High expression of p21WAF1/CIP1 is correlated with human hepatocellular carcinoma in patients with hepatitis C virus–associated chronic liver diseases

Wagayama, Hidetaka; Shiraki, Katsuya; Sugimoto, Kazushi; Ito, Takeshi; Fujikawa, Katsuhiko; Yamanaka, Takenari; Takase, Koujiro; Nakano, Takeshi

doi:10.1053/hupa.2002.124724

Cited by 46 publications

(35 citation statements)

References 37 publications

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“…4; mean p21-LI, 20.6%; P ϭ 0.001 compared with p21-LI in normal liver). 38 The intracellular localization of p21 expression was mainly nuclear (Fig. 3D,F,J).…”

Section: Resultsmentioning

confidence: 91%

“…18,19 High levels of p21 expression in cirrhotic liver have previously been correlated with an increased cancer risk. 38 That telomere shortening and consequent activation of cell cycle checkpoints repress liver regeneration at the cirrhosis stage and that in this molecular context loss of p16/p21-expression represents a selective advantage allowing clonal expansion of hepatocytes with dysfunctional telomeres seem possible.…”

Section: Discussionmentioning

confidence: 99%

“…36,37 In liver, previous studies have demonstrated that p21 checkpoint activation was associated with an increased HCC risk at the cirrhosis stage. 38 Whether the inactivation of DNA damage checkpoints coincides with telomere shortening during carcinogenesis in humans has not been analyzed, however. A combined analysis of these parameters in defined pathological lesions associated with hepatocarcinogenesis could help to delineate the preneoplasiacarcinoma sequence of human HCC.…”

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confidence: 99%

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Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis†

et al. 2007

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Telomere shortening and inactivation of cell cycle checkpoints characterize carcinogenesis. Whether these molecular features coincide at specific stages of human hepatocarcinogenesis is unknown. The preneoplasia-carcinoma sequence of human HCC is not well defined. Small cell changes (SCC) and large cell changes (LCC) are potential precursor lesions. We analyzed hepatocellular telomere length, the prevalence of DNA damage, and the expression of p21 and p16 in biopsy specimens of patients with chronic liver disease (n ‫؍‬ 27) that showed different precursor lesions and/or HCC: liver cirrhosis (n ‫؍‬ 25), LCC (n ‫؍‬ 26), SCC (n ‫؍‬ 13), and HCC (n ‫؍‬ 13). The study shows a decrease in telomere length in nondysplastic cirrhotic liver compared with normal liver and a further significant shortening of telomeres in LCC, SCC, and HCC. HCC had the shortest telomeres, followed by SCC and LCC. Hepatocytes showed an increased p21 labeling index (p21-LI) at the cirrhosis stage, which remained elevated in most LCC. In contrast, most SCC and HCC showed a strongly reduced p21-LI. Similarly, p16 was strongly expressed in LCC but reduced in SCC and not detectable in HCC. ␥H2AX-DNA-damage-foci were not detected in LCC but were present in SCC and more frequently in HCC. These data indicate that LCC and SCC represent clonal expansions of hepatocytes with shortened telomeres. Conclusion: The inactivation of cell cycle checkpoints coincides with further telomere shortening and an accumulation of DNA damage in SCC and HCC, suggesting that SCC represent more advanced precursor lesions compared with LCC. (HEPATOLOGY 2007;45:968-976.) H CC represents the fifth most common neoplasm in humans. 1 Treatment options for HCC patients are limited, and the disease is often diagnosed at an advanced stage. 2 The molecular pathogenesis of hepatocarcinogenesis is poorly understood, 3 thus impairing the development of molecular markers, efficient screening procedures, and molecular therapies.HCC rarely evolve in noncirrhotic liver but the risk sharply increases at the cirrhosis stage of chronic liver diseases, with the yearly incidence of HCC ranging from Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail: Rudolph.Lenhard@MH-hannover.de; fax: 0049-511-532-6998, or to: Massimo Roncalli, Department of Pathology, University of Milan and IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano (Milan), Italy. E-mail: massimo.roncalli@unimi.it; fax: 0039-02-82244791. Copyright © 2007 (2) small cell changes/dysplasia (SCC). 13,14 Whether both of these lesions represent true precursor lesions and which of these precursors is more closely related to HCC are intensely debated. [7][8][9][10][11][12] On the molecular level, HCC are characterized by massive chromosomal instability (CIN) in more than 95% of cases, 15-17 and telomere shortening 18,19 and loss of p53-checkpoint function in more than 70% of the cases. 3,20 Experimental data from telomerase-deficient mic...

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“…4; mean p21-LI, 20.6%; P ϭ 0.001 compared with p21-LI in normal liver). 38 The intracellular localization of p21 expression was mainly nuclear (Fig. 3D,F,J).…”

Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis†

et al. 2007

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“…Kao et al [28] also reported that p21 expression was observed in 37% of HCC tissues, regardless of p53 expression, and was an independent survival good prognosis factor. While most of the reports show that p21 acts as a tumor suppressor, expression levels of p21 in liver cirrhosis have been reported to be correlated with the cumulative incidence of the occurrence HCC [29] and to be dominant in cytoplasm when histology became more undifferentiated [30] . There are also some reported studies examining the relationship between HBV and p21.…”

Section: Hcc Hbx and P21mentioning

confidence: 99%

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

Ohkoshi

Yano

Matsuda

2015

WJG

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A well-known tumor suppressor, p21, acts paradoxically by promoting tumor growth in some cellular conditions. These conflicting functions have been demonstrated in association with the HBx gene and in hepatocarcinogenesis. The molecular behavior of p21 depends on its subcellular localization. Nuclear p21 may inhibit cell proliferation and be proapoptotic, while cytoplasmic p21 may have oncogenic and anti-apoptotic functions. Because most typical tumor suppressive proteins also have different effects according to subcellular localization, elucidating the regulatory mechanisms underlying nucleo-cytoplasmic transport of these proteins would be significant and may lead to a new strategy for anti-hepatocellular carcinoma (HCC) therapy. Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor involved in transport of tumor suppressors from nucleus to cytoplasm. Expression of CRM1 is enhanced in a variety of malignancies and in vitro studies have shown the efficacy of specific inhibition of CRM1 against cancer cell lines. Interestingly, interferon may keep p21 in the nucleus; this is one of the mechanisms of its anti-hepatocarcinogenic function. Here we review the oncogenic property of p21, which depends on its subcellular localization, and discuss the rationale underlying a new strategy for HCC treatment and prevention. Core tip: A well-known tumor suppressor, p21, can act paradoxically by promoting tumor growth, depending on its subcellular localization. Nuclear p21 may inhibit cell proliferation while cytoplasmic p21 may be associated with anti-apoptotic and oncogenic functions. REVIEW

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“…Cdkn1a had a 2-fold increased expression and has been recently implicated in mechanisms of carcinogenesis, although it has been characterized as a tumor suppressor (Roninson et al, 2005). There is emerging evidence that Cdkn1a may not be a classic tumor suppressor as very few human cancers display loss-of-function mutations of this gene (Roninson et al, 2005) and it is overexpressed in human cancers including breast (Winters et al, 2001), liver (Wagayama et al, 2002), and squamous cell carcinomas (Sarbia et al, 1998).…”

Section: Changes In P53 Gene Expression Pathway In Sirt3mentioning

confidence: 99%

Changes in gene expression in SIRT3 knockout liver cells

Tao¹,

Leclerc²,

Yıldız³

et al. 2015

Turk J Biol

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The sirtuin (SIRT) gene family is reported to regulate critical intracellular processes from aging to cellular metabolism and repair. SIRT3 knockout (SIRT3 -/-) mice develop receptor positive mammary tumors starting at 13 months and SIRT3 expression is decreased in human breast cancer samples as well as several other diseases. It is established that carcinogenesis results from the accumulation of multiple aberrant genetic events including the activation of oncogenes and inactivation of tumor-suppressor genes. To determine the potential early genomic events that may play a role in the tumor-permissive phenotype observed in SIRT3 -/cells, we compared gene expression profile in SIRT3 -/and wild-type (SIRT3 +/+ ) mouse livers. Differences between the expression profiles of genes important in the p53 and apoptosis pathway and signal transduction pathways, as well as genes involved with insulin and cholesterol metabolism, were determined. These results demonstrate that the expression of several oncogenes including Cdkn1, Myc, and Nos2 are increased. In contrast, several genes shown to be downregulated in human breast cancer including Btg2, Egr-1, Fos, Jun, Gadd4, and Wnt1 had decreased expression. The current work demonstrates that the loss of function of SIRT3 results in a cellular environment permissive for carcinogenesis and is characterized by altered metabolism.

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High expression of p21WAF1/CIP1 is correlated with human hepatocellular carcinoma in patients with hepatitis C virus–associated chronic liver diseases

Cited by 46 publications

References 37 publications

Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis†

Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis†

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

Changes in gene expression in SIRT3 knockout liver cells

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