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. 2022 Sep 15;22(1):984.
doi: 10.1186/s12885-022-10080-x.

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

Nguyen Truong Duc Hoang #  1 , Ghmkin Hassan #  1 , Tomoya Suehiro  1 , Yuichi Mine  2 , Tohru Matsuki  3 , Makiko Fujii  4
Affiliations

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

Nguyen Truong Duc Hoang et al. BMC Cancer. .

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.

Keywords: BAMBI; CTGF; Malignant mesothelioma; Proliferation; Cell cycle.

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Conflict of interest statement

The authors have no conflict of interest.

Figures

Fig. 1
Fig. 1
Knockdown of CTGF reduces MM cell proliferation rate and suppress the expression of BAMBI. A, Western blots of MM cell lines NCI-H28, MSTO-211H, Y-MESO-8D, Y-MESO-14, Y-MESO-27, NCI-H2052, and NCI-H2452. Antibodies against actin and CTGF were used as the primary antibodies. B, Bar graphs of relative expression levels of CTGF in Y-MESO-14 and Y-MESO-27 cells transfected with a CTGF-targeted siRNA (20 nM) and compared with CTGF levels in non-transfected cells and cells transfect with control siRNA. The blots showing protein levels assessed by western blotting in control cells and cells transfected CTGF-targeted siRNA. C, Graphs of Proliferation rates as measured by viable cell counting assay. D, Graphs of relative mRNA levels and a western blot of BAMBI levels in control cells and cells transfected with CTGF-targeted siRNA. All results are expressed as mean ± SD of three independent experiments (*p < 0.05 vs. control siRNA group by one-way ANOVA with post hoc Bonferroni tests for pair-wise comparisons). Original unprocessed western blots are included in (Supplementary file, original blots)
Fig. 2
Fig. 2
Knockdown of BAMBI suppresses MM cell proliferation and enhances CTGF expression. A, Bar graphs of relative expression levels of BAMBI in Y-MESO-14 and Y-MESO-27 cells transfected with a BAMBI siRNA (20 nM) and compared with BAMBI levels in non-transfected cells and cells transfect with control siRNA. B, Estimated numbers of viable Y-MESO-14 and Y-MESO-27 cells at 0, 24, 48, and 72 h after BAMBI siRNA transfection. C, Representative images of Y-MESO-14 and Y-MESO-27 cell after 72 h of transfection with BAMBI siRNA and control siRNA. Scale bar = 200 μm. D, Graphs of relative mRNA levels and western blots of CTGF levels in control cells and cells transfected BAMBI-targeted siRNA as measured by RT-qPCR and western blotting, respectively. All results are expressed as mean ± SD of three independent experiments (*p < 0.05 vs. control siRNA group by one-way ANOVA with post hoc Bonferroni tests for pair-wise comparisons)
Fig. 3
Fig. 3
Knockdown of CTGF or BAMBI reduces the expression of cell cycle regulators. A, C, E, G, Bar graphs showing relative mRNA levels of cyclin D1, cyclin D3, CDK2, and CDK4 were estimated by RT-qPCR in Y-MESO-14 and Y-MESO-27 cells transfected with BAMBI siRNA (A-D) or CTGF siRNA (E–H) compared with cells transfect control siRNA. Results are expressed as mean ± SD of three independent experiments (*p < 0.05 by two-tailed Student’s t-test). B, D, F, H, Cyclin D1, cyclin D3, CDK2, and CDK4 protein expression by mesothelioma cells following BAMBI or CTGF knockdown. Both cyclin D3 and CDK2 expression levels were reduced by either BAMBI or CTGF knockdown
Fig. 4
Fig. 4
Elevated BAMBI expression predicts shorter overall survival of mesothelioma patients. A, Kaplan–Meier survival plots divided into tertiles were generated by software from the GEPIA webserver using mRNA sequence data from TCGA and GTEX. The samples were split into a high BAMBI expression group (n = 54) and a low BAMBI expression group (n = 29). Log-rank test indicate that overall survival was significantly reduced by high BAMBI expression (p < 0.05)
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