BMP and activin membrane-bound inhibitor regulate connective tissue growth factor controlling mesothelioma cell proliferation

Our plain-English summary of BMP and activin membrane-bound inhibitor regulate connective tissue growth factor controlling mesothelioma cell proliferation, by N.T.D. Hoang, G. Hassan, T. Suehiro, et al (BMC Cancer, 2022).

The study

• Authors: N.T.D. Hoang, G. Hassan, T. Suehiro, Y. Mine, T. Matsuki, M. Fujii
• Journal: BMC Cancer
• Published: 2022;22(1):984
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) is an aggressive mesothelial cell cancer type linked mainly to asbestos inhalation. MM characterizes by rapid progression and resistance to standard therapeutic modalities such as surgery, chemotherapy, and radiotherapy. Our previous studies have suggested that tumor cell-derived connective tissue growth factor (CTGF) regulates the proliferation of MM cells as well as the tumor growth in mouse xenograft models.

Methods: In this study, we knock downed the bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) and CTGF in MM cells and investigated the relationship between both and their impact on the cell cycle and cell proliferation.

Results: The knockdown of CTGF or BAMBI reduced MM cell proliferation. In contrast to CTGF knockdown which decreased BAMBI, knockdown of BAMBI increased CTGF levels. Knockdown of either BAMBI or CTGF reduced expression of the cell cycle regulators; cyclin D3, cyclin-dependent kinase (CDK)2, and CDK4. Further, in silico analysis revealed that higher BAMBI expression was associated with shorter overall survival rates among MM patients.

Conclusions: Our findings suggest that BAMBI is regulated by CTGF promoting mesothelioma growth by driving cell cycle progression. Therefore, the crosstalk between BAMBI and CTGF may be an effective therapeutic target for MM treatment.

© 2022. The Author(s).

In plain English

This was a laboratory study of human mesothelioma cell lines plus a computer analysis of public patient gene data. It did not study asbestos exposure. The authors used small interfering RNA to reduce two proteins, CTGF and BAMBI, and measured cell growth and cell-cycle proteins. Reducing CTGF cut CTGF messenger RNA by more than 75% in all mesothelioma cell lines tested. It also slowed the growth of two lines, Y-MESO-14 and Y-MESO-27, and lowered BAMBI in those two lines and in four of five other lines. Reducing BAMBI also slowed the growth of the two lines. It raised CTGF in Y-MESO-27 but not in Y-MESO-14. Both reductions lowered the cell-cycle proteins cyclin D3 and CDK2 in both lines, and CDK4 in Y-MESO-27. In patient data split into 54 with high and 29 with low BAMBI, the high-BAMBI patients had poorer overall survival (hazard ratio 1.9, p = 0.011). The authors concluded that BAMBI promotes mesothelioma cell growth by acting downstream of CTGF. They stated that the detailed molecular pathways remain unclear.

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 using siRNA knockdown, plus an in silico survival analysis of public gene expression data (GEPIA, using TCGA and GTEx)
• Who was studied: Human malignant mesothelioma cell lines (NCI-H28, NCI-H2052, NCI-H2452, MSTO-211H, Y-MESO-8D, Y-MESO-14, Y-MESO-27) and the SV40-transformed mesothelial cell line MeT-5A. Most experiments used Y-MESO-14 and Y-MESO-27. The survival analysis used mesothelioma patient data split into a high BAMBI group (n = 54) and a low BAMBI group (n = 29).
• Exposure: No asbestos exposure was studied. The experimental treatment was siRNA knockdown of CTGF or BAMBI (20 nM) in cultured cells.
• Main results:
  • CTGF knockdown reduced CTGF mRNA by more than 75% in all examined mesothelioma cell lines
  • CTGF knockdown reduced cell proliferation in Y-MESO-14 and Y-MESO-27 cells compared with control siRNA
  • CTGF knockdown reduced BAMBI expression in Y-MESO-14 and Y-MESO-27 cells and in four of the five other mesothelioma cell lines (not in NCI-H2452)
  • BAMBI knockdown reduced proliferation of Y-MESO-14 and Y-MESO-27 cells
  • BAMBI knockdown increased CTGF mRNA and protein in the Y-MESO-27 cell line
  • The increase in CTGF after BAMBI knockdown was not seen in Y-MESO-14 cells
  • BAMBI knockdown did not change Smad phosphorylation after TGF-beta1 stimulation
  • BAMBI knockdown reduced cyclin D1, cyclin D3 and CDK2 mRNA and protein in Y-MESO-27 and Y-MESO-14 cells
  • BAMBI knockdown reduced CDK4 in Y-MESO-27 cells
  • CTGF knockdown reduced cyclin D3 and CDK2 in Y-MESO-14 and Y-MESO-27 cells, and CDK4 only in Y-MESO-27 cells
  • BAMBI levels were lower in the MeT-5A mesothelial line than in the mesothelioma cell lines
  • In the patient data, those with high BAMBI expression had poorer overall survival than those with low BAMBI expression (hazard ratio 1.9, p = 0.011). The confidence interval values were not printed.
• The authors' conclusion: The authors concluded that BAMBI promotes mesothelioma cell proliferation and tumor aggression by acting downstream of CTGF
• Limitations the authors state:
  • The detailed molecular pathways by which CTGF regulates BAMBI remain unclear
  • The role of TGF-beta/BMP signaling in BAMBI's effect on cell growth needs further study
  • The MeT-5A comparison line is immortalized with SV40, which may alter CTGF regulation compared with normal tissue

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Mesothelial Cells, Chemotherapy, Overall Survival.

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