Expression of cyclins and cyclin-dependent kinases in smooth muscle tumors of the uterus

Zhai, Ya Li; Nikaido, Toshio; Shiozawa, Tanri; Orii, Ayaka; Fujii, Shingo

doi:10.1002/(sici)1097-0215(19990621)84:3<244::aid-ijc8>3.0.co;2-2

Cited by 30 publications

(25 citation statements)

References 19 publications

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“…8 However, the majority of previous works particularly emphasize that overexpression of cyclin A is a marker for poor prognosis in cancer. [24][25][26][27][28][29][30][31][32][33][34] There are 2 known isoforms of cyclin A. Cyclin A1 is the embryonal form of the protein, and its role is limited to male meiosis. 35 Cyclin A1 is also expressed in normal human testis and brain tissues, and in myeloid leuchemia cell lines.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

Prognostic significance of cyclin A in gastric cancer

Mrena

Wiksten

Kokkola

et al. 2006

Intl Journal of Cancer

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“…Further experiments are also required to elucidate the molecular mechanism of human Ut-LMS tumorigenesis involved biological significance of LMP2/1i. Histologic and IHC characteristics of uterine mesenchymal tumors including mitotically active leiomyoma, bizarre leiomyoma, lipoleiomyoma, uterine smooth muscle tumors of uncertain malignant potential (STUMP), leiomyomatoid angiomatous neuroendocrin tumor (LANT) are summarized [60][61][62][63][64][65]. Clarification of the correlation between these factors and the development of human Ut-LMS and the identification of specific risk factors may lead to the development of new clinical treatments for the disease.…”

Section: Discussionmentioning

confidence: 99%

Candidate Molecules as Tumor Suppressor for Human Uterine Mesenchymal Tumor

Hayashi¹

2013

iosrphr

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: Uterine leiomyosarcoma (Ut-LMS) develops more often in myometrium of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion; however, the development of Ut-LMS is not substantially correlated with hormonal conditions, and the risk factor (s) are not yet known. Importantly, a diagnostic-biomarker, which distinguishes malignant tumor Ut-LMS from benign tumor leiomyoma (LMA), is yet to be established. Accordingly, it is necessary to examine risk factor(s) associated with Ut-LMS, to establish a diagnosis and a clinical treatment method. The mice with a homozygous deficiency for proteasome -ring subunit, low-molecular mass polypeptide (LMP)2/1i spontaneously develop Ut-LMS, with a disease prevalence of ~37% by 12 months of age. In the recent study, we found LMP2/1i expression to be absent in human Ut-LMS, but clearly present in other human uterine mesenchymal tumors including uterine LMA. Further analyses with clinical materials and the gene-modified mice have not clarified the biological significance of the TP53 and retinoblastoma (Rb) pathway in malignant myometrium transformation, thus implicating LMP2/1i as an anti-tumorigenic candidate. This role of LMP2/1i as a tumor suppressor may lead to new therapeutic targets in human

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“…The impact of cyclin A2 accumulation as a prognostic marker in human cancers has been underlined by previous studies (Allan et al, 2000;Brechot, 1993;Handa et al, 1999;Huuhtanen et al, 1999;Zhai et al, 1999). Most of these investigations did not speci®cally address the cellular distribution of cyclin A2.…”

Section: Discussionmentioning

confidence: 99%

Centrosome overduplication, increased ploidy and transformation in cells expressing endoplasmic reticulum-associated cyclin A2

et al. 2002

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Cyclin A2 is predominantly, but not exclusively, localized in the nucleus from G1/S transition onwards. It is degraded when cells enter mitosis after nuclear envelope breakdown. We previously showed that a fusion protein (S2A) between the hepatitis B virus (HBV) surface antigen protein and a non-degradable fragment of human cyclin A2 (D152) resides in the endoplasmic reticulum membranes, escapes degradation and transforms normal rat ®broblasts. The present study investigates whether cytoplasmic cyclin A2 may play a role in oncogenesis. We show that the sequestration of non-degradable cyclin A2-D152 by a cellular ER targeting domain (PRL-A2) leads to cell transformation when coexpressed with activated Ha-ras. REF52 cells constitutively expressing PRL-A2 are found to have a high incidence of multinucleate giant cells, polyploidy and abnormal centrosome numbers, giving rise to the nucleation of multipolar spindles. Injection of these cells into athymic nude mice causes tumors, even in the absence of a cooperating Ha-ras oncogene. These results demonstrate that, independently of any viral context, an intracellular redistribution of non-degradable cyclin A2 is capable of deregulating the normal cell cycle to the point where it promotes aneuploidy and cancer.

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Expression of cyclins and cyclin-dependent kinases in smooth muscle tumors of the uterus

Cited by 30 publications

References 19 publications

Prognostic significance of cyclin A in gastric cancer

Prognostic significance of cyclin A in gastric cancer

Candidate Molecules as Tumor Suppressor for Human Uterine Mesenchymal Tumor

Centrosome overduplication, increased ploidy and transformation in cells expressing endoplasmic reticulum-associated cyclin A2

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