FOXO4 and FOXD3 Are Predictive of Prognosis in Gastric Carcinoma Patients

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Mar 31

PMID 27027443

Citations 13

Authors

Jing Li

Zhonghua Jiang

Fang Han

Shenxiang Liu

Xin Yuan

Jiandong Tong

Affiliations

Soon will be listed here.

Abstract

Forkhead box (FOX) transcription factor family plays an important role in cancer growth and metastasis. This study aimed to determine the predictive ability of FOX genes in gastric carcinoma. A total of 360 patients with gastric from The Cancer Genome Atlas (TCGA) cohorts were collected in this study. The expression profile of FOX family were obtained from the TCGA RNAseq database. Clinicopathological characteristics, including age, gender, tumor node metastasis (TNM), tumor grade, and overall survival were collected. Univariate and multivariate Cox proportional hazards model were used to assess the risk factors for survival, and the results were further validated in in-house cohort. In the TCGA cohort, FOXO4 (HR = 0.613, 95%CI 0.452-0.832) and FOXD3 (HR = 1.704, 95%CI 1.212-2.397) were shown independently predictive of overall survival in gastric cancer after Cox proportional hazards analysis. The finding was validated in our in-house cohort, which demonstrated that both FOXO4 and FOXD3 were independent predictors for overall survival (FOXO4 high, HR: 0.445, 95%CI 0.277-0.715, P = 0.001, FOXD3 high, HR: 1.927, 95%CI 1.212-3.063, P = 0.006) and disease free survival (FOXO4 high, HR: 0.628, 95%CI 0.420-0.935, P = 0.022, FOXD3 high, HR: 1.698, 95%CI 1.136-2.540, P = 0.010).Collectively, FOX family paly critical roles in gastric cancer, and FOXO4 and FOXD3 were identified as independent prognostic factors for survival outcomes of gastric cancer. Further functional study is needed to understand more about FOX family in gastric cancer.

Citing Articles

Comprehensive Analyses and Experiments Confirmed IGFBP5 as a Prognostic Predictor Based on an Aging-genomic Landscape Analysis of Ovarian Cancer.

Fan T, Xu L, Zhang H, Peng J, Liu D, Zou W Curr Cancer Drug Targets. 2023; 24(7):760-778.

PMID: 38018207 DOI: 10.2174/0115680096276852231113111412.

The FOXO family of transcription factors: key molecular players in gastric cancer.

Liu Y, Ao X, Jia Y, Li X, Wang Y, Wang J J Mol Med (Berl). 2022; 100(7):997-1015.

PMID: 35680690 DOI: 10.1007/s00109-022-02219-x.

Diverse roles of FOXO family members in gastric cancer.

Chen Y, Li C, Chen W, Liu J, Wu H World J Gastrointest Oncol. 2021; 13(10):1367-1382.

PMID: 34721771 PMC: 8529928. DOI: 10.4251/wjgo.v13.i10.1367.

Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review).

Yang S, Pang L, Dai W, Wu S, Ren T, Duan Y Front Oncol. 2021; 11:667730.

PMID: 34123834 PMC: 8190381. DOI: 10.3389/fonc.2021.667730.

Hypoxia-induced FOXO4/LDHA axis modulates gastric cancer cell glycolysis and progression.

Wang X, Jiang Z, Yang H, Zhang Y, Xu L Clin Transl Med. 2021; 11(1):e279.

PMID: 33463054 PMC: 7809603. DOI: 10.1002/ctm2.279.

References

Sutton J, Costa R, Klug M, Field L, Xu D, Largaespada D . Genesis, a winged helix transcriptional repressor with expression restricted to embryonic stem cells. J Biol Chem. 1996; 271(38):23126-33. DOI: 10.1074/jbc.271.38.23126. View

Chen L, Tang Y, Wang J, Yan Z, Xu R . miR-421 induces cell proliferation and apoptosis resistance in human nasopharyngeal carcinoma via downregulation of FOXO4. Biochem Biophys Res Commun. 2013; 435(4):745-50. DOI: 10.1016/j.bbrc.2013.05.056. View

Myatt S, Lam E . The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 2007; 7(11):847-59. DOI: 10.1038/nrc2223. View

