Journal of Cancer Research and Treatment
ISSN (Print): 2374-1996 ISSN (Online): 2374-2003 Website: Editor-in-chief: Jean Rommelaere
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Journal of Cancer Research and Treatment. 2016, 4(1), 1-8
DOI: 10.12691/jcrt-4-1-1
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FOXO1 Downregulation Correlates with Progression of Esophageal Intraepithelial Neoplasia

Yomna A. Zamzam1, and Aymen M. El-Saka2

1Department of Pathology, Faculty of Medicine, Tanta University, Egypt, Post doctor fellow, Otago University, Wellington, New Zealand

2Department of Pathology, Faculty of Medicine, Tanta University, Egypt

Pub. Date: January 13, 2016

Cite this paper:
Yomna A. Zamzam and Aymen M. El-Saka. FOXO1 Downregulation Correlates with Progression of Esophageal Intraepithelial Neoplasia. Journal of Cancer Research and Treatment. 2016; 4(1):1-8. doi: 10.12691/jcrt-4-1-1


Background: Forkhead transcription protein 1 (FOXO1) is an important transcriptional regulator of cell proliferation and is considered essential for tumor growth and progression. However, the function of FOXO1 in esophageal cancer remains unclear. Esophageal squamous intraepithelial neoplasia (ESIN) has been widely recognized as a precursor lesion for esophageal squamous cell carcinoma (ESCC). Early detection offers the best prognosis for esophageal squamous cell carcinoma. The differentiation of squamous dysplasia from reactive change and the classification of ESIN into high-grade (HGIEN) or low-grade (LGIEN) are sometimes subjective and challenging. In this study, we sought to evaluate the FOXO1 expression in endoscopically biopsied esophageal cases and compare its expression with those of p AKT1, Ki67 and p53 to detect where is the lesion stand in the scale from normal mucosa to HGIEN in order not to miss prone cancer cases. Methodology and results: Immunohistochemical staining was performed on 99 formalin-fixed, paraffin embedded blocks of endoscopic esophageal samples. Out of them, 44 samples were ESIN and 33 samples were ESCC, further, for comparison, 22 samples of reactive hyperplastic, non-dysplastic esophageal mucosa. The current study showed a significant stepwise decrease in the FOXO1 expression as well as increased expression of p AKT1, ki67 and P53 from the progression of LGIEN to HGIEN to ESCC. HGIEN and ESCC strongly associated with low FOXO1 expression. On the other hand, higher expression of p AKT1, ki67 and p53 was more associated with HGIEN and ESCC (all are P: 0.001). Conclusions: This study demonstrated stepwise under-expression of FOXO1 in the progression of esophageal squamous carcinogenesis so that immunohistochemical assessment of this marker might provide a useful adjunct tool for differential diagnosis between LGIEN and HGIEN as well as could be used in targeting therapy.

Forkhead transcription protein 1 _ Esophageal Squamous intraepithelial neoplasia _ Esophageal squamous cell carcinoma_p AKT1_ Ki67_ P53

