Cancer stem cells associated miRNAs serve as prognostic biomarkers in colorectal cancer

Chemoresistance in cancer is linked to a subset of cancer cells termed “cancer stem cells” (CSCs), and in particular, those expressing the CD44 variant appear to represent a more aggressive disease phenotype. Herein, we demonstrate that CD44v6 represents a CSC population with increased resistance to chemotherapeutic agents, and its high expression is frequently associated with poor overall survival (OS) (HR:3.04; CI:1.35–6.85; p<0.001) and disease-free survival (DFS) (HR:5.30, CI:1.64–17.12, p<0.01) in CRC patients. CD44v6+ cells showed elevated resistance to chemotherapeutic drugs and significantly high tumor initiation capacity. The inhibition of CD44v6 resulted in the attenuation of self-renewal capacity and re-sensitization to chemotherapeutic agents. Of note, miRNA profiling of CD44v6+ SDCSCs identified a unique panel of miRNAs indicative of high self-renewal capacity. In particular, miR-1246 was overexpressed in CD44v6+ cells, and associated with poor OS (HR:2.44, CI:1.15–5.18, p<0.05) and DFS (HR:2.37, CI:1.03–5.44, p<0.05) in CRC patients. We demonstrate that CD44v6+ CSCs induced chemoresistance and enhance tumorigenicity in CRC cells, which is in part orchestrated by dysregulated profiles of a distinct panel of miRNAs. These findings provide a rationale for the therapeutic targeting of specific miRNAs, as well as serving as promising prognostic biomarkers in patients with colorectal neoplasia. 8 total samples, 4 CD44v6− HCT116 replicates and 4 CD44v6+ HCT116 replicates

肿瘤化疗耐药与被称为“癌症干细胞（cancer stem cells, CSCs）”的癌细胞亚群密切相关，其中表达CD44变异体的亚群则呈现出更具侵袭性的疾病表型。本研究证实，CD44v6是一类化疗耐药性增强的癌症干细胞亚群，且在结直肠癌（colorectal cancer, CRC）患者中，其高表达常与不良总生存期（overall survival, OS）[风险比（HR）=3.04，置信区间（CI）=1.35~6.85，p<0.001]及无病生存期（disease-free survival, DFS）[HR=5.30，CI=1.64~17.12，p<0.01]显著相关。CD44v6阳性细胞对化疗药物的耐药性更高，且肿瘤起始能力显著增强。抑制CD44v6可减弱细胞的自我更新能力，并使其重新对化疗药物敏感。值得注意的是，对CD44v6阳性SDCSCs的微小RNA（microRNA, miRNA）表达谱分析结果显示，存在一组独特的miRNA可反映细胞的高自我更新能力。具体而言，miR-1246在CD44v6阳性细胞中呈过表达状态，且在CRC患者中，其高表达同样与不良OS[HR=2.44，CI=1.15~5.18，p<0.05]及DFS[HR=2.37，CI=1.03~5.44，p<0.05]相关。本研究证实，CD44v6阳性CSCs可诱导CRC细胞产生化疗耐药性并增强其致瘤性，这一过程部分由一组异常表达的特异性miRNA调控。上述研究结果为靶向特异性miRNA的治疗策略提供了理论依据，同时也可为结直肠肿瘤患者提供极具潜力的预后生物标志物。本数据集共包含8个样本：4个CD44v6阴性HCT116细胞重复样本与4个CD44v6阳性HCT116细胞重复样本。