title: Actinin-4 increases cell motility and promotes lymph node metastasis of colorectal cancer.
abstract: OBJECTIVE
  Enhanced motility of cancer cells by remodeling of the actin cytoskeleton seems crucial in the process of cancer invasion and metastasis. We previously identified an actin-binding protein, actinin-4, as a new biomarker of cancer invasion and an indicator of prognosis for patients with breast cancer. However, its involvement in the mechanisms of cancer invasion and metastasis remains undetermined. The current study tested the role of actinin-4 in the motility and metastatic potential of colorectal cancer cells.
  
  
  RESULTS
  Quantitative immunofluorescence histochemistry showed that the expression level of the actinin-4 protein was increased in 73.1% (19/26) of the cases of colorectal cancer over the corresponding normal intestinal epithelium. The increased expression of actinin-4 was most significant in dedifferentiated cancer cells at the invasive front. A colorectal cancer cell clone capable of inducing actinin-4 using the tetracycline-regulatory system (designated DLD1 Tet-off ACTN-4) was established. Upon the induction of actinin-4, DLD1 Tet-off ACTN-4 cells spread filopodia and significantly increased their motility ( P = .00027); actinin-4 protein was concentrated at the leading edges of these actin-rich podia. When injected into the mesocecum of severe combined immunodeficient mice, DLD1 Tet-off ACTN4 cells, but not the control cells, metastasized into regional mesenteric lymph nodes, resembling the behavior of clinical cancers. The expression of actinin-4 in focally dedifferentiated cancer cells at the invasive front was significantly correlated with the frequency of lymph node metastasis of colorectal cancer ( P = .038).
  
  
  CONCLUSIONS
  Actinin-4 actively increases cell motility and promotes lymph node metastasis of colorectal cancer.
authors.affiliation: Chemotherapy Division and Cancer Proteomics Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuoh-ku, Tokyo 104-0045, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Honda
authors.forename: Tesshi
authors.initials: T
authors.lastname: Yamada
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Hayashida
authors.forename: Masashi
authors.initials: M
authors.lastname: Idogawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sato
authors.forename: Fumio
authors.initials: F
authors.lastname: Hasegawa
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ino
authors.forename: Masaya
authors.initials: M
authors.lastname: Ono
authors.forename: Setsuo
authors.initials: S
authors.lastname: Hirohashi
mesh_terms: D000185:Actinin / Q000096:biosynthesis*; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis
chemical_list: C111453:ACTN4 protein, human; D014408:Biomarkers, Tumor; D008840:Microfilament Proteins; D000185:Actinin