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[1]  Sano A, Kato H, Sakurai S, Sakai M, Tanaka N, Inose T, et al. CD24 expression is a novel prognostic factor in esophageal squamous cell carcinoma. Ann Surg Oncol. 2009; 16:506-514.
[2]  Wang WC, Wu TT, Chandan VS, Lohse CM, Zhang L. Ki-67 and ProExC are useful immunohistochemical markers in esophageal squamous intraepithelial neoplasia. Hum Pathol. 2011; 42(10):1430-7.
[3]  Takubo K, Aida J, Sawabe M, Kurosumi, M, Arima, M, Fujishiro, M, et al. Early squamous cell carcinoma of the oesophagus: the Japanese viewpoint. Histopathology. 2007; 51:733-42.
[4]  Christein JD, Hollinger EF, Millikan KW: Prognostic factors associated with resectable carcinoma of the esophagus. Am Surg. 2002; 68:258-262.
[5]  Ciocirlan M, Lapalus MG, Hervieu V, Souquet JC, Napoléon B, Scoazec JY, et al. Endoscopic mucosal resection for squamous premalignant and early malignant lesions of the esophagus. Endoscopy. 2007 Jan; 39(1):24-9.
[6]  Muto M, Minashi K, Yan T. Early detection of superficial squamous cell carcinoma in the head and neck region and esophagus by narrow band imaging: a multicenter randomized controlled trial. J Clin Oncol. 2010; 28:1566-72.
[7]  Guttilla IK, White BA. Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells. J. Biol. Chem. 2009; 284: 23204-23216.
[8]  Alikhani M, Alikhani Z, Graves DT. FOXO1 functions as a master switch that regulates gene expression necessary for tumor necrosis factor-induced fibroblast apoptosis. J. Biol. Chem. 2005; 80: 12096-12102.
[9]  Arden KC. Multiple roles of FOXO transcription factors in mammalian cells point to multiple roles in cancer.2006; Exp. Gerontol. 41: 709-717.
[10]  Furuyama T, Kitayama K, Shimoda Y, Ogawa M. Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. J. Biol. Chem. 2004; 279: 34741-34749.
[11]  Gilley J, Coffer PJ, Ham J. FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J. Cell Biol. 2003; 162: 613-622.
[12]  Goto T, Takano M, Albergaria A, Briese J. Mechanism and function consequences of loss of FOXO1 expression in endometrioid endometrial cancer cells. Oncogene. 2008; 27: 9-19.
[13]  Nakanishi K, Sakamoto M, Yasuda J, Takamura M, Fujita N, Tsuruo T. Critical involvement of the phosphatidylinositol 3-kinase/ Akt pathway in anchorage-independent growth and hematogeneous intrahepatic metastasis of liver cancer. Cancer Res. 2002; 62:2971-5.
[14]  Woodgett JR. Recent advances in the protein kinase B signaling pathway. Curr Opin Cell Biol 2005;17:150-7
[15]  Dillon RL, Marcotte R, Hennessy BT, Woodgett JR, Mills GB, Muller WJ. Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression. Cancer Res. 2009; 69:5057-64.
[16]  Brunet A, Bonni A, Zigmond MJ. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell. 1999; 96:857-68.
[17]  Chadha KS, Khoury T, Yu J, Black JD, Gibbs JF, Kuvshinoff BW. Activated Akt and Erk Expression and Survival After Surgery in Pancreatic Carcinoma. Ann Surg Oncol. 2006; 13:933-9.
[18]  Sheng S, Qiao M, Pardee AB. Metastasis and AKT activation. J Cell Physiol. 2009; 218:451-4.
[19]  Gabbert HE, Shimoda T, Hainaut P, Nakamura Y, Field JK, Inoue H. Squamous cell carcinoma of the oesophagus. In: Hamilton SR, Aaltonen LA, editors. World Health Organization classification of tumours. Pathology and genetics. Tumours of the digestive system. Lyon: IARC Press; 2000. p. 8-19.
[20]  Li J, Yang L, Song L, Xiong H, Wang L, Yan X, et al. Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1. Oncogene. 2009 Sep 10; 28(36):3188-96.
