Copy number loss of FBXW7 is related to gene expression and poor prognosis in esophageal squamous cell carcinoma

Abstract

Abstract. FBXW7 is a tumor suppressor gene that plays a role in cell cycle regulation via Myc degradation. However, the clinical significance of FBXW7 in esophageal squamous cell carcinoma (ESCC) has not been evaluated. The purpose of this study was to assess the clinical significance of FBXW7 for prognosis in human ESCC. Real-time RT-PCR was used to examine the expression of FBXW7 to determine its clinicopathological significance in 75 cases of ESCC. Overall survival rate was calculated using the Kaplan-Meier method, while multivariate survival was analyzed with the Cox hazard model. FBXW7 suppression analysis was performed to examine proliferation potency and Myc expression in the FBXW7 siRNA groups. The relationship between FBXW7 expression and the copy number loss of FBXW7 was examined in clinical samples of ESCC. Finally, FBXW7 copy number loss was linked to prognosis in 42 ESCC patients. FBXW7 expression in cancer was lower compared to non-cancer tissues (P=0.003) and is an independent prognostic factor. The proliferation rates and Myc protein expression were significantly enhanced in FBXW7 siRNA cells compared to the controls. Cases with a loss of FBXW7 copy number had low FBXW7 expression and a poorer prognosis than cases with no loss of copy number. Genetic alterations in esophageal cancer lead to the loss of FBXW7 expression and increased cell proliferation. These genetic alterations of FBXW7 status may provide a prognostic factor for ESCC patients. IntroductionEsophageal squamous cell carcinoma (ESCC) accounts for most esophageal cancers in East Asia. Although the sensitivity of ESCC to chemoradiotherapy is relatively high, patients with progressive ESCC have poorer prognoses (1, 2). Tumor suppressor inactivation (e.g. p53, p16, RB) and oncogene activation (e.g. Myc, and cyclin D) are involved in ESCC progression (3). In particular, the Myc transcription factor and its downstream targets (e.g., Cyclin D and CDKs) are associated with carcinogenesis and progression of many cancers, including ESCC. The finding that suppression of Myc greatly inhibits tumor formation, has made Myc a promising therapeutic target (4).FBXW7 is an F-box protein that forms one of the four subunits of SCF ubiquitin ligase complexes, which induce the degradation of positive cell cycle regulators (oncoproteins) such as Myc (5-7). The degradation of Myc by FBXW7 leads to cell cycle exit (G0 phase); therefore, altered FBXW7 expression is considered a major cause of carcinogenesis or carcinoma development (8-10). Clinically, low expression of FBXW7 in human solid tumors such as glioma, colorectal cancer and gastric cancer produces a poor prognosis (11)(12)(13)(14). FBXW7 mutation, transcriptional control by p53 and copy number loss are the primary mechanisms of FBXW7 inactivation (10,13-15), which is consistent with our finding that the low expression of FBXW7 in colorectal cancer is due to copy number loss. A deletion of chromosome 4q, which includes FBXW7, has been reported in 30-40% of ESCC cases and is associated with a poor pro...

FBX8 Acts as an Invasion and Metastasis Suppressor and Correlates with Poor Survival in Hepatocellular Carcinoma

“…We also found that FBX8 was down-regulated in four HCC cell lines as well as in 16 matched clinical fresh tissues (P<0.05). Many F-box proteins such as FBXW7, FBXL2, FBX4 and FBXO11 are found to be lost in a wide range of human cancers, and generally considered as tumor suppressor genes [16]–[20]. Our data also clearly demonstrate the decreased expression of FBX8 in HCC.…”

Poor prognosis in cholangiocarcinoma patients with low FBXW7 expression is improved by chemotherapy

“…Low levels of FBXW7 protein and/or messenger RNA were revealed to be associated with poor prognoses in breast (10,26), gastric (25), non-small cell lung (27) and esophageal cancer (12,13). The present study demonstrated that low FBXW7 expression in CC was an independent poor prognostic factor that outweighed existing clinicopathological factors, including TNM stage.…”

“…In a previous study of clinical samples, low FBXW7 expression levels were associated with poor prognosis and cancer progression in a number of human malignancies including breast cancer (10), hepatocellular (11) and esophageal carcinoma (12,13). In intrahepatic and perihilar CC, it was demonstrated that low FBXW7 expression levels are associated with cancer progression and the increase of migration and invasion rates due to the accumulation of mTOR, an FBXW7 degradation target, as demonstrated in vivo and in vitro (14).…”

Fbxw7 Tumor Suppressor

“…Fbxw7 is a member of the F-box protein family, which is the component of an SCF E3 ubiquitin ligase. It contributes to the ubiquitin-mediated degradation of c-Myb, 6 Mediator 13, 7 Kruppel-like factor 2, 8 Kruppel-like factor 5 (KLF5), 9 granulocyte colony stimulating factor receptor, 10 eya1, 11 BCL-3, 12 neurofibromatosis type 1, 13 nuclear factor E2-related factor 1, 14 p100/nuclear factor-κB2 (NF-κB2), 15,16 GATA3, 17 JunB, 18 Myeloid cell leukemia-1 (Mcl-1), 19,20 c-Myc, 21–27 CyclinE, 21–27 CDK2, 16 Hes-1, 16 CyclinD1, 16 sterol regulatory element binding protein (SREBP), 28 c-Jun, 23,29 Hypoxia inducible factor-1α (HIF-1α), 30 Notch1, 23,31,32 DEK, 23 Enolase 1 (ENO1), 33 Yes-associated protein (YAP), 34 mammalian target of rapamycin (mTOR), 35,36 Ki-67, 24,37 TOP2A, 20 coiled-coil-domain containing 6, 38 Aurora kinase A (Aurora-A), 26,37,39 Notch4, 37 proliferation cell nuclear antigen, and 37 MYCN. 40 They all function as cell-cycle promoters or oncogenic regulators of proliferation, growth, and apoptosis.…”

“…27 In pancreatic cancer, Calhoun et al 99 discovered that 6% of pancreatic adenocarcinomas overexpressed cyclin E, which was accompanied by a novel somatic homozygous mutation in Fbxw7. In addition, nuclear retention of Fbxw7 by specific inhibitors of nuclear export led to Notch1 degradation in pancreatic cancer.…”