Wong Nicholas, Gu Yan, Kapoor Anil, Lin Xiaozeng, Ojo Diane, Wei Fengxiang, Yan Judy, de Melo Jason, Major Pierre, Wood Geoffrey, Aziz Tariq, Cutz Jean-Claude, Bonert Michael, Patterson Arthur J, Tang Damu
Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada.
Oncotarget. 2017 Mar 21;8(12):19218-19235. doi: 10.18632/oncotarget.15168.
Although the FAM84B gene lies within chromosome 8q24, a locus frequently altered in prostate cancer (PC), its alteration during prostate tumorigenesis has not been well studied. We report here FAM84B upregulation in DU145 cell-derived prostate cancer stem-like cells (PCSLCs) and DU145 cell-produced lung metastases compared to subcutaneous xenograft tumors. FAM84B protein was detected in bone metastases and primary PCs. Nanostring examination of 7 pairs of tumor adjacent normal and PC tissues revealed elevations in FAM84B mRNA levels in all carcinomas. Furthermore, through analysis of FAM84B expression using large datasets within the Gene Expression Omnibus and OncomineTM database, we demonstrate significant increases in FAM84B mRNA in 343 primary PCs versus 181 normal tissues, and elevations in the FAM84B gene copy number (GCN) in 171 primary PCs versus 61 normal tissues. While FAM84B was not detected at higher levels via immunohistochemistry in high grade (Gleason score/GS 8-10) tumors compared to GS6-7 PCs, analyses of FAM84B mRNA and GCN using datasets within the cBioPortal database demonstrated FAM84B upregulation in 12% (67/549) of primary PCs and 18% (73/412) of metastatic castration resistant PCs (mCRPCs), and GCN increases in 4.8% (26/546) of primary PCs and 26% (121/467) of mCRPCs, revealing an association of the aforementioned changes with CRPC development. Of note, an increase in FAM84B expression was observed in xenograft CRPCs produced by LNCaP cells. Furthermore, FAM84B upregulation and GCN increases correlate with decreases in disease free survival and overall survival. Collectively, we demonstrate a novel association of FAM84B with PC tumorigenesis and CRPC progression.
尽管FAM84B基因位于8号染色体q24区域，这是一个在前列腺癌（PC）中经常发生改变的位点，但其在前列腺肿瘤发生过程中的改变尚未得到充分研究。我们在此报告，与皮下异种移植肿瘤相比，FAM84B在DU145细胞来源的前列腺癌干细胞样细胞（PCSLCs）和DU145细胞产生的肺转移灶中上调。在骨转移灶和原发性前列腺癌中检测到了FAM84B蛋白。对7对肿瘤邻近正常组织和前列腺癌组织进行的纳米串检测显示，所有癌组织中FAM84B mRNA水平均升高。此外，通过使用基因表达综合数据库和OncomineTM数据库中的大型数据集分析FAM84B表达，我们发现343例原发性前列腺癌与181例正常组织相比，FAM84B mRNA显著增加，171例原发性前列腺癌与61例正常组织相比，FAM84B基因拷贝数（GCN）升高。虽然与GS6 - 7的前列腺癌相比，在高级别（Gleason评分/GS 8 - 10）肿瘤中通过免疫组织化学未检测到更高水平的FAM84B，但使用cBioPortal数据库中的数据集对FAM84B mRNA和GCN进行分析显示，12%（67/549）的原发性前列腺癌和18%（73/412）的转移性去势抵抗性前列腺癌（mCRPC）中FAM84B上调，4.8%（26/546）的原发性前列腺癌和26%（121/467）的mCRPC中GCN增加，揭示了上述变化与CRPC发展的关联。值得注意的是，在LNCaP细胞产生的异种移植CRPC中观察到FAM84B表达增加。此外，FAM84B上调和GCN增加与无病生存期和总生存期的降低相关。总体而言，我们证明了FAM84B与前列腺癌肿瘤发生和CRPC进展之间存在新的关联。
