title: SORORIN and PLK1 as potential therapeutic targets in malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is an aggressive type of cancer of the thoracic cavity commonly associated with asbestos exposure and a high mortality rate. There is a need for new molecular targets for the development of more effective therapies for MPM. Using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and an RNA interference-based screening, we examined the SORORIN gene as potential therapeutic targets for MPM in addition to the PLK1 gene, which is known for kinase of SORORIN. Following in vitro investigation of the effects of target silencing on MPM cells, cell cycle analyses were performed. SORORIN expression was analyzed immunohistochemically using a total of 53 MPM samples on tissue microarray. SORORIN was found to be overexpressed in the majority of clinical MPM samples and human MPM cell lines as determined by qRT-PCR. Gene suppression of each SORORIN and PLK1 led to growth inhibition in MPM cell lines. Knockdown of SORORIN showed an increased number of G2M-phase population and a larger nuclear size, suggesting mitotic arrest. High expression of SORORIN (SORORIN-H) was found in 50.9% of all the MPM cases, and there is a tendency towards poorer prognosis for the SORORIN-H group but the difference is not significant. Suppression of SORORIN with PLK1 inhibitor BI 6727 showed a combinational growth suppressive effect on MPM cell growth. Given high-dose PLK1 inhibitor induced drug-related adverse effects in several clinical trials, our results suggest inhibition SORORIN-PLK1 axis may hold promise for the treatment of MPMs.
authors.affiliation: Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kato
authors.affiliation: Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
authors.forename: Daiyoon
authors.initials: D
authors.lastname: Lee
authors.affiliation: Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
authors.forename: Licun
authors.initials: L
authors.lastname: Wu
authors.affiliation: Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
authors.forename: Priya
authors.initials: P
authors.lastname: Patel
authors.affiliation: Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
authors.forename: Ahn Jin
authors.initials: AJ
authors.lastname: Young
authors.affiliation: Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Wada
authors.affiliation: Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
authors.forename: Hsin-Pei
authors.initials: HP
authors.lastname: Hu
authors.affiliation: Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ujiie
authors.affiliation: Department of Thoracic Surgery, Sapporo Minami-sanjo Hospital, Sapporo, Japan.
authors.forename: Mitsuhito
authors.initials: M
authors.lastname: Kaji
authors.affiliation: Department of Pathology, Kinikyo-Chuo Hospital, Sapporo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kano
authors.affiliation: Department of Surgery, Kinikyo-Chuo Hospital, Sapporo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Matsuge
authors.affiliation: Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Domen
authors.affiliation: Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kanno
authors.affiliation: Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hatanaka
authors.affiliation: Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
authors.forename: Kanako C
authors.initials: KC
authors.lastname: Hatanaka
authors.affiliation: Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Kichizo
authors.initials: K
authors.lastname: Kaga
authors.affiliation: Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Matsui
authors.affiliation: Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsuno
authors.affiliation: Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: De Perrot
authors.affiliation: Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yasufuku
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D008654:Mesothelioma / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011621:Pteridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097869:Polo-Like Kinase 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1; C541363:BI 6727; C500695:CDCA5 protein, human