Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Ovarian Cancer | Research article

Prognostic implications of forkhead box protein O1 (FOXO1) and paired box 3 (PAX3) in epithelial ovarian cancer

Authors: Gwan Hee Han, Doo Byung Chay, Sanghee Nam, Hanbyoul Cho, Joon-Yong Chung, Jae-Hoon Kim

Published in: BMC Cancer | Issue 1/2019

Login to get access

Abstract

Background

Transcription factors forkhead box protein O1 (FOXO1) and paired box 3 (PAX3) have been reported to play important roles in various cancers. However, their role in epithelial ovarian cancer (EOC) has not been elucidated yet. Therefore, we evaluated the expression and clinical significance of FOXO1 and PAX3 in EOC.

Methods

Immunohistochemical analyses of FOXO1 and PAX3 in 212 EOCs, 57 borderline ovarian tumors, 153 benign epithelial ovarian tumors, and 79 nonadjacent normal epithelial tissues were performed using tissue microarray. Various clinicopathological variables, including the survival of EOC patients, were compared. In addition, the effect of FOXO1 on cell growth was assessed in EOC cell lines.

Results

FOXO1 and PAX3 protein expression levels were significantly higher in EOC tissues than in nonadjacent normal epithelial tissues, benign tissues, and borderline tumors (all p < 0.001). In EOC tissues, FOXO1 expression was positively correlated with PAX3 expression (Spearman’s rho = 0.118, p = 0.149). Multivariate survival analysis revealed that high FOXO1 expression (hazard ratio = 2.77 [95% CI, 1.48–5.18], p = 0.001) could be an independent prognostic factor for overall survival. Most importantly, high expression of both FOXO1 and PAX3 showed a high hazard ratio (4.60 [95% CI, 2.00–10.55], p < 0.001) for overall survival. Also in vitro results demonstrated that knockdown of FOXO1 was associated with decreased cell viability, migration, and colony formation.

