Reduced P21Waf1/Cip1 Expression and P53 Mutation in Hepatocellular Carcinomas

Abstract

growth of malignant cells in vitro and in vivo. 6,10 These obserp21 WAF1/CIP1 is a universal cyclin-dependent kinase vations suggest that p21 functions as a tumor suppressor (cdk) inhibitor, the expression of which is regulated by protein. p53-dependent and p53-independent pathways. We ex-No mutations of p21 WAF1/CIP1 were detected in 315 samples amined p21 WAF1/CIP1 expression in and p53 status of 21 from 14 different types of human malignancy, 11 suggesting primary hepatocellular carcinomas (HCCs) by reversethat p21 WAF1/CIP1 , if involved in tumorigenesis, exerts its eftranscriptase polymerase chain reaction (RT-PCR) and fect(s) mainly on expression levels rather than on gene mutaby PCR single-strand conformation polymorphism tions. The p21 WAF1/CIP1 gene has a p53 transcriptional regula-(PCR-SSCP) analysis. p21 WAF1/CIP1 messenger RNA extory motif, 6 and the cells lacking functional p53 express very pression was reduced markedly in 8 of 21 HCCs (38.1%) low levels of p21 WAF1/CIP1 , 5,6,12 indicating that p53 regulates and 5 of these 8 HCCs bore p53 mutations. The relative p21 WAF1/CIP1 expression directly. However, recent studies indip21 WAF1/CIP1 messenger RNA expression value of HCCs cated that p53-independent pathways may also lead to inwith p53 mutations (.73 { .13 U, n Å 6) was significantly creased p21 WAF1/CIP1 expression. 13-17 lower than that of HCCs with wild-type p53 (1.00 { 0.21In a previous study, we found that the inactivation of p53 U, n Å 14; P õ .01). The p21 WAF1/CIP1 expression levels in and Rb tumor suppressor genes, 18-21 as well as allelic loss cancerous tissues (.73 { .13 U) were significantly reon chromosomes 4q, 8p, 13q, 16q, and 17p, [21][22][23][24][25][26][27] contribute to duced in comparison with those in noncancerous tissues multistage hepatocarcinogenesis. Recently, we demonstrated (.97 { .13 U) (P õ .01) in the 6 cases with p53 mutations.that p16 INK4 , a member of the cdk inhibitor family, is also These data indicate that p21 WAF1/CIP1 expression in HCCs involved in hepatocarcinogenesis. 27 To determine whether is predominantly regulated by dependence on p53 and p21 WAF1/CIP1 participates in hepatocarcinogenesis and there is that reduced p21 WAF1/CIP1 expression may participate in a relationship between its expression and the p53 status, we hepatocarcinogenesis. (HEPATOLOGY 1997;25:575-579.)analyzed p21 WAF1/CIP1 messenger RNA expression in and the p53 status of primary hepatocellular carcinomas (HCCs). The sequential formation, activation, and subsequent inactivation of a series of cyclin-cyclin dependent kinase (cdk) PATIENTS AND METHODScomplexes regulate the checkpoints that control cell cycle proSamples. Twenty-one HCCs and corresponding noncancerous liver gression. 1,2 In addition to positive regulation of cell cycle pro-tissues were obtained from specimens surgically resected at the Nagression by the activation of cyclin-cdk complexes, negative tional Cancer Center Hospital (Tokyo, Japan). The samples were regulation is achieved through cdk inhibitory proteins, which ...

Expression of cyclin-dependent kinase inhibitor p21 in human liver

“…7,10,11 Studies in other types of proliferating cells suggest that p21 expression may be inversely correlated with malignant transformation 5,52 ; in addition to playing a role in regulating compensatory hepatocyte proliferation, p21 could have an antineoplastic effect in the liver. 53,54 Studies to prospectively examine hepatic p21 expression and clinical outcomes may provide additional insight into the role of this gene in human liver diseases.…”

Adenovirus-mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growth in vitro and in vivo

“…Besides, p21 expression in HCCs was found to be predominantly regulated by dependence on p53. 36 PTTG1, but not PTTG2 and 3, was highly expressed in five of eight hepatoma cell lines at transcript level (Fig. 5A), which may reflect expression pattern in primary HCCs (Fig.…”

p53 missense but not truncation mutations are associated with low levels of p21CIP1/WAF1mRNA expression in primary human sarcomas

“…In support of this, several studies have p53 missense but not truncation mutations are associated with low levels of p21 CIP1/WAF1 mRNA expression in primary human sarcomas shown that tumours with p53 mutations tend to have lower steady state levels of p21 CIP1/WAF1 expression than tumours without such mutations (Ozcelik et al, 1995;Matsushida et al, 1996;Hui et al, 1997). We have investigated this association in human breast cancer and observed that tumours with p53 mutations had a significantly lower distribution of p21 CIP1/WAF1 mRNA levels compared to tumours without detectable p53 mutation (Ozcelik et al, 1995).…”

“…There is mounting evidence that p21 CIP1/WAF1 is also targeted for deregulation in human cancer cells (El-Deiry et al, 1995;Ozcelik et al, 1995;Matsushita et al, 1996;Hui et al, 1997). Despite the fact that somatic mutations are not a common mechanism of inactivating p21 CIP1/WAF1 function (Shiohara et al, 1994;Koopmann et al, 1995;Mousses et al, 1995;Sun et al, 1995;Watanabe et al, 1995;Wan et al, 1996), cancer cells often have very low levels of p21 CIP1/WAF1 in comparison to their normal counterparts (El-Deiry et al, 1995;Ozcelik et al, 1995;Matsushita et al, 1996;Hui et al, 1997). Furthermore, p21 CIP1/WAF1 , which is normally found in a complex with a cyclin, cdk and PCNA, is often missing from this quaternary complex in cancer cell lines (Xiong et al, 1993).…”