Immunohistochemical study of p21WAF1 and p53 proteins in prostatic cancer and their prognostic significance

Matsushima, Hisashi; Sasaki, Takeshi; Gotō, Tetsuo; Hosaka, Yoshio; Homma, Yukio; Kitamura, Tadaichi; Kawabe, Kazuki; Sakamoto, Atsuhiko; Murakami, Toshikazu; Machinami, Rikuo

doi:10.1016/s0046-8177(98)90445-2

Cited by 39 publications

(31 citation statements)

References 14 publications

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“…In eukaryotes, the cell cycle is driven by cyclin-dependent kinases (CDK) and negatively regulated by CDK inhibitors (8). Alterations in CDK inhibitor expression have been implicated in malignancy in general and in prostate carcinoma in particular (9)(10)(11)(12). p27 gene is a member of CDK inhibitors Cip/Kip family and is involved in the cell cycle control.…”

Section: Discussionmentioning

confidence: 99%

Epistatic Relationship between the Cancer Susceptibility Genes CHEK2 and p27

Cybulski

Gliniewicz

Sikorski

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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We studied the effects of p27 and CHEK2 variants on prostate and colon cancer risk in a case-control study. Modest effects on prostate cancer risk were observed for both CHEK2 missense and truncating variants. However, the excess cancer risk was restricted to the subgroup of men who were homozygous for the VV genotype in codon 109 of the p27 gene. Among men with the VV p27 genotype, the odds ratios associated with truncating and missense CHEK2 mutations were 3.1 (P < 0.0001) and 1.9 (P < 0.0001), respectively. Among men with other p27 genotypes (GG and VG), the odds ratios were 1.5 and 1.2 for truncating and missense CHEK2 mutations, respectively, and were not statistically significant. The interaction between CHEK2 and p27 was confirmed in a group of patients with colon cancer. Thus, it seems that the clinical expression of CHEK2 variant alleles on prostate and colon cancer risk may be restricted to individuals with a specific genotype (VV) of the p27 gene. Two-gene models provide numerous challenges for gene identification and cancer risk assessment. (Cancer Epidemiol Biomarkers Prev 2007;16(3):572 -6)

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Section: Discussionmentioning

confidence: 99%

Epistatic Relationship between the Cancer Susceptibility Genes CHEK2 and p27

Cybulski

Gliniewicz

Sikorski

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Interaction of p21 Cip1 with cyclin D1/CDK is known to promote stabilisation and nuclear import of the complex, resulting in enhanced CDK activity (Parry et al, 1999;Gladden and Diehl, 2005). Similarly, p21 Cip1 has been shown to be increased in prostate cancer and holds potential merit as a prognostic indicator (Matsushima et al, 1998;Sarkar et al, 1999;Omar et al, 2001;Rigaud et al, 2004). To determine the relevance of p21 Cip1 to cyclin D1 localisation and proliferation, p21 Cip1 immunoreactivity was assessed in a subset of patient tumours (n ¼ 16) and the three metastatic tumours wherein cyclin D1 and Ki-67 status had been determined.…”

