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p53 apoptotic pathway molecules are frequently and simultaneously altered in nonsmall cell lung carcinoma

Shoichi Mori1, Genshi Ito, Noriyasu Usami

  • 1Department of Clinical Preventive Medicine, Nagoya University School of Medicine, Nagoya, Japan.

Cancer
|April 10, 2004
PubMed
Abstract

Insights

Alterations in the p53 pathway, including p53, p14(ARF), and HDM2, are frequent in nonsmall cell lung carcinoma (NSCLC). These pathway component abnormalities are critical for NSCLC development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Nonsmall cell lung carcinoma (NSCLC) frequently exhibits p53 tumor suppressor inactivation, a key regulator of apoptosis.
  • The study investigates alterations in the p53 apoptotic pathway, particularly in NSCLC tumors lacking p53 mutations.

Purpose of the Study:

  • To assess the alterations in the p53 apoptotic pathway in nonsmall cell lung carcinoma (NSCLC).
  • To identify the specific components of the p53 pathway that are frequently affected in NSCLC, including tumors with and without p53 alterations.

Main Methods:

  • Analyzed p53, p14(ARF), HDM2, BAX, and BCL2 in 118 NSCLC specimens using techniques including single-stranded conformation polymorphism, immunohistochemistry (IHC), and Southern blot analysis.
  • Investigated upstream regulators of p53 stability, PTEN and HAUSP, and molecules involved in p53 transcriptional function, ASPP1 and ASPP2.

Main Results:

  • p53 alterations were found in 63% of NSCLC specimens, p14(ARF) inactivation in 45%, and HDM2 overexpression in 26%.
  • HDM2 gene amplification occurred exclusively in tumors without p53 mutations.
  • Down-regulation of PTEN was observed in 25% of tumors, while BAX and BCL2 expression varied (39% and 14%, respectively).

Conclusions:

  • Two or more p53 pathway components were frequently altered in NSCLC patients.
  • Over 90% of these alterations involved abnormalities in p53, p14(ARF), or HDM2.
  • Inactivation of one or more p53 pathway components is likely a prerequisite for the development of most NSCLCs.

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