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BMC Cancer
Published in: BMC Cancer 1/2024

Open Access 01-12-2024 | Cholangiocarcinoma | Research

Identification of FOXP1 as a favorable prognostic biomarker and tumor suppressor in intrahepatic cholangiocarcinoma

Authors: Chenwei Tang, Hongkai Zhuang, Huanjun Tong, Xiaopeng Yu, Jialu Chen, Qingbin Wang, Xiaowu Ma, Bingkun Wang, Yonglin Hua, Changzhen Shang, Zhaohui Tang

Published in: BMC Cancer | Issue 1/2024

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Abstract

Background

Forkhead-box protein P1 (FOXP1) has been proposed to have both oncogenic and tumor-suppressive properties, depending on tumor heterogeneity. However, the role of FOXP1 in intrahepatic cholangiocarcinoma (ICC) has not been previously reported.

Methods

Immunohistochemistry was performed to detect FOXP1 expression in ICC and normal liver tissues. The relationship between FOXP1 levels and the clinicopathological characteristics of patients with ICC was evaluated. Finally, in vitro and in vivo experiments were conducted to examine the regulatory role of FOXP1 in ICC cells.

Results

FOXP1 was significantly downregulated in the ICC compared to their peritumoral tissues (p < 0.01). The positive rates of FOXP1 were significantly lower in patients with poor differentiation, lymph node metastasis, invasion into surrounding organs, and advanced stages (p < 0.05). Notably, patients with FOXP1 positivity had better outcomes (overall survival) than those with FOXP1 negativity (p < 0.05), as revealed by Kaplan–Meier survival analysis. Moreover, Cox multivariate analysis showed that negative FOXP1 expression, advanced TNM stages, invasion, and lymph node metastasis were independent prognostic risk factors in patients with ICC. Lastly, overexpression of FOXP1 inhibited the proliferation, migration, and invasion of ICC cells and promoted apoptosis, whereas knockdown of FOXP1 had the opposite role.

