Aberrant regulation of FBW7 in cancer

Wang, Lixia; Ye, Xiantao; Liu, Yueyong; Wei, Wenyi; Wang, Zhiwei

doi:10.18632/oncotarget.1859

Cited by 87 publications

(87 citation statements)

References 198 publications

(205 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Notch pathway disruption also results from FBXW7 mutations, which were identified in 5%-17% of ESCC specimens, because FBXW7 forms part of the ubiquitin ligase complex that mediates NOTCH1 degradation [59] .…”

Section: Spta1mentioning

confidence: 99%

Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing

Sasaki¹,

Tamura²,

Koyama³

et al. 2016

WJG

View full text Add to dashboard Cite

Two major types of cancer occur in the esophagus: squamous cell carcinoma, which is associated with chronic smoking and alcohol consumption, and adenocarcinoma, which typically arises in gastric reflux-associated Barrett's esophagus. Although there is increasing incidence of esophageal adenocarcinoma in Western counties, esophageal squamous cell carcinoma (ESCC) accounts for most esophageal malignancies in East Asia, including China and Japan. Technological advances allowing for massively parallel, high-throughput next-generation sequencing (NGS) of DNA have enabled comprehensive characterization of somatic mutations in large numbers of tumor samples. Recently, several studies were published in which whole exome or whole genome sequencing was performed in ESCC tumors and compared with matched normal DNA. Mutations were validated in several genes, including in TP53 , CDKN2A , FAT1 , NOTCH1 , PIK3CA , KMT2D and NFE2L2 , which had been previously implicated in ESCC. Several new recurrent alterations have also been identified in ESCC. Combining the clinicopathological characteristics of patients with information obtained from NGS studies may lead to the development of effective diagnostic and therapeutic approaches for ESCC. As this research becomes more prominent, it is important that gastroenterologist become familiar with the various NGS technologies and the results generated using these methods. In the present study, we describe recent research approaches using NGS in ESCC.

show abstract

Section: Spta1mentioning

confidence: 99%

Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing

Sasaki¹,

Tamura²,

Koyama³

et al. 2016

WJG

View full text Add to dashboard Cite

show abstract

“…Overall, approximately 6% of human tumors harbor FBW7 mutations. Emerging evidence has shown that FBW7 is also regulated by multiple upstream genes, such as p53, Pin1, Hes-5, and Numb4, as well as by miRNAs (7). We previously reported that fewer than 2% of pancreatic cancer samples harbored FBW7 mutations, according to sequencing analysis (8).…”

Section: Introductionmentioning

confidence: 99%

FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer

Qin

Liang

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: FBW7 functions as a tumor suppressor by targeting oncoproteins for destruction. We previously reported that the oncogenic mutation of KRAS inhibits the tumor suppressor FBW7 via the Ras-Raf-MEK-ERK pathway, which facilitates the proliferation and survival of pancreatic cancer cells. However, the underlying mechanism by which FBW7 suppresses pancreatic cancer remains unexplored. Here, we sought to elucidate the function of FBW7 in pancreatic cancer glucose metabolism and malignancy.Experimental Design: Combining maximum standardized uptake value (SUV max ), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUV max and FBW7 expression in pancreatic cancer tissues. The impact of FBW7 on glucose metabolism was further validated in vitro and in vivo. Finally, gene expression profiling was performed to identify core signaling pathways. Results:The expression level of FBW7 was negatively associated with SUV max in pancreatic cancer patients. FBW7 significantly suppressed glucose metabolism in pancreatic cancer cells in vitro. Using a xenograft model, MicroPET/CT imaging results indicated that FBW7 substantially decreased 18F-fluorodeoxyglucose ( 18 F-FDG) uptake in xenograft tumors. Gene expression profiling data revealed that TXNIP, a negative regulator of metabolic transformation, was a downstream target of FBW7. Mechanistically, we demonstrated that TXNIP was a cMyc target gene and that FBW7 regulated TXNIP expression in a c-Myc-dependent manner.Conclusions: Our results thus reveal that FBW7 serves as a negative regulator of glucose metabolism through regulation of the c-Myc/TXNIP axis in pancreatic cancer.

show abstract

“…FBXW7 (also known as Sel-10, hCdc4, or hAgo) is a component of a S-phase kinase-associated protein 1 (Skp1)-Cul1-F-box protein ubiquitin ligase complex that regulates the degradation of Notch, cyclin E, c-Myc, mammalian target of rapamycin, myeloid cell leukemia 1 (Mcl-1), and c-Jun, most of which possess oncogenic functions (9,10). Loss of FBXW7 by means of mutation or deletion has been reported in various human cancers and has been linked to severe chromosomal instability (11). In addition, inactivation of FBXW7 by miR-223 (12), a microRNA deregulated in ATL, has also been reported (13).…”

mentioning

confidence: 99%

Oncogenic mutations in the FBXW7 gene of adult T-cell leukemia patients

Yeh

Bellon

Pancewicz-Wojtkiewicz

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Human T-cell leukemia virus type 1 (HTLV-I) is associated with adult T-cell leukemia (ATL), an aggressive lymphoproliferative disease with a dismal prognosis. We have previously described the presence of Notch1 activating mutations and constitutive Notch1 signaling in patients with acute ATL. In this study, we report a high frequency of F-box and WD repeat domain containing 7 (FBXW7)/hCDC4 mutations within the WD40 substrate-binding domain in 8 of 32 acute ATL patients (25%). Functionally, ATL FBXW7 mutants lost their ability to interact with intracellular Notch (NICD), resulting in increased protein stability and constitutive Notch1 signaling. Consistent with the loss-of-function found in ATL patients, expression of WT FBXW7 in several patient-derived ATL lines demonstrated strong tumor-suppressor activity characterized by reduced proliferation of ATL cells. Remarkably, two FBXW7 mutants, D510E and D527G, demonstrated oncogenic activity when expressed in the presence of HTLV-I Tax, mutated p53 R276H, or c-Myc F138C found in human cancers. Transforming activity was further demonstrated by the ability of the FBXW7 D510E mutant to provide IL-2–independent growth of Tax-immortalized human T cells and increase the tumor formation in a xenograft mouse model of ATL. This study suggests that FBXW7, normally a tumor suppressor, can act as an oncogene when mutated and may play an important role in the pathogenesis of ATL.

show abstract

Aberrant regulation of FBW7 in cancer

Cited by 87 publications

References 198 publications

Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing

Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing

FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer

Oncogenic mutations in the FBXW7 gene of adult T-cell leukemia patients

Contact Info

Product

Resources

About