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p53 apoptotic pathway molecules are frequently and simultaneously altered in nonsmall cell lung carcinoma
Author(s) -
Mori Shoichi,
Ito Genshi,
Usami Noriyasu,
Yoshioka Hiromu,
Ueda Yuichi,
Kodama Yoshinori,
Takahashi Masahide,
Fong Kwun M.,
Shimokata Kaoru,
Sekido Yoshitaka
Publication year - 2004
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.20164
Subject(s) - pten , immunohistochemistry , cancer research , lung cancer , carcinoma , apoptosis , biology , tumor suppressor gene , western blot , pathology , gene , microbiology and biotechnology , carcinogenesis , medicine , immunology , pi3k/akt/mtor pathway , biochemistry
Abstract BACKGROUND Lung carcinomas show frequent inactivation of the p53 tumor suppressor, which regulates an apoptotic pathway. The objective of the current study was to assess how the p53 apoptotic pathway is altered in nonsmall cell lung carcinoma (NSCLC), especially in tumors without p53 alterations. METHODS p53, its upstream regulators (p14 ARF and HDM2), and downstream effectors of the apoptotic pathway (BAX and BCL2) were studied in 118 NSCLC specimens. p53 was analyzed by single‐stranded conformation polymorphism analysis covering exons 2–11 and by immunohistochemistry (IHC). p14 ARF was analyzed by methylation‐specific polymerase chain reaction and IHC. HDM2 was analyzed using Southern blot analysis and IHC. BAX and BCL2 were analyzed by IHC. Two other upstream regulators that regulate the stability of HDM2, PTEN and HAUSP, also were studied. RESULTS Of 118 NSCLC specimens that were analyzed, p53 alterations were detected in 74 tumors (63%), p14 ARF inactivation was detected in 53 tumors (45%), and overexpression of HDM2 was found in 31 tumors (26%), including 6 tumors with gene amplification. Although p53 inactivation and HDM2 overexpression were detected simultaneously, HDM2 gene amplification was observed only in tumor specimens without p53 mutations. IHC revealed PTEN down‐regulation in 22 of 88 tumors (25%). HAUSP Northern blot analysis demonstrated several‐fold differences in gene expression that did not correlate with p53 alterations. Of 118 NSCLC specimens, expression of BAX and BCL2 expression were detected in 46 tumors (39%) and 17 tumors (14%), respectively. Finally, ASPP1 and ASPP2, molecules involved in mediating the transcription function of p53, were not found to be aberrantly expressed when tested by Northern blot analysis. CONCLUSIONS Overall, two or more p53 pathway components were found to be frequently altered in patients with NSCLC. Greater than 90% of the alterations were due to abnormalities of p53, p14 ARF , or HDM2. Therefore, the inactivation of one or more components of the p53 pathway appears to be a prerequisite for the development of most NSCLCs. Cancer 2004. © 2004 American Cancer Society.