Conclusion

Our findings suggest that FOXP1 may serve as a novel outcome predictor for ICC as well as a tumor suppressor that may contribute to cancer treatment.
Appendix
Available only for authorised users
Literature
1.
2.
3.
Zhang H, Yang T, Wu M, Shen F. Intrahepatic cholangiocarcinoma: epidemiology, risk factors, diagnosis and surgical management. Cancer Lett. 2016;379(2):198–205.CrossRefPubMed
4.
Petrick JL, Kelly SP, Altekruse SF, McGlynn KA, Rosenberg PS. Future of hepatocellular carcinoma incidence in the United States forecast through 2030. J Clin Oncol. 2016;34(15):1787–94.CrossRefPubMedPubMedCentral
5.
Mosadeghi S, Liu B, Bhuket T, Wong RJ. Sex-specific and race/ethnicity-specific disparities in cholangiocarcinoma incidence and prevalence in the USA: an updated analysis of the 2000–2011 surveillance, epidemiology and end results registry. Hepatol Res. 2016;46(7):669–77.CrossRefPubMed
6.
7.
Chan KM, Tsai CY, Yeh CN, Yeh TS, Lee WC, Jan YY, Chen MF. Characterization of intrahepatic cholangiocarcinoma after curative resection: outcome, prognostic factor, and recurrence. BMC Gastroenterol. 2018;18(1):180.CrossRefPubMedPubMedCentral
8.
Spolverato G, Kim Y, Alexandrescu S, Marques HP, Lamelas J, Aldrighetti L, Clark Gamblin T, Maithel SK, Pulitano C, Bauer TW, et al. Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma following previous curative-intent surgical resection. Ann Surg Oncol. 2016;23(1):235–43.CrossRefPubMed
9.
Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis. JAMA Surg. 2014;149(6):565–74.CrossRefPubMed
10.
Buttner S, Galjart B, Beumer BR, van Vugt JLA, van Eijck CHJ, Polak WG, de Jonge J, Homs MYV, van Driel L, Pawlik TM, et al. Quality and performance of validated prognostic models for survival after resection of intrahepatic cholangiocarcinoma: a systematic review and meta-analysis. HPB (Oxford). 2021;23(1):25–36.CrossRefPubMed
11.
Miyata T, Yamashita YI, Yoshizumi T, Shiraishi M, Ohta M, Eguchi S, Aishima S, Fujioka H, Baba H. CXCL12 expression in intrahepatic cholangiocarcinoma is associated with metastasis and poor prognosis. Cancer Sci. 2019;110(10):3197–203.CrossRefPubMedPubMedCentral
12.
Katoh M, Igarashi M, Fukuda H, Nakagama H, Katoh M. Cancer genetics and genomics of human FOX family genes. Cancer Lett. 2013;328(2):198–206.CrossRefPubMed
13.
Liu XM, Du SL, Miao R, Wang LF, Zhong JC. Targeting the forkhead box protein P1 pathway as a novel therapeutic approach for cardiovascular diseases. Heart Fail Rev. 2020;27(1):345–55.
14.
Xiao J, He B, Zou Y, Chen X, Lu X, Xie M, Li W, He S, You S, Chen Q. Prognostic value of decreased FOXP1 protein expression in various tumors: a systematic review and meta-analysis. Sci Rep. 2016;6:30437.CrossRefPubMedPubMedCentral
15.
Luo X, Yang Z, Liu X, Liu Z, Miao X, Li D, Zou Q, Yuan Y. The clinicopathological significance of forkhead box P1 and forkhead box O3a in pancreatic ductal adenocarcinomas. Tumour Biol. 2017;39(5):1010428317699129.CrossRefPubMed
16.
He J, Yang Z, Wu Z, Wang L, Xu S, Zou Q, Yuan Y, Li D. Expression of FOXP1 and FOXO3a in extrahepatic cholangiocarcinoma and the implications in clinicopathological significance and prognosis. Onco Targets Ther. 2019;12:2955–65.CrossRefPubMedPubMedCentral
17.
De Smedt L, Palmans S, Govaere O, Moisse M, Boeckx B, De Hertogh G, Prenen H, Van Cutsem E, Tejpar S, Tousseyn T, et al. Expression of FOXP1 and colorectal cancer prognosis. Lab Med. 2015;46(4):299–311.CrossRefPubMed
18.
De Silva P, Garaud S, Solinas C, de Wind A, Van den Eyden G, Jose V, Gu-Trantien C, Migliori E, Boisson A, Naveaux C, et al. FOXP1 negatively regulates tumor infiltrating lymphocyte migration in human breast cancer. EBioMedicine. 2019;39:226–38.CrossRefPubMed
19.
Sheng H, Li X, Xu Y. Knockdown of FOXP1 promotes the development of lung adenocarcinoma. Cancer Biol Ther. 2019;20(4):537–45.CrossRefPubMed
20.
Takayama K, Suzuki T, Tsutsumi S, Fujimura T, Takahashi S, Homma Y, Urano T, Aburatani H, Inoue S. Integrative analysis of FOXP1 function reveals a tumor-suppressive effect in prostate cancer. Mol Endocrinol. 2014;28(12):2012–24.CrossRefPubMedPubMedCentral