Section: Contribution Of P21 Cip1 To Proliferation and Progression Ofmentioning

confidence: 99%

Impact of differential cyclin D1 expression and localisation in prostate cancer

et al. 2007

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Cyclin D1 is a critical regulator of androgen-dependent transcription and cell cycle progression in prostate cancer cells. Despite the influence of D-type cyclins on prostate cancer proliferation, few studies have examined the expression of cyclin D1 in localised tumours or challenged its relevance to disease progression. Cyclin D1 status was characterised using immunohistochemistry in 38 non-neoplastic prostate samples, 138 primary human prostate carcinomas, and three lymph node metastatic specimens. Relevance of cyclin D1 to preoperative prostate-specific antigen (PSA) levels, Ki-67 index, and p21 Cip1 status was also examined. Cyclin D1-positive phenotype was increased in primary carcinoma compared to non-neoplastic tissue, and was evident in all lymph node metastases cases. Interestingly, at least three distinct localisation patterns were observed in the cyclin D1-positive cohort, wherein cytoplasmic localisation was identified in a large fraction, and this pattern was predominant in lower grade tumours. Relevance of altered cyclin D1 status was observed, wherein cyclin D1-positive tumours were associated with low preoperative PSA levels, consistent with in vitro reports that cyclin D1 may alter the expression of this tumour marker. Moreover, tumours with predominantly cytoplasmic cyclin D1 showed the lowest Ki-67 index, whereas nuclear cyclin D1 was associated with higher grade, elevated Ki-67, and increased nuclear p21 Cip1 . These data demonstrate that differential cyclin D1 status may influence clinicopathological parameters, and reveal new insight as to the regulation and potential consequence of cyclin D1 expression in prostate cancer.

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“…The mechanisms by which prostatic tumors gain the capacity for uncontrolled, androgen-independent cellular proliferation are not understood. Although the relationship between p21 expression and prostate cancer prognosis is not clear cut (Matsushima et al, 1998;Aaltomaa et al, 1999, Cheng et al, 2000Fizazi et al, 2002), decreased expression of cyclin-dependent kinase inhibitors (CKIs) has been proposed to explain how prostate tumor cells evade normal growth controls (Agus et al, 1999). Consistent with this hypothesis, androgen-independent human prostate cancer cell lines typically contain lower levels of the CKIs, p21 CIP1 (Zhuang and Burnstein, 1998) and p27 KIP1 (Guo et al, 1997;Cipriano and Chen, 1998) compared to the relatively well-differentiated, androgen-dependent LNCaP line or normal prostate luminal epithelial cells (Zhuang and Burnstein, 1998;Waltregny et al, 2001;Yang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Deregulation of the Rho GTPase, Rac1, suppresses cyclin-dependent kinase inhibitor p21CIP1 levels in androgen-independent human prostate cancer cells

et al. 2004

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Abnormally suppressed levels of cyclin-dependent kinase inhibitors (CKIs) are associated with aggressive androgenindependent prostate cancer and contribute to uncontrolled proliferation. The androgen-independent human prostate cancer cell lines, LNCaP-104R1, ALVA31 and PC-3, express low levels of the CKI, p21 CIP1 , compared to the less-malignant, androgen-dependent LNCaP cells. We investigated the mechanism underlying this suppression by examining the role of Rho GTPases, signaling proteins that play important roles in cell cycle progression, at least in part through regulation of CKIs. Inhibition of Rac1 induced p21 expression in androgen-independent lines but had no effect on the higher p21 levels characteristic of LNCaP cells. This induction of p21 was functionally significant as evidenced by inhibition of cyclin-dependent kinase 2 activity and decreased cell proliferation. Conversely, overexpression of constitutively active Rac1 suppressed the higher p21 levels seen in LNCaP cells. Thus, Rac1 activity is both necessary and sufficient for suppression of p21 in prostate cancer cells. Furthermore, Rac1 activity was significantly higher in all three androgen-independent cell lines compared to LNCaP cells. Thus in three models of aggressive human prostate cancer, hyperactivity of Rac1 corresponds to suppressed levels of p21. These results are unique in describing a role for Rac1 in p21 regulation and may implicate the Rac1 signaling pathway as a potential therapeutic target for controlling prostate cancer cell growth following progression to androgen independence.

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Immunohistochemical study of p21WAF1 and p53 proteins in prostatic cancer and their prognostic significance

Cited by 39 publications

References 14 publications

Epistatic Relationship between the Cancer Susceptibility Genes CHEK2 and p27

Epistatic Relationship between the Cancer Susceptibility Genes CHEK2 and p27

Impact of differential cyclin D1 expression and localisation in prostate cancer

Deregulation of the Rho GTPase, Rac1, suppresses cyclin-dependent kinase inhibitor p21CIP1 levels in androgen-independent human prostate cancer cells

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