Kinesin family members KIF11 and KIF23 as potential therapeutic targets in malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is a rare and aggressive form of cancer commonly associated with asbestos exposure that stems from the thoracic mesothelium with high mortality rate. Currently, treatment options for MPM are limited, and new molecular targets for treatments are urgently needed. Using quantitative reverse transcription-polymerase chain reaction (RT-PCR) and an RNA interference-based screening, we screened two kinesin family members as potential therapeutic targets for MPM. Following in vitro investigation of the target silencing effects on MPM cells, a total of 53 MPMs were analyzed immunohistochemically with tissue microarray. KIF11 and KIF23 transcripts were found to be overexpressed in the majority of clinical MPM samples as well as human MPM cell lines as determined by quantitative RT-PCR. Gene knockdown in MPM cell lines identified growth inhibition following knockdown of KIF11 and KIF23. High expression of KIF11 (KIF11-H) and KIF23 (KIF23-H) were found in 43.4 and 50.9% of all the MPM cases, respectively. Patients who received curative resection with tumors displaying KIF23-H showed shorter overall survival (P=0.0194). These results provide that inhibition of KIF11 and KIF23 may hold promise for treatment of MPMs, raising the possibility that kinesin-based drug targets may be developed in the future.
Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
Tatsuya
T
Kato
Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
Daiyoon
D
Lee
Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
Licun
L
Wu
Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
Priya
P
Patel
Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
Ahn Jin
AJ
Young
Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
Hironobu
H
Wada
Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
Hsin-Pei
HP
Hu
Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
Hideki
H
Ujiie
Department of Thoracic Surgery, Sapporo Minami-sanjo Hospital, Sapporo, Japan.
Mitsuhito
M
Kaji
Department of Pathology, Kinikyo-Chuo Hospital, Sapporo, Japan.
Satoshi
S
Kano
Department of Surgery, Kinikyo-Chuo Hospital, Sapporo, Japan.
Shinichi
S
Matsuge
Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Hiromitsu
H
Domen
Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Kichizo
K
Kaga
Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Yoshiro
Y
Matsui
Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
Hiromi
H
Kanno
Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
Yutaka
Y
Hatanaka
Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
Kanako C
KC
Hatanaka
Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
Yoshihiro
Y
Matsuno
Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
Marc
M
de Perrot
Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
Kazuhiro
K
Yasufuku
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D016547:Kinesins / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010997:Pleural Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014162:Transfection
C470243:KIF11 protein, human; C092935:KIF23 protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D016547:Kinesins