Wang Minglei, Li Xuefeng, Zhang Jin, Yang Qiong, Chen Wenqi, Jin Weilin, Huang Yi-Ran, Yang Ru, Gao Wei-Qiang
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.
School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
Theranostics. 2017 Feb 27;7(5):1100-1113. doi: 10.7150/thno.18198. eCollection 2017.
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 ( = 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.
进行综合数据库分析以鉴定在透明细胞肾细胞癌（ccRCC）中过表达的新型候选癌基因AHNAK2。然而，AHNAK2在癌细胞中的功能目前尚不清楚。在本研究中，我们首先在15对样本中证实了ccRCC组织中AHNAK2的表达高于相邻正常组织。然后我们分析了一大组ccRCC患者样本（n = 355）中AHNAK2的表达，发现AHNAK2的上调与肿瘤进展和不良生存呈正相关（P = 0.032）。敲低AHNAK2可抑制体外癌细胞增殖、集落形成和迁移以及体内致瘤能力。同时，敲低AHNAK2通过抑制脂质合成损害细胞肿瘤代谢。此外，我们观察到癌细胞中的缺氧至少部分地极大地上调了AHNAK2的表达。通过染色质免疫沉淀（CHIP）和启动子 - 荧光素酶报告基因分析，我们确定缺氧诱导的AHNAK2上调是缺氧诱导因子-1α（HIF1α）依赖性的。敲低AHNAK2损害缺氧诱导的上皮-间质转化（EMT）和干细胞样特性。综合考虑，我们揭示AHNAK2在癌细胞中上调，并且AHNAK2的缺氧上调可通过支持EMT和癌细胞干性来驱动肿瘤发生和进展。因此，AHNAK2是ccRCC的一种新型预后标志物和致癌蛋白。
