Oncogenic role of KIAA0101 interacting with proliferating cell nuclear antigen in pancreatic cancer.
To isolate novel diagnostic markers and therapeutic targets for pancreatic cancer, we earlier did expression profile analysis of pancreatic cancer cells using a genome-wide cDNA microarray combined with microdissection. Among dozens of trans-activated genes in pancreatic cancer cells, this study focused on KIAA0101 whose overexpression in pancreatic cancer cells was validated by immunohistochemical analysis. KIAA0101 was previously identified as p15(PAF) [proliferating cell nuclear antigen (PCNA)-associated factor] to bind with PCNA; however, its function remains unknown. To investigate for the biological significance of KIAA0101 overexpression in cancer cells, we knocked down KIAA0101 by small interfering RNA (siRNA) in pancreatic cancer cells and found that the reduced expression by siRNA caused drastic attenuation of their proliferation as well as significant decrease in DNA replication rate. Concordantly, exogenous overexpression of KIAA0101 enhanced cancer cell growth, and NIH3T3 derivative cells expressing KIAA0101 revealed in vivo tumor formation, implying its growth-promoting and oncogenic property. We also showed that the expression of KIAA0101 was regulated tightly by the p53-p21 pathway. To consider the KIAA0101/PCNA interaction as a therapeutic target, we designed the cell-permeable 20-amino-acid dominant-negative peptide and found that it could effectively inhibit the KIAA0101/PCNA interaction and resulted in the significant growth suppression of cancer cells. Our results clearly implicated that suppression of the KIAA0101 and PCNA oncogenic activity, or the inhibition of KIAA0101/PCNA interaction, is likely to be a promising strategy to develop novel cancer therapeutic drugs.
Hosokawa
Masayo
M
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Takehara
Akio
A
Matsuda
Koichi
K
Eguchi
Hidetoshi
H
Ohigashi
Hiroaki
H
Ishikawa
Osamu
O
Shinomura
Yasuhisa
Y
Imai
Kohzoh
K
Nakamura
Yusuke
Y
Nakagawa
Hidewaki
H
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C425208:PCLAF protein, human; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering