Association of allelic loss at the FHIT locus and p53 alterations with tumour kinetics and chromosomal instability in non‐small cell lung carcinomas (NSCLCs)

Abstract

The FHIT gene, located at the FRA3B fragile site of chromosome 3p14.2, encodes a 16.8 kD homologue of the yeast enzyme diadenosine tetraphosphate (Ap(4)A) hydrolase. Frequent allelic losses at this region in various malignancies, including non-small cell lung carcinomas (NSCLCs), imply that FHIT may represent a tumour suppressor gene (TSG). Increasing evidence suggests that multiple TSG impairment has a synergistic effect on tumour growth. The present study of 67 NSCLCs investigated the allelic imbalance (AIm) within the FHIT locus and its relationship with p53 abnormalities, kinetic parameters [proliferative activity or proliferation index (PI) and apoptotic index (AI)], and ploidy status of the carcinomas. Allelic imbalance at FHIT was observed in 35 out of 55 informative (heterozygous: H) cases (64%). Similar frequencies of loss of heterozygosity (LOH) were noticed among squamous cell lung carcinomas and adenocarcinomas. The high percentage of AIm in stage I tumours (71%) is indicative of its relatively early involvement in NSCL carcinogenesis. No association was found between LOH at FHIT, kinetic parameters, and ploidy status of the tumours. Concurrent loss at FHIT and p53 overexpression [FHIT(LOH)/p53(P)] was the most frequent pattern and was observed in 39% of the informative cases. The latter pattern was not associated with smoking, supporting the hypothesis that in patients with a history of tobacco exposure, FHIT allelic loss may not be a consequence of p53 checkpoint defects, but the outcome of tobacco-induced mutagenesis. Statistically significant differences in the presence of FHIT(LOH)/p53(P) and FHIT(LOH)/p53(N) patterns were noted at the proliferative and apoptotic level, whereas ploidy was similar amongst all groups, implying that wild-type (wt) p53 may play a safeguard role against altered FHIT function. However, the possibility of a masking effect from wt p53 cannot be excluded, since the FHIT(LOH)/p53(P) profile demonstrated a higher growth index (GI=PI/AI mean value ratio) than FHIT(H)/p53(P) (32 vs. 8), although this was not significant. Further studies are needed in order to elucidate the role of FHIT and its relationships with other cell-cycle regulatory molecules involved in NSCL carcinogenesis.

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.…”

“…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]. Exogenous expression of the FHIT gene in 3p14.2-deficient cancer cells induces apoptosis and alters cell cycle kinetics in various types of cancer cells [13][14][15]. Also, a previous study implicated the FHIT-induced tumor suppression in FHIT-mediated inactivation of MDM2 and subsequent stabilization of p53 protein in human lung cancer cells [9].…”

Roles of Fhit and p53 in Taiwanese surgically treated non-small-cell lung cancers

“…Alteration of the TP53 gene may be involved in the initiation, development, progression, and invasion of lung cancer (Caamano et al, 1991;Sozzi et al, 1992;Marchetti et al 1993;Fontanini et al, 1994). Even though correlation of p53 protein expression with clinical and biological characteristics of lung cancer has been extensively studied, the results of these studies are quite diverse (Top et al, 1995;Passlick et al, 1995;Dalquen et al, 1996;Lee et al 1999;Garinis et al, 2001;Zienolddiny et al, 2001). The results of this study indicated that p53 expression was closely related to distant metastasis of the overall NSCLCs and the adenocarcinoma subtype; and p53 was especially useful as a prognostic factor in adenocarcinoma.…”

Loss of FHIT protein expression is related to high proliferation, low apoptosis and worse prognosis in non-small-cell lung cancer

“…3 Frequent allelic losses and homozygous deletions, [3][4][5][6][7][8][9][10][11][12][13][14][15][16] as well as the loss of heterozygosity (LOH) in microsatellites located at FHIT gene 5,11,12,[17][18][19][20][21][22][23][24] have been described at the FHIT locus in several human solid tumors arising from epithelial cells, including lung cancer.…”