title: Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer.
abstract: Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. BNIP3 and NIX are critical mediators for the Mieap-regulated mitochondrial quality control. Mieap suppresses murine intestinal tumor via its mitochondrial quality control function. To explore the role of the Mieap-regulated mitochondria quality control function in colorectal cancer patients, we examined the statuses of p53, Mieap, BNIP3 and NIX in 57 primary colorectal cancer tissues. Promoter methylation of the Mieap and BNIP3 genes was found in 9% and 47% of colorectal cancer cases, respectively, whereas p53 mutation was found in more than 50% of colorectal cancer tissues lacking methylation of the Mieap and BNIP3 promoters, implying that the p53/Mieap/BNIP3-regulated mitochondria quality control pathway is inactivated in more than 70% of colorectal cancer patients. In LS174T colorectal cancer cells, hypoxia activated the Mieap-regulated mitochondria quality control function. Knockdown of p53, Mieap or BNIP3 in LS174T cells severely impaired the hypoxia-activated function, leading to the accumulation of unhealthy mitochondria and increase of mitochondrial reactive oxygen species generation. The mitochondrial reactive oxygen species generated by unhealthy mitochondria in the p53/Mieap/BNIP3-deficient cells remarkably enhanced cancer cell migration and invasion under hypoxic condition. These results suggest that the Mieap-regulated mitochondria quality control has a critical role in colorectal cancer suppression in the in vivo hypoxic tumor microenvironment.
authors.affiliation: Division of Cancer Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kamino
authors.affiliation: Division of Cancer Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Division of Cancer Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tsuneki
authors.affiliation: Division of Cancer Biology, National Cancer Center Research Institute, Tokyo, Japan.|Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sano
authors.affiliation: Division of Cancer Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Division of Cancer Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kitamura
authors.affiliation: Division of Cancer Biology, National Cancer Center Research Institute, Tokyo, Japan.|Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Futamura
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Shida
authors.affiliation: Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kanemitsu
authors.affiliation: Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Moriya
authors.affiliation: Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Division of Cancer Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Arakawa