Mieap suppresses murine intestinal tumor via its mitochondrial quality control

Abstract

Mieap, a novel p53-inducible protein, plays a key role in maintaining healthy mitochondria in various pathophysiological states. Here, we show that Mieap deficiency in ApcMin/+ mice is strikingly associated with the malignant progression of murine intestinal tumors. To understand the role that Mieap plays in in vivo tumorigenesis, we generated Mieap heterozygous (ApcMin/+ Mieap+/−) and homozygous (ApcMin/+ Mieap−/−) ApcMin/+ mice. Interestingly, the ApcMin/+ mice with the Mieap+/− and Mieap−/− genetic background revealed remarkable shortening of the lifetime compared to ApcMin/+ mice because of severe anemia. A substantial increase in the number and size of intestinal polyps was associated with Mieap gene deficiency. Histopathologically, intestinal tumors in the Mieap-deficient ApcMin/+ mice clearly demonstrated advanced grades of adenomas and adenocarcinomas. We demonstrated that the significant increase in morphologically unhealthy mitochondria and trace accumulations of reactive oxygen species may be mechanisms underlying the increased malignant progression of the intestinal tumors of Mieap-deficient ApcMin/+ mice. These findings suggest that the Mieap-regulated mitochondrial quality control plays a critical role in preventing mouse intestinal tumorigenesis.

Possible role of p53/Mieap‐regulated mitochondrial quality control as a tumor suppressor in human breast cancer

“…Sections were incubated overnight at 4°C with the rabbit polyclonal anti‐human Mieap antibody (diluted 1:200). Then, sections were incubated with EnVision reagents for 1 hour at room temperature . IHC evaluation was performed by experienced pathologists.…”

“…Although Mieap has been shown to be a key player in mitochondrial quality control, emerging evidence suggests that it also plays an important role in tumor suppression. In a mouse model, Mieap‐deficient (adenomatous polyposis coli) ApcMin/+ mice had a much shorter lifespan and increased numbers and sizes of intestinal tumors compared to those in Mieap ‐wild type ApcMin/+ mice, suggesting that loss of Mieap increases ROS production in the intestinal mucosa and accelerates tumor progression . Furthermore, Mieap‐regulated mitochondrial quality control is frequently inactivated in human colorectal cancer by Mieap promoter methylation, BNIP3 promoter methylation or p53 mutation .…”

Mitochondrial dysfunction and potential anticancer therapy

“…On the other hand, a mitochondrial quality control system regulated by the mitochondria‐eating (Mieap) protein responsible for removal of mitochondria with MDF. Mieap is a protein inducible by tumor suppressor p53 . Interestingly, Mieap suppresses murine intestinal tumors by the elimination of oxidized mitochondrial proteins…”

Discovery of Mieap‐regulated mitochondrial quality control as a new function of tumor suppressor p53

“…Apc Min/+ mice develop multiple benign tumors in the small intestine, and are therefore a murine intestinal tumor model . Mieap‐deficient Apc Min/+ mice showed a much shorter lifetime compared to the Mieap‐WT Apc Min/+ mice . This was due to substantially higher number and size of intestinal tumors in Mieap‐deficient Apc Min/+ mice .…”

“…Mieap KO mice were born normally and were able to grow after birth. Using these Mieap KO mice, we generated Mieap‐deficient Apc Min/+ mice . Apc Min/+ mice develop multiple benign tumors in the small intestine, and are therefore a murine intestinal tumor model .…”