Active Cyclin A-CDK2 Complex, a Possible Critical Factor for Cell Proliferation in Human Primary Lung Carcinomas

Abstract

Expression of cyclins A and E and cyclin-dependent kinase 2 (CDK2) was examined immunohistochemically in 190 cases of human lung carcinoma. Cyclin A and CDK2 were expressed in the majority of squamous cell carcinomas , small cell carcinomas, and large cell carcinomas , but in significantly fewer cases of adenocarcinomas. Cyclin E was expressed in a minority of all subtypes. In particular , well differentiated cells in squamous cell carcinoma stained positively for cyclin E; in contrast , cyclin A was expressed in the nonkeratinized proliferating areas of the tumor nests. Immunoblotting revealed that all these proteins were expressed at higher levels in tumor tissues than in adjacent normal tissues. Immunoprecipitation also revealed higher levels of cyclin A and cyclin E associated with CDK2 in tumor tissues. Furthermore , tumor tissues which exhibited higher cyclin A and CDK2 expression also had higher CDK2 kinase activity. However , cyclin E-associated kinase activity was barely detectable even in tumor samples exhibiting higher cyclin E expression. Consistent with these data , elevated expression of cyclin A correlated to shorter survival periods in contrast to expression of cyclin E , which correlated to longer survival periods. These results suggest that in human lung carcinomas, elevated expression of active cyclin A-CDK2 complexes with associated higher CDK2 kinase activity is critical for promoting cell cycle progression and unrestrained proliferation of tumor cells and can be a predictive marker for patients' prognosis. Cell proliferation is ultimately dependent on cell cycle control and the decision to continue to proliferate is made mainly during G 1 phase as a result of the activities of G 1 cyclins and CDK complexes. 1-8 Cyclin D is expressed initially in the G 1 phase and associated kinase activity, manifested mainly by CDK4, oscillates from mid-G 1 . Cyclin E is expressed periodically, assembling with CDK2 and inducing maximum kinase activity at the G 1 /S transition. 7,8 Subsequently cyclin A is expressed and is thought to be required, in association with CDK2 and CDC2 (cell-cycle division 2), for progression through the S phase and the G 2 /M transition, respectively. 9 Among these cyclins only cyclin D1 has been identified as a proto-oncogene, designated PRAD1. It is overexpressed in lung, breast, gastric, and esophageal carcinomas at a frequency ranging from 13 to 60% with or without amplification of the 11q13 region. 10 -15 Amplification and/or overexpression of cyclin E has also been reported in colorectal and breast carcinomas. 16 -21 Overexpression of cyclin A has been reported in several cases of cultured cell lines from alveolar epithelial cells of the lung. 22 In addition, the cyclin A gene was found to be the unique insertion site of hepatitis B virus (HBV) in one clonal hepatoma. Cyclin A may thus play a role in the continuous proliferation of liver cells and ultimately in the pathogenesis of hepatocellular carcinoma. 23,24 Based on these observations cyclins and CDKs are simply belie...

Prognostic significance of cyclin A in gastric cancer

“…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.…”

Role of cell‐cycle regulators in lung cancer

“…The overexpression of cyclin A has been consistently shown to be a negative prognostic indicator of lung cancer (Volm et al, 1997;Dobashi et al, 1998). Recently, overexpression of cyclin F, which is involved in significant increase in the G 2 population, was found in lung adenocarcinomas (Singhal et al, 2003a).…”

Chromosome instability in human lung cancers: possible underlying mechanisms and potential consequences in the pathogenesis

“…Reactivation of telomerase, which is observed in 80 -90% of lung cancers, allows cells to escape from telomere crisis. Note that telomere erosion may lead to the formation of unstable chromosomes such as dicentric and ring chromosomes, which are susceptible to entering the BFB cycle (See text and Figure 4) 1997; Dobashi et al, 1998;Mishina et al, 2000;Fukuse et al, 2000). In addition, frequent genetic and epigenetic alterations present in lung cancer may be associated with the induction of CIN in this scheme.…”