Identification of mitochondrial FoF1-ATP synthase involved in liver metastasis of colorectal cancer.
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.
Chang
Hee Jin
HJ
Research Institute and Hospital, National Cancer Center, 809 Madu 1-dong, Ilsandong-gu, Goyan-si, Gyeonggi-do 410-769, Korea.
Lee
Min Ro
MR
Hong
Sung-Hye
SH
Yoo
Byong Chul
BC
Shin
Young-Kyoung
YK
Jeong
Jun Yong
JY
Lim
Seok-Byung
SB
Choi
Hyo Seong
HS
Jeong
Seung-Yong
SY
Park
Jae-Gahb
JG
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
D021122:Protein Subunits; D025261:Mitochondrial Proton-Translocating ATPases