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p21 is associated with cyclin D1, p16INK4a and pRb expression in resectable non-small cell lung cancer
S Vonlanthen1, J Heighway, A Kappeler
1Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
Abstract:
p21 (p21WAF1/CIP1) is involved in cell cycle regulation, as an inhibitor of cyclin dependent kinases (CDK2, CDK4 and CDK6). However, subsequent in vitro studies have suggested that p21 may influence this process by an additional mechanism, in particular through the regulation of cyclin D1 subcellular localisation. This study of primary resectable non-small cell lung cancer (NSCLC) was designed to examine p21 functions in association with the expression of cyclin D1 (including its subcellular localisation), p16INK4a and pRb. p21 expression was examined in 50 NSCLC (stage I-IIIA) and in several normal lung samples all of which had previously been studied for cyclin D1 (DNA, RT-PCR, immunostaining), p16INK4a (DNA, RT-PCR, immunostaining), and pRb (immunostaining). As assessed by immunoblotting and immunostaining, p21 was expressed at low levels in normal lung tissue with immunoreactivity seen in a small number of bronchial epithelial cells only. In NSCLC, p21 expression (> or =10% of positive cells) was observed in 42% (21/50) of cases. High p21 expression was associated with well differentiated tumours (p = 0.01) and cyclin D1 nuclear staining (p = 0.02). Furthermore, we found an inverse correlation with p16INK4a (p = 0.004) and a direct correlation with pRb expression (p = 0.02). Risk of relapse was associated with p16INK4a and p21 status with no relapse in patients with normal p16INK4a and p21. Our results confirm that a large number of NSCLC have a low level of p21 expression. The associations of p21 and nuclear cyclin D1, pRb, p16INK4a support the relevance of pathways linked to lung carcinogenesis that involve p21 but may act in addition to direct CDK inhibition.
Insights
p21 expression is altered in non-small cell lung cancer (NSCLC), correlating with tumor differentiation and cell cycle regulators. Low p21 and p16INK4a levels predict no relapse, suggesting their role in lung carcinogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- p21 (p21WAF1/CIP1) is a known inhibitor of cyclin-dependent kinases (CDKs) involved in cell cycle regulation.
- Emerging evidence suggests p21 may also regulate cyclin D1 subcellular localization, indicating additional roles beyond direct CDK inhibition.
Purpose of the Study:
- To investigate the function of p21 in non-small cell lung cancer (NSCLC).
- To analyze the association between p21 expression, cyclin D1 (including subcellular localization), p16INK4a, and pRb in NSCLC.
Main Methods:
- Immunoblotting and immunostaining were used to assess p21 expression in 50 NSCLC tissues (stage I-IIIA) and normal lung samples.
- Previous analyses included DNA, RT-PCR, and immunostaining for cyclin D1, p16INK4a, and pRb.
Main Results:
- p21 was expressed at low levels in normal lung tissue.
- p21 expression was observed in 42% of NSCLC cases and associated with well-differentiated tumors (p=0.01).
- High p21 expression correlated with nuclear cyclin D1 (p=0.02), inversely with p16INK4a (p=0.004), and directly with pRb (p=0.02).
- p16INK4a and p21 status were associated with the risk of relapse; patients with normal levels of both showed no relapse.
Conclusions:
- A significant proportion of NSCLC cases exhibit low p21 expression.
- The observed associations of p21 with nuclear cyclin D1, pRb, and p16INK4a support p21's relevance in lung carcinogenesis pathways beyond direct CDK inhibition.