Cyclin D2 Overexpression and Lack of p27 Correlate Positively and Cyclin E Inversely with a Poor Prognosis in Gastric Cancer Cases

Takano, Yasuo; Kato, Yukio; Diest, Paul J. van; Masuda, Mitsunobu; Mitomi, Hiroyuki; Okayasu, Isao

doi:10.1016/s0002-9440(10)64763-3

Cited by 146 publications

(117 citation statements)

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“…This may suggest that the overexpression of cyclin D2, and not that of cyclins D1 and D3, is related to metastatic tumours. These results are in agreement with reports that overexpression of cyclin D2, but not of cyclin D1, in gastric cancer correlates with disease progression and poor prognosis (Takano et al, 2000). In addition, in flat and exophytic human colon adenomas, cyclin D2 was overexpressed in considerably larger proportions than cyclin D1 (Bartkova et al, 2001).…”

Section: Discussionsupporting

confidence: 92%

“…However, not all three D-type cyclins are overexpressed in the same tumour and the three cyclins are differentially linked to poor outcome of the disease. For example, overexpression of cyclin D2 in gastric cancer was shown to correlate with disease progression and poor prognosis (Yasogawa et al, 1998;Takano et al, 1999Takano et al, , 2000. On the other hand, cyclin D2 mRNA and protein were absent in breast cancer cell lines and primary cancer tissues, while in normal breast epithelial cells, cyclin D2 was abundantly expressed (Evron et al, 2001).…”

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confidence: 99%

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Expression of D-type cyclins in colon cancer and in cell lines from colon carcinomas

et al. 2005

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Cyclins D1, D2 and D3 play important roles in cell proliferation and differentiation. Although their abnormal expression has been linked to cancer development and progression in a number of tissues, the expression of cyclin D2 and D3 proteins in colon cancer has not yet been characterised. In this study, we examined cyclin D1, D2 and D3 protein expression by Western blot analysis in tumour and adjacent normal colon tissues of 57 patients. In addition, we examined D-type cyclins protein expression in HT29 and LoVo39 cell lines from colon carcinomas, as a function of induced proliferation and differentiation. In both cell lines, the expression of the three D-type cyclins increased as a result of induced proliferation, whereas the expression of cyclin D3 increased as a result of induced differentiation. In colon tumours, cyclin D1 was overexpressed in 44%, cyclin D2 was overexpressed in 53% and cyclin D3 was overexpressed in 35% of the cases. We also found that in 16% of the cases, cyclin D3 protein expression was reduced in the tumour, as compared to the adjacent normal tissue. Examination of D-type cyclin protein overexpression in relation to the TNM stage of the tumours revealed that overexpression of cyclins D1 and/or D2, but not cyclin D3, is linked to colon carcinogenesis and that overexpression of cyclin D2 may be related to a higher TNM stage of the tumour.

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

Expression of D-type cyclins in colon cancer and in cell lines from colon carcinomas

et al. 2005

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“…5 However, there are also reports indicating that cyclin E expression does not correlate with clinicopathological parameters, 6 or is associated with good prognosis. 7 Overexpression of cyclin A correlates with poor outcome in various cancer patients 2 but thus far has not been shown to affect prognosis of gastric cancer patients. 8 During the cell cycle, expression of cyclins and cell cyclerelated proteins is strictly regulated.…”

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confidence: 99%

Prognostic significance of cyclin A in gastric cancer

Mrena

Wiksten

Kokkola

et al. 2006

Intl Journal of Cancer

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High level of cyclin A promotes carcinogenesis, and overexpression of cyclin A has been associated with poor prognosis of cancer patients. We validated the prognostic role of cyclin A in gastric cancer and evaluated its correlation with expression of an mRNA stability factor HuR. From 342 consecutive histologically confirmed gastric cancer patients were obtained 325 representative tissue specimens for cyclin A and 316 for HuR immunohistochemistry. Specimens were stained by cyclin A and HuR specific monoclonal antibodies. Nuclear immunostaining detected in 5% of the tumor cells was considered the cut-off for cyclin A positivity. Positive HuR immunoreactivity was scored as nuclear or cytoplasmic. Associations between scores, clinicopathological factors and survival were calculated by the v 2 -test, Fisher's exact test, Kaplan-Meier test and Cox model. Cyclin A detected in the nuclei of cancer cells was positive in 55% (179 of 325) of the specimens; 40% (127 of 316) of the specimens had cytoplasmic and 88% (279 of 316) nuclear immunoreactivity of HuR. Cyclin A expression was an independent prognostic factor for poor survival. Cyclin A immunoreactivity was associated with old age, high stage, proximal location of the tumor, intestinal type, noncurative resection, advanced penetration depth and with nodal metastases but not distant metastases. Furthermore, cyclin A expression was associated with cytoplasmic HuR expression, whereas no association with nuclear HuR was evident. Cyclin A is an independent prognostic factor in gastric cancer, and one mechanism for its overexpression may depend on cytoplasmic localization of HuR. ' 2006 Wiley-Liss, Inc.Key words: cyclin A; HuR; gastric cancer; prognosis; survival Cyclin A belongs to the cyclin protein superfamily, and it can activate two different cyclin-dependent kinases, CDK1 and CDK2. The level of cyclin A accumulates progressively throughout the interphase and disappears rapidly at the end of mitosis. Currently, phosphorylated cyclin A-CDK complex is suggested to play an important role in the initiation of DNA replication in the S phase. The precise function of cyclin A in mitosis is unclear, but it may prevent other cyclins from degradation. Overexpression of cyclin A and dysregulation of CDK-cyclin complexes promote tumor cell growth, which can be facilitated by phosphorylation of oncoproteins and tumor suppressors. 1,2 In gastric cancer, cell-cycle regulators have been connected with poor prognosis. For example, overexpression of cyclin E, which also binds to CDK2 and controls the G1-S transition, has been associated with aggressive disease. 3,4 Furthermore, strongly positive cyclin E in the tumors of patients having surgery with intent to cure is a marker of poor prognosis, and concurrent expression of cyclin E and p53 is an independent prognostic factor. 5 However, there are also reports indicating that cyclin E expression does not correlate with clinicopathological parameters, 6 or is associated with good prognosis. 7 Overexpression of cyclin A correlates with po...

