter in the PBK-strong group than in the PBK-weak group (hazard ratio 3.355, 95% CI 1.25 to 9.04; log-rank p = 0.0024).
  • In 85 TCGA mesothelioma cases split into four PBK mRNA groups, high PBK mRNA expression was associated with worse overall survival (p less than 0.0001, log-rank test).
  • The TCGA multivariable analysis adjusted for sex, age, histology, stage and OXTR mRNA. In it, PBK mRNA expression was the strongest independent predictor of overall survival. The hazard ratio for death was 4.65 (95% CI 1.978 to 10.94; p less than 0.001) per one-unit increase in log10-transformed PBK mRNA, that is, per tenfold increase.
  • In the TCGA Cox analysis, PBK and OXTR mRNA levels were log10-transformed and entered as continuous variables.
• The authors' conclusion: The authors concluded that PBK is a promising therapeutic target and a potential prognostic biomarker for mesothelioma.
• Limitations the authors state:
  • The number of patients in the tumor-staining analysis was limited because mesothelioma is rare.
  • A proposed mechanism for how OXTR regulates PBK (via the JAK/STAT pathway and FoxM1) was not directly confirmed in mesothelioma.

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, Prognosis, Overall Survival, Hazard Ratio, confidence interval, Recurrence-Free Survival, Biomarker.

Related studies

• Hypoxia promotes acquisition of aggressive phenotypes in human malignant mesothelioma — M.C. Kim, S.H. Hwang, et al. (2018)
• Oxytocin receptor is a promising therapeutic target of malignant mesothelioma — Y. Kodama, I. Tanaka, et al. (2021)
• Group I p21-activated kinases (PAKs) promote tumor cell proliferation and survival through the AKT1 and Raf-MAPK pathways — C.W. Menges, E. Sementino, et al. (2012)
• Activated leukocyte cell-adhesion molecule (ALCAM) promotes malignant phenotypes of malignant mesothelioma — F. Ishiguro, H. Murakami, et al. (2012)
• ACTL6A suppresses p21Cip1 tumor suppressor expression to maintain an aggressive mesothelioma cancer cell phenotype — S. Shrestha, G. Adhikary, et al. (2021)
• Genes associated with prognosis after surgery for malignant pleural mesothelioma promote tumor cell survival in vitro — G.J. Gordon, R. Bueno, et al. (2011)

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