Theranostics 2017; 7(5):1100-1113. doi:10.7150/thno.18198
AHNAK2 is a Novel Prognostic Marker and Oncogenic Protein for Clear Cell Renal Cell Carcinoma
1. State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
2. School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China;
3. Department of Medical Oncology, The First Affiliated Hospital, University of South China, Hengyang 421001, China;
4. Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
5. Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Lab. for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, China;
6. Collaborative Innovation Center of Systems Biomedicine, Shanghai 200240, China.
* These authors contributed equally to this work.
Integrative database analysis was performed to identify novel candidate oncogene AHNAK2 overexpressed in clear cell renal cell carcinoma (ccRCC). However, the function of AHNAK2 in cancer cells is currently unknown. In this study, we first confirmed the upregulation of AHNAK2 in ccRCC tissues compared with adjacent normal tissues in 15 pairs of samples. Then we analyzed AHNAK2 expression in a large cohort of ccRCC patient samples (n = 355), and found that up-regulation of AHNAK2 was positively correlated with tumor progression and poor survival (p = 0.032). Knockdown of AHNAK2 inhibited cancer cell proliferation, colony formation and migration in vitro and tumorigenic ability in vivo. Meanwhile, knockdown of AHNAK2 impaired the cell oncologic-metabolism by inhibiting lipid synthesis. Moreover, we observed that expression of AHNAK2 was greatly upregulated, at least in part, by hypoxia in cancer cells. By using chromatin immune-precipitation (CHIP) and promoter-luciferase reporter assays, we identified that upregulation of AHNAK2 induced by hypoxia was hypoxia-inducible factor-1α (HIF1α)-dependent. Knockdown of AHNAK2 impaired hypoxia-induced epithelial-mesenchymal transition (EMT) and stem cell-like properties. Considered together, we reveal that AHNAK2 is upregulated in cancer cells and hypoxic upregulation of AHNAK2 can drive tumorigenesis and progression by supporting EMT and cancer cell stemness. Thus, AHNAK2 is a novel prognostic marker and an oncogenic protein for ccRCC.
Keywords: AHNAK2, hypoxia-inducible factor-1α, clear cell Renal Cell Carcinoma, hypoxia pathway, epithelial-mesenchymal transition.
Wang M, Li X, Zhang J, Yang Q, Chen W, Jin W, Huang YR, Yang R, Gao WQ. AHNAK2 is a Novel Prognostic Marker and Oncogenic Protein for Clear Cell Renal Cell Carcinoma. Theranostics 2017; 7(5):1100-1113. doi:10.7150/thno.18198. Available from http://www.thno.org/v07p1100.htm