Research ArticleExperimental Studies

FOXM1 Promotes Mesothelioma Cell Migration and Invasion via Activation of SMAD Signaling

IHIRO ENDO, VISHWA JEET AMATYA, KEI KUSHITANI, TAKAHIRO KAMBARA, TETSUYA NAKAGIRI, KOHEI AOE and YUKIO TAKESHIMA
Anticancer Research September 2023, 43 (9) 3961-3968; DOI: https://doi.org/10.21873/anticanres.16583

Abstract

Background/Aim: Forkhead box M1 (FOXM1) is a transcription factor closely associated with various human malignancies and is considered an attractive target for cancer therapy. Mesothelioma is a malignancy primarily due to asbestos exposure and certain genetic factors, requiring a better understanding of tumorigenesis for improved treatment. Asbestos-exposed human mesothelial cells have been reported to up-regulate FOXM1 expression in a dose-dependent manner. Materials and Methods: FOXM1 expression was evaluated in mesothelioma tissues and cell lines. FOXM1 small interfering RNA was transfected into mesothelioma cell lines to analyze its biological functions and regulatory mechanisms. Results: FOXM1 was over-expressed in mesothelioma tissues and cell lines. Knock-down of FOXM1 in mesothelioma cell lines inhibited cell proliferation, migration, and invasion. These results suggest that up-regulation of FOXM1 expression promotes mesothelioma tumorigenesis and progression. We previously reported that insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) promotes the proliferation, migration, and invasion of mesothelioma cell lines. In this study, IGF2BP3 knock-down suppressed FOXM1 expression in mesothelioma cell lines. Our results suggest that IGF2BP3, an upstream regulator, contributes to increased FOXM1 expression. Furthermore, IGF2BP3 and FOXM1 knock-down suppressed SMAD signaling by inhibiting SMAD2/3 phosphorylation in mesothelioma cell lines. Conclusion: IGF2BP3/FOXM1 promotes mesothelioma cell migration and invasion via SMAD signaling, highlighting IGF2BP3/FOXM1 as a potential target for mesothelioma treatment.

Key Words:

Mesothelioma is a malignant tumor that originates from mesothelial cells that has a complex molecular etiology, resulting in limited therapeutic efficacy (1, 2). Occupational and environmental exposure to asbestos is widely recognized as the primary risk factor for the development of mesothelioma. Additionally, certain high-risk genetic factors can also contribute to an individual’s susceptibility to this cancer (3). Despite global bans on asbestos, the incidence of mesothelioma is expected to rise, especially in developing countries (4). This is because the latency period between asbestos exposure and the incidence of mesothelioma is 40 years (5). Population-based studies have reported that mesothelioma has a poor prognosis, with a five-year survival rate of approximately 5%, highlighting the difficulty in its treatment (6). Therefore, an in-depth understanding of mesothelioma pathogenesis at the molecular level is necessary for its accurate diagnosis, prognostic evaluation, and development of effective treatment strategies (7).

Forkhead box M1 (FOXM1) is a transcription factor involved in several important biological processes, such as cell proliferation, metastasis, and epithelial–mesenchymal transition (EMT), which is considered a potential therapeutic target in various cancers (8, 9). FOXM1 is suggested to be involved in the regulation of gene expression at the transcriptional level by entering the nucleus and binding to the regulatory sites of target genes via its DNA-binding domain (10). FOXM1 over-expression is observed in several human cancers and is closely associated with the poor prognosis (11). FOXM1 over-expression promotes cell proliferation and survival in hepatocellular carcinoma (12), lung cancer (13), and colorectal cancer (14). FOXM1 expression is elevated in mesothelial cells exposed to crocidolite asbestos (15). We previously reported that FOXM1 is a downstream target of plasmacytoma variant translocation 1 (PVT1) in mesothelioma cell lines (16); however, its mechanism of action in mesothelioma remains largely unknown. To the best of our knowledge, this is the first study to focus on the biological functions and regulatory mechanisms of FOXM1 in mesothelioma cell lines and tissues.