Conclusions

This study revealed that high expression of FOXO1/PAX3 is an indicator of poor prognosis in EOC. Our results suggest the promising potential of FOXO1 and PAX3 as prognostic and therapeutic markers. The possible link between biological functions of FOXO1 and PAX3 in EOC warrants further studies.
Literature
1.
2.
3.
Xing YQ, Li A, Yang Y, Li XX, Zhang LN, Guo HC. The regulation of FOXO1 and its role in disease progression. Life Sci. 2018;193:124–31.PubMedCrossRef
4.
Wang Y, Zhou Y, Graves DT. FOXO transcription factors: their clinical significance and regulation. Biomed Res Int. 2014;2014:925350.PubMedPubMedCentral
5.
6.
7.
8.
Schafer BW. Emerging roles for PAX transcription factors in cancer biology. Gen Physiol Biophys. 1998;17(3):211–24.PubMed
9.
10.
Xia L, Huang Q, Nie D, Shi J, Gong M, Wu B, Gong P, Zhao L, Zuo H, Ju S, et al. PAX3 is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. Brain Res. 2013;1521:68–78.PubMedCrossRef
11.
Fang WH, Wang Q, Li HM, Ahmed M, Kumar P, Kumar S. PAX3 in neuroblastoma: oncogenic potential, chemosensitivity and signalling pathways. J Cell Mol Med. 2014;18(1):38–48.PubMedCrossRef
12.
13.
Frascella E, Toffolatti L, Rosolen A. Normal and rearranged PAX3 expression in human rhabdomyosarcoma. Cancer Genet Cytogenet. 1998;102(2):104–9.PubMedCrossRef
14.
Schulte TW, Toretsky JA, Ress E, Helman L, Neckers LM. Expression of PAX3 in Ewing's sarcoma family of tumors. Biochem Mol Med. 1997;60(2):121–6.PubMedCrossRef
15.
Zhang L, Xia L, Zhao L, Chen Z, Shang X, Xin J, Liu M, Guo X, Wu K, Pan Y, et al. Activation of PAX3-MET pathways due to miR-206 loss promotes gastric cancer metastasis. Carcinogenesis. 2015;36(3):390–9.PubMedCrossRef
16.
17.
Zhang B, Gui LS, Zhao XL, Zhu LL, Li QW. FOXO1 is a tumor suppressor in cervical cancer. Genet Mol Res. 2015;14(2):6605–16.PubMedCrossRef
18.
Kojima T, Shimazui T, Horie R, Hinotsu S, Oikawa T, Kawai K, Suzuki H, Meno K, Akaza H, Uchida K. FOXO1 and TCF7L2 genes involved in metastasis and poor prognosis in clear cell renal cell carcinoma. Genes Chromosom Cancer. 2010;49(4):379–89.PubMed
19.
Fendler A, Jung M, Stephan C, Erbersdobler A, Jung K, Yousef GM. The antiapoptotic function of miR-96 in prostate cancer by inhibition of FOXO1. PLoS One. 2013;8(11):e80807.PubMedPubMedCentralCrossRef
20.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.CrossRefPubMed
21.
Coomans de Brachene A, Demoulin JB. FOXO transcription factors in cancer development and therapy. Cell Mol Life Sci. 2016;73(6):1159–72.PubMedCrossRef
22.
Li R, Erdamar S, Dai H, Wheeler TM, Frolov A, Scardino PT, Thompson TC, Ayala GE. Forkhead protein FKHR and its phosphorylated form p-FKHR in human prostate cancer. Hum Pathol. 2007;38(10):1501–7.PubMedPubMedCentralCrossRef
23.
Zhang Y, Jia L, Zhang Y, Ji W, Li H. Higher expression of FOXOs correlates to better prognosis of bladder cancer. Oncotarget. 2017;8(56):96313–22.PubMedPubMedCentral
24.
Goto T, Takano M, Albergaria A, Briese J, Pomeranz KM, Cloke B, Fusi L, Feroze-Zaidi F, Maywald N, Sajin M, et al. Mechanism and functional consequences of loss of FOXO1 expression in endometrioid endometrial cancer cells. Oncogene. 2008;27(1):9–19.PubMedCrossRef
25.
Dansen TB, Burgering BM. Unravelling the tumor-suppressive functions of FOXO proteins. Trends Cell Biol. 2008;18(9):421–9.PubMedCrossRef
26.
Chung SY, Huang WC, Su CW, Lee KW, Chi HC, Lin CT, Chen ST, Huang KM, Tsai MS, Yu HP, et al. FoxO6 and PGC-1alpha form a regulatory loop in myogenic cells. Biosci Rep. 2013;33(3):485-97.
27.
Renault VM, Thekkat PU, Hoang KL, White JL, Brady CA, Kenzelmann Broz D, Venturelli OS, Johnson TM, Oskoui PR, Xuan Z, et al. The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor. Oncogene. 2011;30(29):3207–21.PubMedPubMedCentralCrossRef
28.
Gan B, Lim C, Chu G, Hua S, Ding Z, Collins M, Hu J, Jiang S, Fletcher-Sananikone E, Zhuang L, et al. FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis. Cancer Cell. 2010;18(5):472–84.PubMedPubMedCentralCrossRef
29.
Bouchard C, Lee S, Paulus-Hock V, Loddenkemper C, Eilers M, Schmitt CA. FoxO transcription factors suppress Myc-driven lymphomagenesis via direct activation of Arf. Genes Dev. 2007;21(21):2775–87.PubMedPubMedCentralCrossRef
30.
Habashy HO, Rakha EA, Aleskandarany M, Ahmed MA, Green AR, Ellis IO, Powe DG. FOXO3a nuclear localisation is associated with good prognosis in luminal-like breast cancer. Breast Cancer Res Treat. 2011;129(1):11–21.PubMedCrossRef
31.
Hillion J, Le Coniat M, Jonveaux P, Berger R, Bernard OA. AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily. Blood. 1997;90(9):3714–9.PubMedCrossRef
32.
Kim SY, Yoon J, Ko YS, Chang MS, Park JW, Lee HE, Kim MA, Kim JH, Kim WH, Lee BL. Constitutive phosphorylation of the FOXO1 transcription factor in gastric cancer cells correlates with microvessel area and the expressions of angiogenesis-related molecules. BMC Cancer. 2011;11:264.PubMedPubMedCentralCrossRef
33.
