TGFβ‐induced FOXS1 controls epithelial–mesenchymal transition and predicts a poor prognosis in liver cancer

Bévant, Kevin; Desoteux, Matthis; Angenard, Gaëlle; Pineau, Raphaël; Caruso, Stefano; Louis, Corentin; Papoutsoglou, Panagiotis; Sulpice, Laurent; Gilot, David; Zucman‐Rossi, Jessica; Coulouarn, Cédric

doi:10.1002/hep4.1866

Cited by 12 publications

(22 citation statements)

References 45 publications

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“…Like alpha-fetoprotein (AFP) in HCC, FOXS1 may have the oncofetal expression pattern: a peculiar gene highly expressed in embryonic tissues and silenced in normal adult cells but reactivated in tumors. 31 , 32 This view has been confirmed in our study as the FOXS1 promoter methylation level was negatively correlated with its transcription in most cancer types. A high FOXS1 promoter methylation level can serve as a prognostic biomarker.…”

Section: Discussionsupporting

confidence: 84%

Pan-Cancer Analysis Predicts FOXS1 as a Key Target in Prognosis and Tumor Immunotherapy

Liu¹,

Tu²,

Wang³

2022

IJGM

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Purpose Only a few studies have reported the role of FOXS1, a transcriptional factor, in the tumor development process. In this article, we investigate the function of FOXS1 in distinct neoplastic development and the tumor immune microenvironment (TIME). Patients and Methods The latent roles of FOXS1 in various tumors were prospected based on TCGA, GTEx, CCLE, GEPIA2, cBioPortal, TIMER, ImmuCellAI databases, GSVA datasets, GSEA datasets, and R packages. The expression difference, gene alteration, clinical characteristics, prognostic values, biological mechanism, potential pathways, tumor microenvironment, and immune cell infiltration related to FOXS1 were appraised. Results FOXS1 was strongly expressed in pan-cancer, and this gene was associated with low survival rates. FOXS1 was linked to many pathways that are cancer-promoting and immune-related. The expression of this transcriptional factor in cancers was positively related to immune cell infiltration, especially M2-like macrophages and Treg cells. In addition to that, FOXS1 demonstrated a positive relationship with many immune-suppression genes, such as TGFB1 and ARORA2A . Conclusion Our study identified an oncogenic effect of FOXS1, which may play a vital role as a prognosticative biological marker in pan-cancer. Exorbitant expression of FOXS1 is associated with high TAMs and Treg cells infiltration. These cells have an immunosuppressive function and promote the development of the immunosuppressive tumor microenvironment. The research of FOXS1 provided a potential drug target for tumor immunotherapy.

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Section: Discussionsupporting

confidence: 84%

Pan-Cancer Analysis Predicts FOXS1 as a Key Target in Prognosis and Tumor Immunotherapy

Liu¹,

Tu²,

Wang³

2022

IJGM

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“…The role of FOXS1 in the development and progression of human cancers is largely unknown. There are only a few studies that have reported that FOXS1 was involved in the regulation of cancer cell biology in gastric cancer ( 24 , 25 ), hepatocellular carcinoma ( 26 , 27 ), and glioma cells ( 28 ). Nevertheless, the role of FOXS1 in cancer remains controversial according to the results from these studies.…”

Section: Discussionmentioning

confidence: 99%

“…A high expression of FOXS1 predicted a poor prognosis in liver cancer. In addition, overexpression of FOXS1 induced EMT markers and promoted cell migration and metastasis in liver cancer ( 26 ). On the contrary, Lei et al.…”

Section: Discussionmentioning

confidence: 99%

“…In liver cancer, Bévant et al. showed that FOXS1 evidently promoted EMT in PLC/PRF/5 ( 26 ), while Lei et al. demonstrated that FOXS1 suppressed EMT in Huh7 and Hep3B cell lines ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of FOXS1 promoted cell proliferation and EMT in gastric cancer ( 24 ). Moreover, FOXS1 induced by TGFβ promoted a classical model of EMT by activating the expression of EMT-transcription factors (SNAI1, and SNAI2) in hepatocellular carcinoma ( 26 ). As compared with the role of FOXS1 in EMT, the function of FOXS1 tumor angiogenesis is rarely known.…”

Section: Discussionmentioning

confidence: 99%

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FOXS1 Promotes Tumor Progression by Upregulating CXCL8 in Colorectal Cancer

Qiu

et al. 2022

Front. Oncol.

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BackgroundForkhead box S1 (FOXS1) is a member of the forkhead box (FOX) transcriptional factor superfamily. The biological roles and underlying regulatory mechanism of FOXS1 in CRC remain unclear.MethodsBioinformatics analysis, Western blotting, real-time PCR, and immunohistochemistry (IHC) were used to detect the expression FOXS1 in CRC. MTT assay, transwell assay, human umbilical vein endothelial cell tube formation assay, and chicken chorioallantoic membrane assay were performed to investigate the effects of FOXS1 on proliferation, invasion, and angiogenesis. Additionally, tumor formation assay and orthotopic implantation assay were used to investigate the effects of FOXS1 on tumor growth and metastasis in vivo. Furthermore, gene set enrichment analysis (GSEA) was used to analyze the correlation between FOXS1 and EMT or angiogenesis. The correlation between FOXS1 and CXCL8 expression was analyzed in clinical CRC samples using IHC.ResultsThe results showed that FOXS1 expression was upregulated in CRC tissues compared with adjacent normal intestine tissues. A high FOXS1 expression is positively correlated with poor survival. FOXS1 promoted the malignant behavior of CRC cancer cells in vitro, including proliferation, invasion, and angiogenesis. In addition, FOXS1 promoted tumor growth and metastasis in nude mice. Mechanistically, FOXS1 upregulated the expression of C–X–C motif chemokine ligand 8 (CXCL8) at the transcriptional level. Knockdown of CXCL8 blocked FOXS1 induced the enhancement of the EMT and angiogenesis. GSEAs in public CRC datasets revealed strong correlations between FOXS1 expression and EMT marker and angiogenesis markers. IHC showed that FOXS1 expression was positively correlated with CXCL8 expression and CD31 expression in clinical CRC samples.ConclusionThe results suggest that FOXS1 promotes angiogenesis and metastasis by upregulating CXCL8 in CRC. Interference with the FOXS1/CXCL8 axis may serve as a potential therapeutic target for the treatment of metastatic CRC.

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Transcriptomic evidence for tumor‐specific beneficial or adverse effects of TGFβ pathway inhibition on the prognosis of patients with liver cancer

et al. 2023

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Therapeutic targeting of the transforming growth factor beta (TGFβ) pathway in cancer represents a clinical challenge since TGFβ exhibits either tumor suppressive or tumor promoting properties, depending on the tumor stage. Thus, treatment with galunisertib, a small molecule inhibitor of TGFβ receptor type 1, demonstrated clinical benefits only in subsets of patients. Due to the functional duality of TGFβ in cancer, one can hypothesize that inhibiting this pathway could result in beneficial or adverse effects depending on tumor subtypes. Here, we report distinct gene expression signatures in response to galunisertib in PLC/PRF/5 and SNU‐449, two cell lines that recapitulate human hepatocellular carcinoma (HCC) with good and poor prognosis, respectively. More importantly, integrative transcriptomics using independent cohorts of patients with HCC demonstrates that galunisertib‐induced transcriptional reprogramming in SNU‐449 is associated with human HCC with a better clinical outcome (i.e., increased overall survival), while galunisertib‐induced transcriptional reprogramming in PLC/PRF/5 is associated with human HCC with a worse clinical outcome (i.e., reduced overall survival), demonstrating that galunisertib could indeed be beneficial or detrimental depending on HCC subtypes. Collectively, our study highlights the importance of patient selection to demonstrate a clinical benefit of TGFβ pathway inhibition and identifies Serpin Family F Member 2 (SERPINF2) as a putative companion biomarker for galunisertib in HCC.

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TGFβ‐induced FOXS1 controls epithelial–mesenchymal transition and predicts a poor prognosis in liver cancer

Cited by 12 publications

References 45 publications

Pan-Cancer Analysis Predicts FOXS1 as a Key Target in Prognosis and Tumor Immunotherapy

Pan-Cancer Analysis Predicts FOXS1 as a Key Target in Prognosis and Tumor Immunotherapy

FOXS1 Promotes Tumor Progression by Upregulating CXCL8 in Colorectal Cancer

Transcriptomic evidence for tumor‐specific beneficial or adverse effects of TGFβ pathway inhibition on the prognosis of patients with liver cancer

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