A comprehensive understanding of the interaction network between cancer-related genes and FOXM1 in mesothelioma will provide insights into the importance of FOXM1 as a master regulator of mesothelioma progression. Since FOXM1 is targeted by many upstream genes in various human cancers and also acts as a transcription factor for many target genes, it may serve as a central hub for regulating cell proliferation and malignant transformation (8, 17). Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) stabilizes and enhances FOXM1 expression and promotes cell proliferation and migration in lung adenocarcinoma (18). IGF2BP3 is a standard diagnostic marker for distinguishing reactive mesothelial hyperplasia from mesothelioma (19). We recently reported that IGF2BP3 promotes mesothelioma cell proliferation and invasion (20). However, little is known about the interactions between FOXM1 and IGF2BP3 in mesothelioma cells. Therefore, in this study, we aimed to elucidate the regulatory mechanism involved in the IGF2BP3-induced over-expression of FOXM1 in mesothelioma cells.

The SMAD family of intracellular signaling molecules regulates various biological processes, including cell differentiation, angiogenesis, migration, and invasion, which are stimulated by the transforming growth factor-beta (TGF-β) superfamily (21). After stimulation by TGF-β, SMAD2 and SMAD3 are phosphorylated to form a complex with SMAD4, which translocate to the nucleus to regulate gene expression (22). SMAD signaling is involved in the acquisition of malignant phenotypes in several human cancers (23). Activation of SMAD signaling by cancer-related genes promotes cell migration and invasion in the prostate and non-small cell lung cancers (24, 25). Similarly, activation of SMAD signaling may also be involved in carcinogenesis and metastasis in mesothelioma (26, 27).

Here, we analyzed FOXM1 expression in mesothelioma tissues and performed biological functional analysis of mesothelioma cell lines after FOXM1 knock-down. We also investigated the regulatory relationship between FOXM1 and IGF2BP3 in mesothelioma cells. Additionally, we evaluated the effects of IGF2BP3/FOXM1 and the involvement of SMAD signaling in the migration and invasion of mesothelioma cell lines.

Materials and Methods

Mesothelioma cell lines and tissues. The mesothelioma cell line ACC-MESO1 was obtained from the RIKEN BioResource Research Center (Tsukuba, Japan) and CRL-5915 was obtained from the American Type Culture Collection (Manassas, VA, USA). Mesothelioma cells were cultured as described previously (28). Mesothelioma and non-neoplastic pleural tissues were obtained and treated as described previously (28).

Transient transfection of mesothelioma cells. Small interfering RNA (siRNA) was transfected into mesothelioma cells as described previously (28). The following siRNA products were purchased from Thermo Fisher Scientific (Waltham, MA, USA): Silencer Select FOXM1 siRNA (Product ID s5248), Silencer Select IGF2BP3 siRNA (Product ID s20919), and Silencer Select negative control #1 siRNA (NC; Cat# 4390843).

Proliferation assay. The siRNA-transfected mesothelioma cells were cultured in 96-well plates and proliferation assay was performed as previously described (28) using the Cell Titer Glo 2.0 reagent (Promega, Madison, WI, USA). Briefly, proliferation was determined by measuring the level of ATP, which is proportional to the number of cells, every 24 h.

Transwell migration assay. Transwell migration assays were conducted to analyze migration ability, and the specific protocol is described previously (28). Briefly, cells that passed through the 8 μm pores of the culture inserts were stained and then photographed using a fluorescence microscope, and the number of migrated cells was determined using ImageJ software (version 1.53k; Wayne Rasband and contributors, National Institutes of Health, Bethesda, MD, USA).

Transwell invasion assay. Transwell invasion assays were conducted to analyze invasive ability, and the specific protocol is described previously (28). Briefly, cells that passed through the 8 μm pores of the basement membrane extract-coated culture inserts were stained and then photographed using a fluorescence microscope, and the number of invaded cells was determined using ImageJ software (version 1.53k; Wayne Rasband and contributors, National Institutes of Health).

Real-time reverse transcription polymerase chain reaction. siRNAs (25 pmol) were transfected into mesothelioma cells (3×105) in 6-well plates for 72 h. RNA extraction, reverse transcription, and amplification of RNA were performed as described previously (28). The following primer sequences were used in this study:

FOXM1 forward: 5′-GGAGCAGCGACAGGTTAAGG-3′

FOXM1 reverse: 5′-GTTGATGGCGAATTGTATCATGG-3′

GAPDH forward: 5′-ACAACTTTGGTATCGTGGAAGG-3′

GAPDH reverse: 5′-GCCATCACGCCACAGTTTC-3′

Western blotting analysis. siRNAs (25 pmol) were transfected into mesothelioma cells (3×105) in 6-well plates for 72 h. The process from cell lysate preparation to protein detection was performed as previously described (28). The following primary antibodies were used: anti-FOXM1 (1:2,000; rabbit monoclonal; Cat# 20459; Cell Signaling Technology, Danvers, MA, USA), anti-IGF2BP3 (1:2,000; rabbit polyclonal; Cat# 14642-1-AP, Proteintech, Rosemont, IL, USA), anti-Smad2 (1:2,000; rabbit monoclonal; Cat# 5339, Cell Signaling Technology), anti-Smad3 (1:2,000; rabbit monoclonal; Cat# 9523, Cell Signaling Technology), anti-phospho-Smad2 (1:2,000; rabbit monoclonal; Cat# 3108, Cell Signaling Technology), anti-phospho-Smad3 (1:2,000; rabbit monoclonal; Cat# 9520, Cell Signaling Technology), anti-p27 (1:2,000; rabbit monoclonal; Cat# 3686, Cell Signaling Technology) and anti-GAPDH (1:5,000; rabbit monoclonal; Cat# 2118; Cell Signaling Technology) antibodies. Anti-rabbit IgG-HRP antibody (1:2,000; Cat# 7074; Cell Signaling Technology) was used as the secondary antibody.

Statistical analysis. All experiments were conducted in triplicate. Data are presented as mean±standard deviation. An unpaired student’s t-test was used for comparisons between groups. Statistical significance was set at p<0.05.

Ethics approval. Mesothelioma and non-neoplastic pleural tissues were handled in accordance with the Declaration of Helsinki. This study was approved by the Ethical Committee for Epidemiology of Hiroshima University (E-974).

Results

FOXM1 is over-expressed in mesothelioma tissues. FOXM1 over-expression has been reported to promote carcinogenesis and progression in various human cancers. In this study, we investigated FOXM1 expression in mesothelioma and non-neoplastic pleural tissues. FOXM1 expression levels were significantly up-regulated in the four mesothelioma tissues than in the four non-neoplastic pleural tissues (Table I). ΔΔCt analysis revealed that FOXM1 expression was 19.86-fold higher in the mesothelioma tissues than in the non-neoplastic pleural tissues.

View this table:
Table I.

FOXM1 expression in mesothelioma tissues.

FOXM1 knock-down inhibits the proliferation, migration, and invasion of mesothelioma cells. Functional analysis was performed to determine the potential roles of FOXM1 in mesothelioma. In this study, we identified FOXM1 over-expression in mesothelioma cells and investigated the effect of FOXM1 knock-down on biological processes. First, we evaluated the suppression of FOXM1 expression using FOXM1 siRNA. FOXM1 knock-down suppressed FOXM1 mRNA expression by 94.6 and 93.8% and FOXM1 protein expression by 94.2 and 94.4% in ACC-MESO1 and CRL-5915 cells, respectively (Figure 1). Biological functional analysis revealed significant inhibition of cell proliferation, migration, and invasion in mesothelioma cell lines transfected with FOXM1 siRNA (Figure 2). Notably, FOXM1 knock-down significantly suppressed the migration by 55.9 and 56.5% and invasion by 80.3 and 67.2% in ACC-MESO1 and CRL-5915 cells, respectively.

Figure 1.
Figure 1.

Validation of forkhead box M1 (FOXM1) knock-down. Compared to the transfection with the negative control (NC) small interfering RNA (siRNA), transfection with FOXM1 siRNA suppresses FOXM1 expression in mesothelioma cell lines (ACC-MESO1 and CRL- 5915). A) FOXM1 mRNA expression was confirmed using reverse transcription-polymerase chain reaction (RT-PCR). B) FOXM1 protein expression was confirmed using western blotting. NC: Negative control. *p<0.05.

Figure 2.
Figure 2.

Functional analysis of FOXM1. FOXM1 functions as a cancer-promoting factor. A) Proliferation assay. Transfection with FOXM1 siRNA significantly suppressed the mesothelioma cell proliferation compared to the transfection with NC siRNA. The vertical axis of the figure shows the relative luminescence level, which reflects the number of viable cells. Number of viable cells is shown at 0, 24, 48, and 72 h. B) Transwell migration assay. FOXM1 knock-down inhibited mesothelioma cell migration compared to the transfection with NC siRNA. The number of cells that passed through the 8-μm pores in the culture insert was measured 72 h after transfection with FOXM1 or NC siRNA. C) Transwell invasion assay. FOXM1 knock-down inhibited mesothelioma cell invasion compared to the transfection with NC siRNA. The number of cells passing through the 8-μm pores of the Matrigel-coated culture inserts was measured 72 h after transfection with FOXM1 or NC siRNA. NC: Negative control. *p<0.05.

