Loss of FBXW7, a cell cycle regulating gene, in colorectal cancer: clinical significance.
This study focused on a cell cycle regulatory gene, FBXW7, which ubiquitinates c-Myc and cyclin E and promotes exit from the cell cycle. We determined the expression level of FBXW7 in colorectal cancer (CRC) cases, correlated those values with clinicopathologic features, and characterized the molecular mechanism of reduced expression of FBXW7 in CRC cells in vitro. FBXW7 mRNA and protein expression were evaluated in 93 CRC cases. Using CGH array, the copy number aberrations of the flanking region of FBXW7 were evaluated in another 130 CRC specimens. In vitro analysis of FBXW7 gene silencing in CRC cells was conducted. FBXW7 mRNA expression was significantly lower in tumor tissues than the corresponding normal tissues. The low FBXW7 expression group showed a significantly poorer prognosis than patients in the high expression group. A concordant relationship was observed between the incidence of FBXW7 repression and the genetic alteration. The incidence of genetic alteration was associated with the stage of disease progression. In vitro, FBXW7-specific siRNA enhanced expression of c-MYC and cyclin E proteins and up-regulated cell proliferation. Genetic alterations in tumors led to the loss of FBXW7 expression and increased cell proliferation. FBXW7 expression provides a prognostic factor for patients with CRC.
Iwatsuki
Masaaki
M
Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.|Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Mimori
Koshi
K
Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.
Ishii
Hideshi
H
Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.
Yokobori
Takehiko
T
Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.
Takatsuno
Yasushi
Y
Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.
Sato
Tetsuya
T
Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Toh
Hiroyuki
H
Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Onoyama
Ichiro
I
Department of Molecular and Cellular Biology, Division of Cell Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Nakayama
Keiichi I
KI
Department of Molecular and Cellular Biology, Division of Cell Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Baba
Hideo
H
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Mori
Masaki
M
Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.
D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D019927:Cyclin E / Q000096:biosynthesis; D044783:F-Box Proteins / Q000096:biosynthesis / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007834:Lasers; D008297:Male; D042282:Microdissection; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D034622:RNA Interference; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics*
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D019927:Cyclin E; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D044767:Ubiquitin-Protein Ligases