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Disruption of the RB pathway and cell-proliferative activity in non-small-cell lung cancers
H Tanaka1, Y Fujii, H Hirabayashi
1First Department of Surgery, Osaka University Medical School, Japan. hitanaka@surg1.med.osaka-u.ac.jp
Abstract:
The pathway consisting of retinoblastoma protein (pRB), cyclin D1 and p16 (RB pathway) which is involved in the phosphorylation of pRB plays an important role in G1/S progression. The disruption of this RB pathway has been reported in several types of human neoplasm. An immunohistochemical study of 101 non-small-cell lung cancers (NSCLCs) showed loss of p16 is in 47 tumors (46.5%) and loss of pRB in 42 tumors (41.6%). In 79 of 101 NSCLCs (78.2%), the expression of p16 and pRB was complementary (p < 0.0001). Methylation of the cdkn2 gene was detected in 50% of p16-negative tumors and in 11% of p16-positive tumors. Aberrant expression of cyclin D1 was found in 45 tumors (44.5%). The cyclin-D1-positive tumors had significantly higher Ki-67 indices than the cyclin-D1-negative tumors irrespective of the tumor p16 or pRB expression. Thus, 91 (90%) of 101 NSCLCs showed disturbed expression of at least 1 of the 3 components of the RB pathway. Our results suggest that the disruption of the RB pathway plays an important role in tumorigenesis in NSCLCs and that increased cyclin-D1 expression leads to strong proliferative activity which may over-ride the suppressive effect of p16 and pRB.
Insights
Disruption of the retinoblastoma (RB) pathway, involving p16, cyclin D1, and pRB, is common in non-small-cell lung cancers (NSCLCs). Aberrant expression of these proteins drives tumor growth and proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Cell Cycle Regulation
Background:
- The retinoblastoma (RB) pathway, comprising pRB, cyclin D1, and p16, is crucial for G1/S cell cycle progression.
- Disruptions in the RB pathway are implicated in various human neoplasms, including lung cancer.
Purpose of the Study:
- To investigate the frequency and significance of RB pathway alterations in non-small-cell lung cancers (NSCLCs).
- To determine the correlation between RB pathway component expression and tumor proliferation markers.
Main Methods:
- Immunohistochemical analysis of p16, pRB, and cyclin D1 expression in 101 NSCLC tumors.
- Analysis of cdkn2 gene methylation in relation to p16 expression.
- Correlation of protein expression with Ki-67 proliferation indices.
Main Results:
- Loss of p16 was observed in 46.5% and loss of pRB in 41.6% of NSCLCs.
- Complementary expression of p16 and pRB was found in 78.2% of tumors.
- Aberrant cyclin D1 expression occurred in 44.5% of tumors, associated with higher Ki-67 indices.
- 90% of NSCLCs exhibited disturbed expression of at least one RB pathway component.
Conclusions:
- The RB pathway is frequently disrupted in NSCLCs, suggesting its significant role in tumorigenesis.
- Increased cyclin D1 expression correlates with high proliferative activity, potentially overriding p16 and pRB suppressive functions.