DeGraff D, Clark P, Cates J, Yamashita H, Robinson V, Yu X . Loss of the urothelial differentiation marker FOXA1 is associated with high grade, late stage bladder cancer and increased tumor proliferation. PLoS One. 2012; 7(5):e36669. PMC: 3349679. DOI: 10.1371/journal.pone.0036669. View

Tuteja G, Kaestner K . Forkhead transcription factors II. Cell. 2007; 131(1):192. DOI: 10.1016/j.cell.2007.09.016. View

Su L, Liu X, Chai N, Lv L, Wang R, Li X . The transcription factor FOXO4 is down-regulated and inhibits tumor proliferation and metastasis in gastric cancer. BMC Cancer. 2014; 14:378. PMC: 4063225. DOI: 10.1186/1471-2407-14-378. View

Su B, Gao L, Baranowski C, Gillard B, Wang J, Ransom R . A genome-wide RNAi screen identifies FOXO4 as a metastasis-suppressor through counteracting PI3K/AKT signal pathway in prostate cancer. PLoS One. 2014; 9(7):e101411. PMC: 4077825. DOI: 10.1371/journal.pone.0101411. View

Liu H, Yin J, Wang H, Jiang G, Deng M, Zhang G . FOXO3a modulates WNT/β-catenin signaling and suppresses epithelial-to-mesenchymal transition in prostate cancer cells. Cell Signal. 2015; 27(3):510-8. DOI: 10.1016/j.cellsig.2015.01.001. View

Tran H, Brunet A, Grenier J, Datta S, Fornace Jr A, DiStefano P . DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science. 2002; 296(5567):530-4. DOI: 10.1126/science.1068712. View

10.

Li D, Mei H, Qi M, Yang D, Zhao X, Xiang X . FOXD3 is a novel tumor suppressor that affects growth, invasion, metastasis and angiogenesis of neuroblastoma. Oncotarget. 2013; 4(11):2021-44. PMC: 3875767. DOI: 10.18632/oncotarget.1579. View

11.

Medema R, Kops G, Bos J, Burgering B . AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature. 2000; 404(6779):782-7. DOI: 10.1038/35008115. View

12.

Torre L, Bray F, Siegel R, Ferlay J, Lortet-Tieulent J, Jemal A . Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65(2):87-108. DOI: 10.3322/caac.21262. View

13.

Teng L, Mundell N, Frist A, Wang Q, Labosky P . Requirement for Foxd3 in the maintenance of neural crest progenitors. Development. 2008; 135(9):1615-24. PMC: 2562748. DOI: 10.1242/dev.012179. View

14.

Giraud P, Morvan E, Claude L, Mornex F, Le Pechoux C, Bachaud J . Respiratory gating techniques for optimization of lung cancer radiotherapy. J Thorac Oncol. 2011; 6(12):2058-68. DOI: 10.1097/JTO.0b013e3182307ec2. View

15.

Hu M, Lee D, Xia W, Golfman L, Ou-Yang F, Yang J . IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004; 117(2):225-37. DOI: 10.1016/s0092-8674(04)00302-2. View

16.

Li Q, Wu J, Wei P, Xu Y, Zhuo C, Wang Y . Overexpression of forkhead Box C2 promotes tumor metastasis and indicates poor prognosis in colon cancer via regulating epithelial-mesenchymal transition. Am J Cancer Res. 2015; 5(6):2022-34. PMC: 4529621. View

17.

Hollier B, Tinnirello A, Werden S, Evans K, Taube J, Sarkar T . FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer. Cancer Res. 2013; 73(6):1981-92. PMC: 3602160. DOI: 10.1158/0008-5472.CAN-12-2962. View

18.

Siegel R, Miller K, Jemal A . Cancer statistics, 2015. CA Cancer J Clin. 2015; 65(1):5-29. DOI: 10.3322/caac.21254. View

19.

Tuteja G, Kaestner K . SnapShot: forkhead transcription factors I. Cell. 2007; 130(6):1160. DOI: 10.1016/j.cell.2007.09.005. View

20.

Lupertz R, Chovolou Y, Unfried K, Kampkotter A, Watjen W, Kahl R . The forkhead transcription factor FOXO4 sensitizes cancer cells to doxorubicin-mediated cytotoxicity. Carcinogenesis. 2008; 29(11):2045-52. DOI: 10.1093/carcin/bgn184. View