Cancer and the FRA3B/FHIT fragile locus: it's a HIT

Abstract

The FHIT gene encompassing the most active common human chromosomal fragile region, FRA3B, was discovered in 1996 and proposed as a tumour suppressor gene for important human cancers. Seven years and more than 350 reports later, early questions concerning its tumour suppressor role have been answered. Recent studies on the role of Fhit loss in major types of human cancers report association with high proliferative and low apoptotic indices, node positivity, loss of mismatch repair protein, likelihood of progression and reduced survival.

Protein Expression Profiling Identifies Cyclophilin A as a Molecular Target in Fhit-Mediated Tumor Suppression

“…Although the approach of protein separation by two-dimensional PAGE coupled with protein identification by MALDI-TOF analysis has inherent limitations, we identified 12 proteins that were apparently differentially expressed in wild-type and Y114F mutant FHITinfected H1299 human lung cancer cells. According to the biological evidence supporting Fhit tumor suppressor function, Fhit is likely to possess diverse functions in controlling cell proliferation, proapoptotic signaling, and sensitivity to DNA damage responses (5,8), but protein effectors of these diverse functions have not been identified. We now report that cyclophilin A is a target protein suppressed by Fhit in the transition of the cells into S phase.…”

“…Over the last several years, evidence confirming tumor suppressor functions of Fhit has accumulated: Fhit À/À and Fhit +/À mice exhibit increased susceptibility to spontaneous tumors and deletion of a Fhit allele in mice enhances sensitivity to carcinogens, N-nitrosomethylbenzylamine and dimethylnitrosoamine (8)(9)(10)(11); deficiency of Fhit protein decreases sensitivity to DNA-damaging agents, such as mitomycin C, UVC, and ionizing radiation (12,13). Furthermore, overexpression of FHIT by adenoviral gene delivery effectively suppressed cell growth and induced caspase-dependent apoptosis in in vitro and in vivo experiments (14)(15)(16)(17).…”

Induction of apoptosis by tumor suppressor FHIT via death receptor signaling pathway in human lung cancer cells

“…Exogenous expression of FHIT selectively mediates upregulation of the expression of DR3, DR4, and DR5 and stimulates the DR-associated apoptotic pathway. Although several lines of evidence showed that FHIT exhibits potent tumor suppression function via diverse mechanisms, previous reports focused primarily on the classical pathways, such as cell cycle arrest and apoptosis induction [5,6,8,11,[13][14][15]. The precise molecular mechanism involved in the antitumor function of FHIT remains largely unclear.…”

“…The FHIT protein consists of 147 amino acids and is a member of the histidine triad nucleotide-binding protein superfamily. Inactivation of the FHIT protein plays an important role in the development of several human cancers, including lung cancer [5][6][7]. Several lines of in vitro and in vivo experimental evidence have demonstrated the tumor suppression function of the FHIT gene [8][9][10][11][12].…”

Development of spontaneous tumours and intestinal lesions in Fhit gene knockout mice

“…Chromosomal deletion of the FHIT-containing locus or inactivation of FHIT is frequently observed in various types of cancers (for a review, see Huebner and Croce, 2003), consistent with a tumour suppressor function in a variety of organs. The Fhit protein carries a proapoptotic activity through a caspasedependent pathway in human cancer cells, which may contribute to the tumour suppressor activity (Ji et al, 1999;Ishii et al, 2001;Roz et al, 2002).…”