IGF2BP3 knock-down suppresses FOXM1 expression in mesothelioma cells. In our previous study, we observed that IGF2BP3 is over-expressed in mesothelioma and promotes cell proliferation, migration, and invasion (20). In this study, we investigated whether IGF2BP3 had an influence on FOXM1 expression in mesothelioma cells. Results revealed that IGF2BP3 knock-down significantly reduced the FOXM1 mRNA and protein levels in mesothelioma cell lines (Figure 3). Specifically, IGF2BP3 knock-down reduced the FOXM1 mRNA expression by 56.8 and 77.0% in ACC-MESO1 and CRL-5915 cells, respectively. These findings indicate that IGF2BP3 plays a role in promoting FOXM1 over-expression in mesothelioma cells.

Figure 3.
Figure 3.

Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) knock-down suppresses FOXM1 expression. Transfection with IGF2BP3 siRNA significantly suppresses FOXM1 expression in mesothelioma cell lines (ACC-MESO1 and CRL- 5915). A) FOXM1 mRNA expression after transfection with IGF2BP3 siRNA confirmed using RT-PCR. B) FOXM1 protein expression after transfection with IGF2BP3 siRNA confirmed using western blotting. NC: Negative control. *p<0.05.

IGF2BP3 and FOXM1 knock-down inhibits SMAD2/3 phosphorylation in mesothelioma cells. Next, we investigated the effects of IGF2BP3/FOXM1 and the involvement of SMAD signaling in mesothelioma cell migration and invasion. Activation of SMAD signaling promotes cell migration and invasion in various human cancers. Accumulating evidence suggests that FOXM1 activates or stabilizes SMAD signaling. Here, we investigated the extent of SMAD2 and SMAD3 phosphorylation in mesothelioma cell lines induced by IGF2BP3 and FOXM1 knock-down. Phosphorylation of SMAD2 and SMAD3 in mesothelioma cells was suppressed by both IGF2BP3 (Figure 4) and FOXM1 knock-down (Figure 5). Our results indicate that increased expression of IGF2BP3/FOXM1 promotes cell migration and invasion via SMAD signaling in mesothelioma.

Figure 4.
Figure 4.

SMAD activation by IGF2BP3. Transfection with IGF2BP3 siRNA significantly suppresses SMAD2/3 phosphorylation in mesothelioma cell lines (ACC-MESO1 and CRL- 5915), as confirmed using western blotting.

Figure 5.
Figure 5.

SMAD activation by FOXM1. Transfection with FOXM1 siRNA significantly suppresses SMAD2/3 phosphorylation in mesothelioma cell lines (ACC-MESO1 and CRL- 5915), as confirmed using western blotting.

Discussion

Mesothelioma is a malignancy closely associated with asbestos exposure (29). Similar to other malignant tumors, mesothelioma is suggested to be caused by the multistep accumulation of genomic aberrations; however, the specific mechanism remains unclear. Most common inactivating mutations in the tumor suppressor genes CDKN2A, NF2, and BAP1 are involved in the tumorigenesis in mesothelioma (30). While asbestos exposure is a well-established cause of mesothelioma, it is important to note that not all patients with mesothelioma have a history of asbestos exposure (31). Genetic predisposition also plays a significant role in the development of mesothelioma (3). To date, no definitive driver oncogenes have been identified in mesothelioma, resulting in fewer treatment options for mesothelioma than for lung cancer (32, 33). The number of patients with mesothelioma is expected to increase over the next few decades. Being one of the most malignant tumors with the worst prognosis, the development of innovative therapies based on a molecular understanding of the tumor is necessary for mesothelioma treatment.

In this study, we performed a biological functional analysis of FOXM1 using mesothelioma cell lines as well as follow-up experiments to assess the regulatory relationship between FOXM1 and previously reported cancer-related genes. Our results suggest FOXM1 as a potential therapeutic target in mesothelioma. The major oncogenes reported in other cancers cannot be accurately confirmed for mesothelioma due to the lack of studies. FOXM1 is a major tumor-promoting factor in several human organs; its over-expression often implicates the invasive behavior of cancer cells (9, 17). To the best of our knowledge, this study is the first to address the roles of FOXM1 in mesothelioma, providing valuable insights that can serve as a foundation for future FOXM1-related research on mesothelioma.

