E2F-1, Skp2 and cyclin E oncoproteins are upregulated and directly correlated in high-grade neuroendocrine lung tumors

Oncogene. 2007 Oct 18;26(48):6927-36. doi: 10.1038/sj.onc.1210499. Epub 2007 Apr 30.

Abstract

The transcription factor E2F-1 plays a crucial role in the control of cellular growth. We previously reported its differential pattern of expression in human lung tumors. In this study, we have investigated the relationships linking the status of E2F-1 and a mediator of its proteasomal degradation, the S-phase kinase-associated protein 2 (Skp2) F-box protein. Using immunohistochemistry in a series of 129 lung tumors of all histological types, we demonstrate that Skp2 accumulates preferentially in high-grade neuroendocrine (HGNE) lung carcinomas (86%, P<0.0001), and show that Skp2 overexpression is associated with advanced stages (P<0.0001) and nodal metastasis (P<0.0001) in neuroendocrine (NE) lung tumors. Unexpectedly, we observe that Skp2 and E2F-1 expression directly correlates in NE lung tumors (P<0.0001). Moreover, using cellular models, we identify Skp2 as a new E2F-1 transcriptional target. Furthermore, we also provide evidence that Skp2 interacts physiologically with E2F-1 and stimulates its transcriptional activity toward the cyclin E promoter. Consistently, we demonstrate that cyclin E expression directly correlates with Skp2 (P<0.0001) and E2F-1 (P=0.0001) status in NE lung tumors. Overall, our data provide the first evidence of a direct and functional interconnection between the E2F-1, Skp2 and cyclin E oncoproteins in HGNE lung carcinomas.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / secondary
  • Cyclin E / genetics
  • Cyclin E / metabolism*
  • E2F1 Transcription Factor / metabolism*
  • Humans
  • Immunoblotting
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Lymphatic Metastasis / pathology
  • Neoplasm Staging
  • Neuroendocrine Tumors / metabolism*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • S-Phase Kinase-Associated Proteins / genetics
  • S-Phase Kinase-Associated Proteins / metabolism*
  • Transcription, Genetic
  • Up-Regulation

Substances

  • Biomarkers, Tumor
  • CCNE1 protein, human
  • Cyclin E
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Oncogene Proteins
  • RNA, Small Interfering
  • S-Phase Kinase-Associated Proteins