Disruption of the RB pathway and cell-proliferative activity in non-small-cell lung cancers.
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.
Tanaka
H
H
First Department of Surgery, Osaka University Medical School, Japan. hitanaka@surg1.med.osaka-u.ac.jp
Fujii
Y
Y
Hirabayashi
H
H
Miyoshi
S
S
Sakaguchi
M
M
Yoon
H E
HE
Matsuda
H
H
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D018287:Carcinoma, Large Cell / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D002455:Cell Division; D019938:Cyclin D1 / Q000032:analysis / Q000096:biosynthesis*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D008297:Male; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D016160:Retinoblastoma Protein / Q000032:analysis / Q000096:biosynthesis*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D016160:Retinoblastoma Protein; D019938:Cyclin D1