Here, FOXM1 over-expression was observed in mesothelioma tissues, and FOXM1 knock-down in mesothelioma cell lines suppressed cell proliferation, migration, and invasion. Moreover, the knock-down of IGF2BP3, an oncogene in mesothelioma, suppressed FOXM1 expression and showed the relationship between IGF2BP3 and FOXM1 expression. IGF2BP3 acts as an oncogene in various cancers, such as lung (34), gallbladder (35), colon (36), and ovarian (37) cancers. FOXM1 promotes the proliferation and migration of lung adenocarcinoma cells, while IGF2BP3 stabilizes the FOXM1 mRNA (18). We previously reported that IGF2BP3 knock-down suppresses the proliferation, migration, and invasion of mesothelioma cells, and p27 is a regulatory bottleneck for IGF2BP3 in cell proliferation (20). To investigate the extent of FOXM1’s contribution to the proliferation promoted by IGF2BP3, we examined the expression of p27 in mesothelioma cell lines after FOXM1 knock-down. FOXM1 knock-down increased p27 expression in ACC-MESO1 cells but not significant in CRL-5915 cells, suggesting that FOXM1 partially contributes to IGF2BP3-induced cell proliferation (Figure 6). In this study, the degree of suppression of migration and invasion by FOXM1 knock-down was characteristic, indicating that FOXM1 is a crucial downstream gene involved in the promotion of migration and invasion by IGF2BP3.

Figure 6.
Figure 6.

p27 suppression by FOXM1. Transfection with FOXM1 siRNA increases p27 expression in ACC-MESO1 but not significantly in CRL-5915, as confirmed using western blotting.

Knock-down of IGF2BP3 and FOXM1 suppressed SMAD2/3 phosphorylation in mesothelioma cells suggesting IGF2BP3/FOXM1 promotes the migration and invasion of mesothelioma cells via SMAD signaling. SMAD signaling is involved in various cellular processes, including cell migration and invasion, by regulating the expression of target genes (38). TGF-β/SMAD signaling promotes EMT (39). Although several studies have demonstrated that FOXM1 activates or stabilizes SMAD signaling (40-42), this study is the first to highlight its novelty in mesothelioma. The close association between mesothelioma pathogenesis and asbestos fiber exposure is well-established; reactive oxygen species and cytokine release are associated with unsatisfied phagocytosis of asbestos fibers by macrophages and inflammatory cells, which affects the acquisition of malignant traits by mesothelial cells (2). Asbestos exposure leads to the elevated secretion of TGF-β, and the activation of SMAD signaling, a downstream pathway of TGF-β, contributes to the tumorigenesis and progression of mesothelioma (26, 27). FOXM1 expression also increases with the generation of oxidative free radicals by asbestos exposure in mesothelial cells (15). Therefore, FOXM1 may be a predictive biomarker for mesothelioma.

Conclusion

In conclusion, our study demonstrated the high expression of FOXM1 in mesothelioma and its promoting effects on the proliferation, migration, and invasion of mesothelioma cells. Notably, SMAD signaling was found to be involved in IGF2BP3/FOXM1-induced mesothelioma progression. These findings highlight the potential of targeting IGF2BP3/FOXM1 as a promising approach for the development of effective therapeutic strategies against mesothelioma.

Acknowledgements

The Authors are grateful to Yukari Go and Naomi Fukuhara for their technical assistance and administrative support in this study. The Authors would like to thank Editage (www.editage.com) for English language editing.

Footnotes

  • Authors’ Contributions

    Ihiro Endo designed the study, performed the experiments, analyzed the data, interpreted the results, and prepared the manuscript. Vishwa Jeet Amatya designed and supervised the study and interpreted the results. Yukio Takeshima designed and supervised the study. Kei Kushitani, Takahiro Kambara, Tetsuya Nakagiri, and Kohei Aoe collected the data and samples. All Authors have approved the final manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Funding

    This study received no specific grants from any funding agency in the public, commercial, or not-for-profit sectors.

  • Received June 7, 2023.
  • Revision received July 4, 2023.
  • Accepted July 5, 2023.

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FOXM1 Promotes Mesothelioma Cell Migration and Invasion via Activation of SMAD Signaling
IHIRO ENDO, VISHWA JEET AMATYA, KEI KUSHITANI, TAKAHIRO KAMBARA, TETSUYA NAKAGIRI, KOHEI AOE, YUKIO TAKESHIMA
Anticancer Research Sep 2023, 43 (9) 3961-3968; DOI: 10.21873/anticanres.16583
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