title: Identification of mitochondrial FoF1-ATP synthase involved in liver metastasis of colorectal cancer.
abstract: Liver metastasis is a major cause of poor survival of colorectal cancer patients. In order to identify the proteins associated with liver metastasis in colorectal cancer, we carried out two-dimensional gel electrophoresis-based comparative proteomic analysis of normal colon mucosa, primary colon cancer tissue and corresponding metastatic tumor tissue in liver. The proteins identified were further validated by immunohistochemical analysis of 67 quadruplet samples of normal colon primary colorectal cancer and normal liver-synchronous liver metastasis, and 251 colorectal cancers as well as in vitro invasion assay of the human colon cancer cell line, SNU-81. From proteomic assessment, the mitochondrial FoF1-ATP synthase (ATP synthase) alpha-subunit was identified as a protein that is upregulated in liver metastasis compared with the primary tumor. Immunohistochemical analyses confirmed a significant increase in the expression of ATP synthase alpha- and d-subunits in synchronous liver metastasis compared with primary tumor and normal mucosa, respectively. ATP synthase alpha- and d-subunits were overexpressed in 197 (78.5%) and 190 (75.7%), respectively, of the 251 colorectal cancers. The alpha- and d-subunits were significantly associated with liver metastasis (P < 0.05) as well as low histological grade (P < 0.0001). The d-subunit also correlated with venous invasion (P = 0.026) and distant metastasis (P = 0.032). In stage III cancers, d-subunit expression was independently associated with poor survival (P = 0.017). Furthermore, transfection of small interfering RNA targeted to ATP synthase alpha- and d-subunits resulted in decreased in vitro invasiveness of the human colon cancer cell line. Our overall findings demonstrate that increased ATP synthase is associated with liver metastasis of colorectal cancer.
authors.affiliation: Research Institute and Hospital, National Cancer Center, 809 Madu 1-dong, Ilsandong-gu, Goyan-si, Gyeonggi-do 410-769, Korea.
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Chang
authors.forename: Min Ro
authors.initials: MR
authors.lastname: Lee
authors.forename: Sung-Hye
authors.initials: SH
authors.lastname: Hong
authors.forename: Byong Chul
authors.initials: BC
authors.lastname: Yoo
authors.forename: Young-Kyoung
authors.initials: YK
authors.lastname: Shin
authors.forename: Jun Yong
authors.initials: JY
authors.lastname: Jeong
authors.forename: Seok-Byung
authors.initials: SB
authors.lastname: Lim
authors.forename: Hyo Seong
authors.initials: HS
authors.lastname: Choi
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Jeong
authors.forename: Jae-Gahb
authors.initials: JG
authors.lastname: Park
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D040901:Proteomics; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D021122:Protein Subunits; D025261:Mitochondrial Proton-Translocating ATPases