Kim JH, Kim MK, Lee HE, Cho SJ, Cho YJ, Lee BL, Lee HS, Nam SY, Lee JS, Kim WH. Constitutive phosphorylation of the FOXO1A transcription factor as a prognostic variable in gastric cancer. Mod Pathol. 2007;20(8):835–42.PubMedCrossRef
34.
Santamaria CM, Chillon MC, Garcia-Sanz R, Perez C, Caballero MD, Ramos F, de Coca AG, Alonso JM, Giraldo P, Bernal T, et al. High FOXO3a expression is associated with a poorer prognosis in AML with normal cytogenetics. Leuk Res. 2009;33(12):1706–9.PubMedCrossRef
35.
Chen J, Gomes AR, Monteiro LJ, Wong SY, Wu LH, Ng TT, Karadedou CT, Millour J, Ip YC, Cheung YN, et al. Constitutively nuclear FOXO3a localization predicts poor survival and promotes Akt phosphorylation in breast cancer. PLoS One. 2010;5(8):e12293.PubMedPubMedCentralCrossRef
36.
Hagenbuchner J, Rupp M, Salvador C, Meister B, Kiechl-Kohlendorfer U, Muller T, Geiger K, Sergi C, Obexer P, Ausserlechner MJ. Nuclear FOXO3 predicts adverse clinical outcome and promotes tumor angiogenesis in neuroblastoma. Oncotarget. 2016;7(47):77591–606.PubMedPubMedCentralCrossRef
37.
Corno C, Stucchi S, De Cesare M, Carenini N, Stamatakos S, Ciusani E, Minoli L, Scanziani E, Argueta C, Landesman Y, et al. FoxO-1 contributes to the efficacy of the combination of the XPO1 inhibitor selinexor and cisplatin in ovarian carcinoma preclinical models. Biochem Pharmacol. 2018;147:93–103.PubMedCrossRef
38.
Beretta GL, Corno C, Zaffaroni N, Perego P. Role of FoxO Proteins in Cellular Response to Antitumor Agents. Cancers (Basel). 2019;11(1).PubMedCentralCrossRef
39.
Wang Z, Ji G, Wu Q, Feng S, Zhao Y, Cao Z, Tao C. Integrated microarray meta-analysis identifies miRNA-27a as an oncogene in ovarian cancer by inhibiting FOXO1. Life Sci. 2018;210:263–70.PubMedCrossRef
40.
Tenbaum SP, Ordonez-Moran P, Puig I, Chicote I, Arques O, Landolfi S, Fernandez Y, Herance JR, Gispert JD. Mendizabal L et al: beta-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med. 2012;18(6):892–901.PubMedCrossRef
41.
Feng X, Wu Z, Wu Y, Hankey W, Prior TW, Li L, Ganju RK, Shen R, Zou X. Cdc25A regulates matrix metalloprotease 1 through Foxo1 and mediates metastasis of breast cancer cells. Mol Cell Biol. 2011;31(16):3457–71.PubMedPubMedCentralCrossRef
42.
Muratovska A, Zhou C, He S, Goodyer P, Eccles MR. Paired-box genes are frequently expressed in cancer and often required for cancer cell survival. Oncogene. 2003;22(39):7989–97.PubMedCrossRef
43.
Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH, Perry CJ, Cui G, Li MO, Kaech SM. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection. Immunity. 2014;41(5):802–14.PubMedPubMedCentralCrossRef
44.
Xu Y, Shao QS, Yao HB, Jin Y, Ma YY, Jia LH. Overexpression of FOXC1 correlates with poor prognosis in gastric cancer patients. Histopathology. 2014;64(7):963–70.PubMedCrossRef
45.
Kubic JD, Little EC, Kaiser RS, Young KP, Lang D. FOXD3 promotes PAX3 expression in melanoma cells. J Cell Biochem. 2016;117(2):533–41.PubMedCrossRef
46.
Lin A, Piao HL, Zhuang L, Sarbassov dos D, Ma L, Gan B. FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacologic inhibition of the PI3K-AKT pathway. Cancer Res. 2014;74(6):1682–93.PubMedPubMedCentralCrossRef
47.
Chen CC, Jeon SM, Bhaskar PT, Nogueira V, Sundararajan D, Tonic I, Park Y, Hay N. FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev Cell. 2010;18(4):592–604.PubMedPubMedCentralCrossRef
48.
Liu W, Sui F, Liu J, Wang M, Tian S, Ji M, Shi B, Hou P. PAX3 is a novel tumor suppressor by regulating the activities of major signaling pathways and transcription factor FOXO3a in thyroid cancer. Oncotarget. 2016;7(34):54744–57.PubMedPubMedCentral
49.
Kim HJ, Lee SY, Kim CY, Kim YH, Ju W, Kim SC. Subcellular localization of FOXO3a as a potential biomarker of response to combined treatment with inhibitors of PI3K and autophagy in PIK3CA-mutant cancer cells. Oncotarget. 2017;8(4):6608–22.PubMed
Metadata
Title
Prognostic implications of forkhead box protein O1 (FOXO1) and paired box 3 (PAX3) in epithelial ovarian cancer
Authors
Gwan Hee Han
Doo Byung Chay
Sanghee Nam
Hanbyoul Cho
Joon-Yong Chung
Jae-Hoon Kim
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-6406-6

Other articles of this Issue 1/2019

BMC Cancer 1/2019 Go to the issue

Research article

Role of delayed salvage bevacizumab at symptomatic progression of chemorefractory glioblastoma

Study protocol

A randomized phase II study of nutritional and exercise treatment for elderly patients with advanced non-small cell lung or pancreatic cancer: the NEXTAC-TWO study protocol

Research article

LncRNA ENST00000539653 acts as an oncogenic factor via MAPK signalling in papillary thyroid cancer

Research article

Prognostic impact of mRNA levels of LGR5 transcript variants in OSCC patients

Research article

Relative efficacy of interventions in the treatment of second-line non-small cell lung cancer: a systematic review and network meta-analysis

Research article

Radical radiotherapy in patients with cervix uteri carcinoma: experience of Ondokuz Mayis University
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits