The expression of FOXP3 and its role in human cancers

Hao, Jia; Qi, Haolong; Gong, Zhongqin; Yang, Shengsheng; Ren, Jianwei; Liu, Yi; Li, Mingyue; Chen, George G

doi:10.1016/j.bbcan.2018.12.004

Cited by 55 publications

(60 citation statements)

References 79 publications

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“…For instance, in colorectal cancer, breast cancer and gastric cancer, C-FOXP3 is a tumor suppressor gene, whereas in NSCLC, esophageal cancer and pancreatic cancer, it is an oncogene contributing to a poor prognosis from the tumor. 32 Therefore, whether the regulatory role of C-FOXP3 on PD-L1 is a ubiquitous mechanism needs to be further determined.…”

Section: Discussionmentioning

confidence: 99%

PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC

Wang

Wei

et al. 2020

Sig Transduct Target Ther

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High expression of PD-L1 marks the poor prognosis of pancreatic ductal adenocarcinomas (PDAC). However, the regulatory mechanism of PD-L1 remains elusive. We recently reported that cancer Forkhead box protein 3 (Cancer-FOXP3 or C-FOXP3) promoted immune evasion of PDAC by recruiting Treg cells into PDAC via upregulation of CCL5. In this study, we confirmed that PD-L1 was overexpressed in PDAC samples from two independent cohorts of patients with radical resection. Moreover, C-FOXP3 was colocalized and correlated with the expression of PD-L1 in tumor cells at the mRNA and protein levels, and this finding was confirmed by the The Cancer Genome Atlas (TCGA) database. Chromatin immunoprecipitation (ChIP) revealed that C-FOXP3 directly bound to the promoter region of PD-L1 in pancreatic cancer cells. Furthermore, overexpression of C-FOXP3 activated the luciferase reporter gene under the control of the PD-L1 promoter. However, mutation of the binding motif-a completely reversed the luciferase activity. In addition, C-FOXP3-induced upregulation of PD-L1 effectively inhibited the activity of CD8 + T cells. Based on our recent finding that the CCL-5 antibody achieved a better response to PDAC models with high C-FOXP3 levels, we further demonstrated that the PD-L1 antibody strengthened the antitumor effect of CCL-5 blockade in xenograft and orthotopic mouse models with high C-FOXP3 levels. In conclusion, C-FOXP3 directly activates PD-L1 and represents a core transcription factor that mediates the immune escape of PDAC. Combined blockade of PD-L1 and CCL-5 may provide an effective therapy for patients with PDAC that have high C-FOXP3 levels.

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Section: Discussionmentioning

confidence: 99%

PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC

Wang

Wei

et al. 2020

Sig Transduct Target Ther

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“…Therefore, the role of FOXP3 + regulatory T cells in the microenvironment of HCC is complicated. In addition to the presence in lymphocytes, there are increasing publications showing the expression of FOXP3 in the cancer cells [12,19]. Here, our data showed that hepatocytes could express FOXP3 and its isoforms but only full-length FOXP3 functioned as a tumor suppressor in HCC.…”

Section: Discussionmentioning

confidence: 49%

FOXP3 inhibits tumor growth and induced apoptosis in hepatocellular carcinoma by targeting c-Myc

Gong

Hao

et al. 2020

Preprint

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Background The status of FOXP3 and its isoforms in hepatocellular carcinoma (HCC) is unclear. We aimed to investigate the expression and function of FOXP3 and its isoforms in HCC. Methods The study was performed on 84 HCC patients, HCC cell lines and a mouse tumor model. The levels of FOXP3 and its isoforms were determined by nested PCR, quantitative real-time PCR and immunohistochemistry (IHC) staining. The correlation between their levels and clinicopathologic characteristics was analyzed. Results The full length of FOXP3 (FOXP3) and exon 3-deleted FOXP3 (FOXP3Δ3) were found to be the major isoforms in HCC. The levels of FOXP3Δ3 mRNA and protein in HCC tumor samples were not significantly different from their adjacent normal tissues. The high expression of FOXP3 protein in HCC patients showed a good overall survival. The overexpression of FOXP3 significantly reduced tumor cell proliferation, migration and invasion. The immunofluorescence result indicated that FOXP3 needed to be translocated into the nucleus to exert its inhibitory function. The luciferase assay demonstrated that FOXP3 could be synergistic with Smad2/3/4 to inhibit the oncogene c-Myc. The co-immunoprecipitation results further revealed that FOXP3 could interact with Smad2/3/4. The chromatin immunoprecipitation (ChIP) assay showed that both FOXP3 and Smad2/3/4 bound the promoter of the c-Myc to inhibit it. The in vivo mouse tumor model study confirmed the inhibitory effect of FOXP3. Conclusion Collectively, the expression of tumor FOXP3 can inhibit the growth of HCC via suppressing c-Myc directly or indirectly via interacting with Smad2/3/4. Therefore, FOXP3 is a tumor suppressor in HCC.

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“…In addition to the presence in lymphocytes, there are increasing publications showing the expression of FOXP3 in the cancer cells 12 , 19 , suggested that FOXP3 has a broader role than initial thoughts. However, the levels and roles of FOXP3 and its isoforms in HCC cells remains largely unknown or/and contradicted.…”

Section: Discussionmentioning

confidence: 99%

“…To better know the exact role of FOXP3 in HCC, we focused on the FOXP3 and its isoforms in HCC. To date, five isoforms of the FOXP3 have been identified in different human cells and tissues 12 . In HCC, the full-length FOXP3 and exon3,4- deleted FOXP3 have been reported 10 .…”

Section: Discussionmentioning

confidence: 99%

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Nuclear FOXP3 inhibits tumor growth and induced apoptosis in hepatocellular carcinoma by targeting c-Myc

Gong

Hao

et al. 2020

Oncogenesis

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The status of FOXP3 and its isoforms in hepatocellular carcinoma (HCC) is unclear. We aimed to investigate the expression and function of FOXP3 and its isoforms in HCC. The study was performed on 84 HCC patients, HCC cell lines and a mouse tumor model. The levels of FOXP3 and its isoforms were determined by nested PCR, quantitative real-time PCR and immunohistochemistry (IHC) staining. The correlation between their levels and clinicopathologic characteristics was analyzed. The full length of FOXP3 (FOXP3) and exon 3-deleted FOXP3 (FOXP3Δ3) were found to be the major isoforms in HCC. The levels of FOXP3Δ3 mRNA and protein in HCC tumor samples were not significantly different from their adjacent normal tissues. The high expression of FOXP3 protein in HCC patients showed a good overall survival. The overexpression of FOXP3 significantly reduced tumor cell proliferation, migration and invasion. The immunofluorescence result indicated that FOXP3 needed to be translocated into the nucleus to exert its inhibitory function. The luciferase assay demonstrated that FOXP3 could be synergistic with Smad2/3/4 to inhibit the oncogene c-Myc. The co-immunoprecipitation results further revealed that FOXP3 could interact with Smad2/3/4. The chromatin immunoprecipitation (ChIP) assay showed that both FOXP3 and Smad2/3/4 bound the promoter of the c-Myc to inhibit it. The in vivo mouse tumor model study confirmed the inhibitory effect of FOXP3. Collectively, the expression of tumor FOXP3 can inhibit the growth of HCC via suppressing c-Myc directly or indirectly via interacting with Smad2/3/4. Therefore, FOXP3 is a tumor suppressor in HCC.

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The expression of FOXP3 and its role in human cancers

Cited by 55 publications

References 79 publications

PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC

PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC

FOXP3 inhibits tumor growth and induced apoptosis in hepatocellular carcinoma by targeting c-Myc

Nuclear FOXP3 inhibits tumor growth and induced apoptosis in hepatocellular carcinoma by targeting c-Myc

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