AIF downregulation and its interaction with STK3 in renal cell carcinoma

Shengqiang Xu; Hongjin Wu; Huan Nie; Lei Yue; Huadong Jiang; Sheng Xiao; Yu Li

doi:10.1371/journal.pone.0100824

AIF downregulation and its interaction with STK3 in renal cell carcinoma

PLoS One. 2014 Jul 3;9(7):e100824. doi: 10.1371/journal.pone.0100824. eCollection 2014.

Authors

Shengqiang Xu¹, Hongjin Wu², Huan Nie², Lei Yue², Huadong Jiang², Sheng Xiao³, Yu Li²

Affiliations

¹ School of Life Science and Technology, Harbin Institute of Technology, Harbin, China; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
² School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
³ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

Abstract

Apoptosis-inducing factor (AIF) plays a crucial role in caspase-independent programmed cell death by triggering chromatin condensation and DNA fragmentation. Therefore, it might be involved in cell homeostasis and tumor development. In this study, we report significant AIF downregulation in the majority of renal cell carcinomas (RCC). In a group of RCC specimens, 84% (43 out of 51) had AIF downregulation by immunohistochemistry stain. Additional 10 kidney tumors, including an oxyphilic adenoma, also had significant AIF downregulation by Northern blot analysis. The mechanisms of the AIF downregulation included both AIF deletion and its promoter methylation. Forced expression of AIF in RCC cell lines induced massive apoptosis. Further analysis revealed that AIF interacted with STK3, a known regulator of apoptosis, and enhanced its phosphorylation at Thr180. These results suggest that AIF downregulation is a common event in kidney tumor development. AIF loss may lead to decreased STK3 activity, defective apoptosis and malignant transformation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenoma, Oxyphilic / genetics
Adenoma, Oxyphilic / metabolism*
Adenoma, Oxyphilic / pathology
Apoptosis Inducing Factor / biosynthesis*
Apoptosis Inducing Factor / genetics
Carcinoma, Renal Cell / genetics
Carcinoma, Renal Cell / metabolism*
Carcinoma, Renal Cell / pathology
DNA Methylation
Down-Regulation*
Female
Gene Expression Regulation, Neoplastic*
HEK293 Cells
Humans
Kidney Neoplasms / genetics
Kidney Neoplasms / metabolism*
Kidney Neoplasms / pathology
Male
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Phosphorylation
Promoter Regions, Genetic
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Serine-Threonine Kinase 3

Substances

AIFM1 protein, human
Apoptosis Inducing Factor
Neoplasm Proteins
Protein Serine-Threonine Kinases
STK3 protein, human
Serine-Threonine Kinase 3

Grants and funding

This work was financed by grants from Heilongjiang Province Department of Education in China (http://www.hlje.net/), and LC04C02 Returned Overseas Personnel Fund from Heilongjiang Province Department of Science and Technology (http://www.hljkjt.gov.cn/) and Support from China Scholarship Council (http://www.csc.edu.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.