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Abstract
The ubiquitin-proteasome system (UPS) is involved in multiple aspects of cellular processes, such as cell cycle progression, cellular differentiation, and survival (Davis RJ et al., Cancer Cell 26:455-64, 2014; Skaar JR et al., Nat Rev Drug Discov 13:889-903, 2014; Nakayama KI and Nakayama K, Nat Rev Cancer 6:369-81, 2006). F-box and WD repeat domain containing 7 (FBXW7), also known as Sel10, hCDC4 or hAgo, is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a critical tumor suppressor and one of the most commonly deregulated ubiquitin-proteasome system proteins in human cancer. FBXW7 controls proteasome-mediated degradation of oncoproteins such as cyclin E, c-Myc, Mcl-1, mTOR, Jun, Notch and AURKA. Consistent with the tumor suppressor role of FBXW7, it is located at chromosome 4q32, a genomic region deleted in more than 30% of all human cancers (Spruck CH et al., Cancer Res 62:4535-9, 2002). Genetic profiles of human cancers based on high-throughput sequencing have revealed that FBXW7 is frequently mutated in human cancers. In addition to genetic mutations, other mechanisms involving microRNA, long non-coding RNA, and specific oncogenic signaling pathways can inactivate FBXW7 functions in cancer cells. In the following sections, we will discuss the regulation of FBXW7, its role in oncogenesis, and the clinical implications and prognostic value of loss of function of FBXW7 in human cancers.
Highlights
The ubiquitin-proteasome system (UPS) is involved in multiple aspects of cellular processes, such as cell cycle progression, cellular differentiation, and survival (Davis RJ et al, Cancer Cell 26:455-64, 2014; Skaar JR et al, Nat Rev Drug Discov 13: 889-903, 2014; Nakayama KI and Nakayama K, Nat Rev Cancer 6:369-81, 2006)
This is equivalent to the 88 T-Acute lymphoblastic leukemia (ALL) patients who were treated on the UKALLXII/ECOG E2993 protocol, a chemotherapy regime specific to newly diagnosed adult ALL patients [110]
In T-ALL patients treated in either the Lymphoblastic Acute Leukemia in Adults-94 trials (LALA-94) (n = 87) or the Group for Research on Adult Acute Lymphoblastic Leukemia-2003 trials (GRAALL-2003) (n = 54), Notch1/F-box and WD repeat domain containing 7 (FBXW7)-mutated patients have better overall survival and event-free survival compared with other patients, there is no correlation between Notch1/FBXW7 mutation and clinical biologic features [111]
Summary
Previous studies have reported that mutations in the WD40 domain prevent interactions between FBXW7 and its known substrates. Additional studies show that reduced FBXW7 expression is correlated with lymph node metastasis, tumor size, and poor prognosis in primary gastric cancer [128]. This is mainly due to mutations in p53, which lead to reductions in FBXW7 transcripts [128]. P53 mutations can lead to increased expression of miR-25 [146] and overexpression of miR-25 increases NSCLC cell proliferation and migration by targeting FBXW7 [144]. Reduced FBXW7 expression is correlated with lymph node metastasis, tumor size, and poor prognosis in primary gastric cancer. In HCC patients, FBXW7 correlates with tumor differentiation, the incidence of portal or hepatic venous invasion, metastasis, and poorer clinical pathologic features (including large tumor size, high pathological grading, and advanced TNM stage). FBXW7 down-regulation is associated with EGFR inhibitor-resistance in NSCLC
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