title: HNRNPLL, a newly identified colorectal cancer metastasis suppressor, modulates alternative splicing ofCD44during epithelial-mesenchymal transition.
abstract: Despite the recent advances in treatment of colon cancer, the prognosis is unfavourable for patients with distant metastases. The aim of this study was to identify targets for prevention and/or therapy of colon cancer metastasis.
  
  
  
  CMT93 cells, a murine rectal cancer cell line with poor metastasising activity, were transduced with lentiviral shRNA library and transplanted into the rectum of syngeneic C57BL/6 mice. Genomic DNA was collected from metastatic lesions, and the integrated shRNA were retrieved by PCR for sequencing, followed by identification of the candidate genes targeted by the shRNA.
  
  
  
  The genome-wide shRNA library screen identifiedHnrnpll(heterogeneous nuclear ribonucleoprotein L-like) encoding a pre-mRNA splicing factor as a candidate metastasis suppressor gene. Knockdown ofHnrnpllenhanced matrigel invasion activity of colon cancer cells in vitro, as well as their metastatic ability in vivo. An RNA-immunoprecipitation analysis showed Hnrnpll-binding toCd44pre-mRNAs, and the level ofCd44 variable exon 6(Cd44v6),a poor prognosis marker of colorectal cancer, was increased by knocking downHnrnpll. A neutralising Cd44v6 antibody suppressed the matrigel invasion ability induced byHnrnpllknockdown. HNRNPLL expression was downregulated when colon cancer cells were induced to undergo epithelial-mesenchymal transition (EMT). Immunohistochemistry of clinical samples indicated that colorectal cancer cells with low E-cadherin expression at the invasion front exhibited decreased HNRNPLL expression.
  
  
  
  HNRNPLL is a novel metastasis suppressor of colorectal cancer, and modulates alternative splicing ofCD44during EMT.
authors.affiliation: Division of Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Sakuma
authors.affiliation: Departments of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sasaki
authors.affiliation: Departments of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Kenya
authors.initials: K
authors.lastname: Kimura
authors.affiliation: Departments of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Komori
authors.affiliation: Departments of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Departments of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.affiliation: Division of Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.|Department of Cancer Genetics, Program in Function Construction Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Aoki
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C112697:CD44v6 antigen; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D018960:Hyaluronan Receptors; D025521:Tumor Suppressor Proteins; C534662:hnRNPLL protein, mouse
keywords: COLORECTAL CANCER; COLORECTAL METASTASES; MOLECULAR MECHANISMS