The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers.
High-density array comparative genomic hybridization (CGH) showed amplification of chromosome 1q22 centered on the RAB25 small GTPase, which is implicated in apical vesicle trafficking, in approximately half of ovarian and breast cancers. RAB25 mRNA levels were selectively increased in stage III and IV serous epithelial ovarian cancers compared to other genes within the amplified region, implicating RAB25 as a driving event in the development of the amplicon. Increased DNA copy number or RNA level of RAB25 was associated with markedly decreased disease-free survival or overall survival in ovarian and breast cancers, respectively. Forced expression of RAB25 markedly increased anchorage-dependent and anchorage-independent cell proliferation, prevented apoptosis and anoikis, including that induced by chemotherapy, and increased aggressiveness of cancer cells in vivo. The inhibition of apoptosis was associated with a decrease in expression of the proapoptotic molecules, BAK and BAX, and activation of the antiapoptotic phosphatidylinositol 3 kinase (PI3K) and AKT pathway, providing potential mechanisms for the effects of RAB25 on tumor aggressiveness. Overall, these studies implicate RAB25, and thus the RAB family of small G proteins, in aggressiveness of epithelial cancers.
Cheng
Kwai Wa
KW
Department of Molecular Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
Lahad
John P
JP
Kuo
Wen-Lin
WL
Lapuk
Anna
A
Yamada
Kyosuke
K
Auersperg
Nelly
N
Liu
Jinsong
J
Smith-McCune
Karen
K
Lu
Karen H
KH
Fishman
David
D
Gray
Joe W
JW
Mills
Gordon B
GB
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D049109:Cell Proliferation; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009693:Nucleic Acid Hybridization / Q000379:methods; D010051:Ovarian Neoplasms / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D020691:rab GTP-Binding Proteins; C494772:BAK1 protein, human; C494826:BAX protein, human; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; C494918:AKT1 protein, human