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“…A number of studies reported that cylin D2 was highly expressed in transformed cells and various tumor cells, particularly in the germ cell tumors [4,19,20], suggesting that the cyclin D2 could act as a proliferating marker just as cyclin D1. However, some papers indicated that the level of cyclin D2 was not associated with the transformation nor various types of tumors [1][2][3].…”

Section: Discussionmentioning

confidence: 99%

“…Aberrant expression of cyclin D2 has been linked to the human male germ cell tumorigenesis [9]. Moreover, overexpression of the cyclin D2 has been determined in chronic B-cell malignancies [5] and is known to be closely correlated with the gastric cancer progression and prognosis [19,20]. Cyclin D2 was expressed highly in transformed cells as well [6].…”

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confidence: 99%

Low Expression of Cyclin D2 in G2/M-Arrested and Transformed Proliferating Balb/3T3 Cells.

Fang

Lee

et al. 2002

The Journal of Veterinary Medical Science

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ABSTRACT. At present, the effect of cyclin D2 implicated in cell cycle regulation, differentiation, and oncogenic transformation is not fully confirmed. To better elucidate the role of cyclin D2 in controling the cell proliferation, cyclin D2 expression level was determined at the early initiation and promotion stages during the in vitro two-stage transformation process of Balb/3T3 A31 cells. N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced G2/M-arrested cells expressed low level of cyclin D2 mRNA, while the contact-inhibited nonproliferating cells expressed high level of cyclin D2 mRNA. In the transformed proliferating cells at the promotion stage, cyclin D2 mRNA was not expressed. These data suggest that cyclin D2 expression may be associated with the type of growth arrest and nonproliferating state, but not with the cell proliferation and transformation.KEY WORDS: cyclin D2, G2/M arrest, transformation.J. Vet. Med. Sci. 64(3): 201-205, 2002 The D-type cyclins synthesized during the early G1 phase consist of three family members, cyclins D1, D2, and D3. Cyclin D1, encoded by bcl-1/PRAD1 oncogene, is an important cell cycle positive regulator facilitating the G1 progression toward the S phase similar to cyclin E and PCNA [23]. Cyclins D2 and D3 were cloned as a consequence of their homologies to cyclin D1 [10,15,23], and cyclin D2 was also independently identified to be encoded by a gene mutated with proviral insertion [8]. Aberrant expression of cyclin D2 has been linked to the human male germ cell tumorigenesis [9]. Moreover, overexpression of the cyclin D2 has been determined in chronic B-cell malignancies [5] and is known to be closely correlated with the gastric cancer progression and prognosis [19,20]. Cyclin D2 was expressed highly in transformed cells as well [6]. In addition, this cyclin has been linked to the differentiation of neural cell populations [16,17] and the activation of macrophage [21]. Furthermore, coexpression of cyclin D2 and Ha-Ras under low-serum conditions can induce a senescence-like phenotype [12]. However, several papers also reported that cyclin D2 was overexpressed in various nonproliferating states [11,14,18]. These results suggest that cyclin D2 may have different roles depending on its levels of expression and cell type. Therefore, to further understand the role of cyclin D2 on the cell proliferation, we determined the cyclin D2 mRNA expression level in G2/M-arrested cells initiated by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), contact-inhibited cells, and proliferating cells during the in vitro two-stage transformation process of Balb/ 3T3 A31 cells. MATERIALS AND METHODSChemicals: MNNG, cadmium chloride (CdCl 2 ), Tri reagent, and other commonly used chemicals were purchased from Sigma (St. Louis, MO, U.S.A.). Dulbecco's modified Eagle's medium (DMEM), DMEM/F12 medium and bovine calf serum (BCS) were obtained from GIBCO-BRL (Gaithesburg, MD, U.S.A.). Digoxigenin (DIG)-RNA labeling and detection kit, and β-actin plasmid cDNA were purchased from Boehringer Mannheim (Ma...

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Cyclin D2 Overexpression and Lack of p27 Correlate Positively and Cyclin E Inversely with a Poor Prognosis in Gastric Cancer Cases

Cited by 146 publications

References 41 publications

Expression of D-type cyclins in colon cancer and in cell lines from colon carcinomas

Expression of D-type cyclins in colon cancer and in cell lines from colon carcinomas

Prognostic significance of cyclin A in gastric cancer

Low Expression of Cyclin D2 in G2/M-Arrested and Transformed Proliferating Balb/3T3 Cells.

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