21.
Donizy P, Pagacz K, Marczuk J, Fendler W, Maciejczyk A, Halon A, Matkowski R. Upregulation of FOXP1 is a new independent unfavorable prognosticator and a specific predictor of lymphatic dissemination in cutaneous melanoma patients. Onco Targets Ther. 2018;11:1413–22.CrossRefPubMedPubMedCentral
22.
Hu Z, Zhu L, Gao J, Cai M, Tan M, Liu J, Lin B. Expression of FOXP1 in epithelial ovarian cancer (EOC) and its correlation with chemotherapy resistance and prognosis. Tumour Biol. 2015;36(9):7269–75.CrossRefPubMed
23.
Feng J, Zhang X, Zhu H, Wang X, Ni S, Huang J. High expression of FoxP1 is associated with improved survival in patients with non-small cell lung cancer. Am J Clin Pathol. 2012;138(2):230–5.CrossRefPubMed
24.
25.
Xue W, Dong B, Zhao Y, Wang Y, Yang C, Xie Y, Niu Z, Zhu C. Upregulation of TTYH3 promotes epithelial-to-mesenchymal transition through Wnt/beta-catenin signaling and inhibits apoptosis in cholangiocarcinoma. Cell Oncol (Dordr). 2021;44(6):1351–61.CrossRefPubMed
26.
He S, Tang S. WNT/beta-catenin signaling in the development of liver cancers. Biomed Pharmacother. 2020;132:110851.CrossRefPubMed
27.
28.
29.
Kim JH, Hwang J, Jung JH, Lee HJ, Lee DY, Kim SH. Molecular networks of FOXP family: dual biologic functions, interplay with other molecules and clinical implications in cancer progression. Mol Cancer. 2019;18(1):180.CrossRefPubMedPubMedCentral
30.
Katoh M, Katoh M. Human FOX gene family (Review). Int J Oncol. 2004;25(5):1495–500.PubMed
31.
Mizunuma M, Yokoyama Y, Futagami M, Horie K, Watanabe J, Mizunuma H. FOXP1 forkhead transcription factor is associated with the pathogenesis of endometrial cancer. Heliyon. 2016;2(5):e00116.CrossRefPubMedPubMedCentral
32.
Hu Z, Zhu L, Tan M, Cai M, Deng L, Yu G, Liu D, Liu J, Lin B. The expression and correlation between the transcription factor FOXP1 and estrogen receptors in epithelial ovarian cancer. Biochimie. 2015;109:42–8.CrossRefPubMed
33.
Wan L, Huang J, Chen J, Wang R, Dong C, Lu S, Wu X. Expression and significance of FOXP1, HIF-1a and VEGF in renal clear cell carcinoma. J BUON. 2015;20(1):188–95.PubMed
34.
Sun X, Wang J, Huang M, Chen T, Chen J, Zhang F, Zeng H, Xu Z, Ke Y. STAT3 promotes tumour progression in glioma by inducing FOXP1 transcription. J Cell Mol Med. 2018;22(11):5629–38.CrossRefPubMedPubMedCentral
35.
36.
37.
Chen X, Xu J, Bao W, Li H, Wu W, Liu J, Pi J, Tomlinson B, Chan P, Ruan C, et al. Endothelial Foxp1 regulates neointimal hyperplasia via matrix Metalloproteinase-9/Cyclin dependent kinase inhibitor 1B signal pathway. J Am Heart Assoc. 2022;11(15):e026378.CrossRefPubMedPubMedCentral
38.
Feng X, Wang H, Takata H, Day TJ, Willen J, Hu H. Transcription factor Foxp1 exerts essential cell-intrinsic regulation of the quiescence of naive T cells. Nat Immunol. 2011;12(6):544–50.CrossRefPubMedPubMedCentral
39.
Wei H, Geng J, Shi B, Liu Z, Wang YH, Stevens AC, Sprout SL, Yao M, Wang H, Hu H. Cutting edge: Foxp1 controls naive CD8+ T cell quiescence by simultaneously repressing key pathways in cellular metabolism and cell cycle progression. J Immunol. 2016;196(9):3537–41.CrossRefPubMed
40.
Wang A, Wu L, Lin J, Han L, Bian J, Wu Y, Robson SC, Xue L, Ge Y, Sang X, et al. Whole-exome sequencing reveals the origin and evolution of hepato-cholangiocarcinoma. Nat Commun. 2018;9(1):894.CrossRefPubMedPubMedCentral
41.
Guest RV, Boulter L, Kendall TJ, Minnis-Lyons SE, Walker R, Wigmore SJ, Sansom OJ, Forbes SJ. Cell lineage tracing reveals a biliary origin of intrahepatic cholangiocarcinoma. Cancer Res. 2014;74(4):1005–10.CrossRefPubMed
Metadata
Title
Identification of FOXP1 as a favorable prognostic biomarker and tumor suppressor in intrahepatic cholangiocarcinoma
Authors
Chenwei Tang
Hongkai Zhuang
Huanjun Tong
Xiaopeng Yu
Jialu Chen
Qingbin Wang
Xiaowu Ma
Bingkun Wang
Yonglin Hua
Changzhen Shang
Zhaohui Tang
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-024-11882-x

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