[21]  Zhu Z, Yu W, Fu X, Sun M, Wei Q, Li D, et al. Phosphorylated AKT1 is associated with poor prognosis in esophageal squamous cell carcinoma. Journal of Experimental & Clinical Cancer Research.2015; 34(1), 95.
[22]  Xue LY, Hu N, Song YM, Zou SM, Shou JZ, Qian LX, et al. Tissue microarray analysis reveals a tight correlation between protein expression pattern and progression of esophageal squamous cell carcinoma. BMC Cancer. 2006, 6:296.
[23]  Wang GQ, Abnet CC, Shen Q, Lewin KJ, Sun XD, Roth MJ, et al. Histological precursors of oesophageal squamous cell carcinoma: results from a 13 year prospective follow up study in a high risk population. Gut. 2005; 54: 187-92.
[24]  Geddert H, Kiel S, Heep HJ, Gabbert HE, Sarbia M. The role of p63 and deltaNp63 (p40) protein expression and gene amplification in esophageal carcinogenesis. Hum Pathol. 2003; 34:850-6.
[25]  Nakayama H, Mitomi H, Imamhasan A, Uchida S, Tomita N, Kajiyama Y, et al. Stepwise overexpression of p63, p53, and cytokeratin 14 during progression of esophageal squamous intraepithelial neoplasia: useful immunohistochemical markers for differential diagnosis. Esophagus. 2012; 9: 1-8.
[26]  Takashima M, Kawachi H, Yamaguchi T, Nakajima Y, Kitagaki K, Sekine M, et al. Reduced expression of cytokeratin 4 and 13 is a valuable marker for histologic grading of esophageal squamous intraepithelial neoplasia. J Med Dent Sci. 2012 Mar 13; 59(1):17-28.
[27]  Jackson JG, Kreisberg JI, Koterba AP, Yee D, et al. Phosphorylation and nuclear exclusion of forkhead transcription factor FKHR after epidermal growth factor treatment in human breast cancer cells. Oncogene. 2000; 19: 4574-4581.
[28]  Quinn MA, Benedet JL, Odicino F, Maisonneuve P. Carcinoma of the cervix uteri. Int. J. Gyneeol Obstet. 2006; 95: 43-103.
[29]  Zhang B, Gui LS, Zhao XL, Zhu LL, Li QW. FOXO1 is a tumor suppressor in cervical cancer. Genet Mol Res. 2015 Jun 18; 14(2):6605-16.
[30]  Maekawa T, Maniwa Y, Doi T, Nishio W, Yoshimura M, Ohbayashi C, et al. Expression and localization of FOXO1 in non-small cell lung cancer. Oncol Rep. 2009 Jul; 22(1):57-64.
[31]  Kreisberg JI, Malik SN, Prihoda TJ, Bedolla RG, Troyer DA, Kreisberg S, et al. Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res. 2004; 64:5232-6.
[32]  Dai DL, Martinka M, Li G. Prognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases. J Clin Oncol. 2005; 23:1473-82.
[33]  Riemenschneider MJ, Betensky RA, Pasedag SM. AKT activation in human glioblastomas enhances proliferation via TSC1 and S6 kinase signaling. Cancer Res. 2006; 66: 5618-5623.
[34]  Han S, Khuri FR, Roman J. Fibronectin stimulates non-small cell lung cancinoma cell growth through activation of Akt/mammalian target of rapamycin/S6 kinase and inactivation of LKB1/AMP-activated protein kinase signal pathways. Cancer Res. 2006; 66: 315-323.
[35]  Maroulakou IG, Oemler W, Naber SP, Tsichlis PN. Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)- ErbB2/neu and MMTV-polyoma middle T transgenic mice. Cancer Res. 2007; 67:167-77.
[36]  Taniere P, Martel-Planche G, Saurin JC, Lombard-Bohas C, Berger F, Scoazec JY, et al. TP53 mutations, amplification of P63 and expression of cell cycle proteins in squamous cell carcinoma of the oesophagus from a low incidence area in Western Europe. Br J Cancer. 2001; 85:721-6.
[37]  Parenti AR, Rugge M, Frizzera E, Ruol A, Noventa F, Ancona E, et al. p53 overexpression in the multistep process of esophageal carcinogenesis. Am J Surg Pathol. 1995; 19:1418-22.
[38]  Walts AE, Bose S. p16, Ki-67, and BD ProExC immunostaining: a practical approach for diagnosis of cervical intraepithelial neoplasia. Hum Pathol. 2009; 40:957-64.