BRAF mutation associated with dysregulation of apoptosis in human colorectal neoplasms

Int J Cancer. 2005 Jul 20;115(6):943-50. doi: 10.1002/ijc.20957.


To understand the role of BRAF dysfunction in the carcinogenesis and progression/development of colorectal tumors, the authors investigated genetic alterations in the BRAF gene in human colorectal neoplasms as well as the effects of an RAS inhibitor in BRAF-mutant cells. Seven colon cancer cell lines and 116 colorectal tumors (34 adenomas and 82 adenocarcinomas) were analyzed. Genetic alterations in the BRAF and K-ras genes were examined using polymerase chain reaction-single strand conformation polymorphism and direct sequencing analyses. The growth-inhibitory and apoptosis-inducing effects of the FTI-277 RAS inhibitor in colon cancer cell lines were analyzed as well. An immunohistochemical study was also performed to investigate the correlations between the clinicopathologic parameters involved in the Ki-67 labeling index and the number of apoptotic bodies in tumor cells. FTI-277 did not suppress the proliferation of BRAF-mutant cells (WiDr and TCO), but remarkably inhibited the growth of K-ras mutant cells (LoVo). Interestingly, LoVo cells underwent apoptosis by FTI-277 in a dose-dependent manner, whereas WiDr cells were resistant to this agent. In tumor samples, BRAF mutations were found in 1 (3.0%) of 33 adenomas and 6 (7.2%) of 83 adenocarcinomas. No tumor exhibited mutations in both the BRAF and K-ras genes. Neither BRAF nor K-ras mutations correlated with the Ki-67 labeling index immunohistochemically. However, the number of apoptotic bodies was significantly decreased in the BRAF-mutant tumors. Mutation in the BRAF gene may contribute to colorectal carcinogenesis by upregulating the antiapoptotic role of the RAS/RAF/MEK/ERK pathway.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenoma / genetics
  • Apoptosis / genetics*
  • Base Sequence
  • Cell Proliferation
  • Colorectal Neoplasms / genetics*
  • DNA Fragmentation
  • Enzyme Inhibitors / pharmacology
  • Female
  • Genes, ras*
  • Humans
  • Immunohistochemistry
  • Ki-67 Antigen / metabolism
  • Male
  • Methionine / analogs & derivatives*
  • Methionine / pharmacology
  • Middle Aged
  • Mutation*
  • Polymorphism, Single-Stranded Conformational
  • Proto-Oncogene Proteins B-raf*
  • Tumor Cells, Cultured


  • Enzyme Inhibitors
  • FTI 277
  • Ki-67 Antigen
  • Methionine
  • Proto-Oncogene Proteins B-raf