Ectopic Otoconin 90 expression in triple negative breast cancer cell lines is associated with metastasis functions

Triple negative breast cancer (TNBC) is an aggressive tumor with propensity to metastasize and poor treatment options. Improving treatment options would be impactful; thus, finding a tumor-specific cell surface protein with metastasis promoting functions that could be knocked out was the goal of this study. The Otoconin 90 gene (OC90), frequently amplified in tumors on chromosome 8q24.22, was identified as a potential therapeutic candidate. Normally OC90 is expressed in the cochlea with no known function in other normal tissues. In silico analysis of The Cancer Genome Atlas (TCGA) multi-tumor RNAseq cohorts revealed that OC90 is expressed in many tumor types at high prevalence and genomic amplification is associated with the elevated mRNA expression. In vitro assays in TNBC cell lines revealed OC90 expression with control over cell viability, apoptosis and invasion. RNA-seq analysis of OC90-siRNA knockdown and OC90-overexpression in BT20, BT549, HCC38 cell lines identified co-expressed transcripts, HMGA2, POLE2 and TRIB3. Altered expression of HMGA2, POLE2 and TRIB3 was predictive of survival among members of the Metabric breast cancer cohort. Thus, OC90 represents a potential therapeutic target whose knockdown could improve the treatment of TNBC.

三阴性乳腺癌（Triple negative breast cancer, TNBC）是一类侵袭性极强的肿瘤，具备高转移倾向且治疗手段匮乏。改善其治疗方案具有重要临床价值，因此本研究的核心目标是寻获一类兼具促转移功能、可被靶向敲除的肿瘤特异性细胞表面蛋白。耳垢蛋白90基因（Otoconin 90 gene, OC90）定位于染色体8q24.22区域，在多种肿瘤中常发生基因扩增，被鉴定为潜在的治疗候选靶点。生理状态下，OC90仅在耳蜗组织中表达，其余正常组织中未发现其已知功能。通过对癌症基因组图谱（The Cancer Genome Atlas, TCGA）多肿瘤RNA测序队列开展计算机模拟（in silico）分析，本研究发现OC90在多种肿瘤中均呈现高表达率，且基因扩增与mRNA表达水平上调显著相关。针对三阴性乳腺癌细胞系的体外实验结果显示，OC90的表达可调控细胞活力、凋亡及侵袭能力。进一步对BT20、BT549、HCC38细胞系分别进行OC90小干扰RNA（small interfering RNA, siRNA）敲低与OC90过表达的RNA测序分析，鉴定出HMGA2、POLE2及TRIB3这三个共表达转录本。Metabric乳腺癌队列的分析表明，HMGA2、POLE2与TRIB3的表达异常可有效预测患者的生存预后。综上，OC90是一项极具潜力的治疗靶点，其靶向敲除有望改善三阴性乳腺癌的临床治疗效果。