Long Non-Coding RNA ANRIL as a Potential Biomarker of Chemosensitivity and Clinical Outcomes in Osteosarcoma.
Long Non-Coding RNA ANRIL as a Potential Biomarker of Chemosensitivity and Clinical Outcomes in Osteosarcoma.
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DOI：
10.3390/ijms222011168
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发表时间：
2021-10-16
影响因子：
5.6
通讯作者：
Huang RS
中科院分区：
文献类型：
--
作者：
Lee AM;Ferdjallah A;Moore E;Kim DC;Nath A;Greengard E;Huang RS
骨肉瘤是一种预后不良的骨癌。这部分是由于对当前标准护理化学治疗的抗性。随着个性化治疗计划的广泛应用，患者特异性基因组标记的作用可能有助于在诊断开始时识别患有化疗耐药疾病的个体。ANRIL是一种长的非编码RNA，有望成为预测性生物标志物。利用骨肉瘤细胞系，我们观察到改变ANRIL的表达显著改变了对顺铂和多柔比星的敏感性，这两种药物是治疗的标准药物。对来自TARGET数据集的临床数据的分析证实了ANRIL表达越高预示着预后越差，如诊断时与死亡和转移的相关性所证明的。骨肉瘤由于化疗耐药和/或转移而具有不良预后。越来越多的证据表明，长链非编码RNA（lncRNA）在肿瘤的药物敏感性和转移中起重要作用。使用骨肉瘤细胞系，我们确定了lncRNA和ANRIL的表达之间的正相关性，以及对治疗骨肉瘤的三种标准治疗药物中的两种-顺铂和多柔比星的抗性。为了证实ANRIL在化疗敏感性中的潜在作用，我们在骨肉瘤细胞系中独立地抑制和过度表达ANRIL，然后用顺铂或多柔比星治疗。在SAOS 2中敲低ANRIL导致细胞对顺铂和多柔比星的敏感性显著增加，而在HOS和U2 OS细胞中ANRIL的过表达导致对两种药物的抗性增加。为了研究ANRIL在骨肉瘤中的临床意义，我们使用来自产生有效治疗的治疗适用研究（TARGET）数据集的骨肉瘤数据评估了ANRIL表达与临床表型的关系。较高的ANRIL表达与诊断时转移率和死亡率的增加显著相关，并且是总生存率降低的重要预测因子。总的来说，我们的研究结果表明，lncRNA ANRIL可以成为骨肉瘤化疗敏感性和预后的生物标志物。此外，降低ANRIL表达可能是克服当前标准治疗耐药性的治疗策略。
Osteosarcoma is a bone cancer with a poor prognosis. This is, in part, due to resistance to current standard-of-care chemotherapeutic treatment. As personalized treatment plans become more widely utilized, the role of patient-specific genome markers may serve to identify individuals with chemo-resistant disease at the outset of diagnosis. ANRIL, a long non-coding RNA, has promise as a predictive biomarker. Utilizing osteosarcoma cell lines, we observed that altering the expression of ANRIL significantly alters the sensitivity to cisplatin and doxorubicin, two agents that are a standard-of-care for treatment. Analysis of clinical data from the TARGET dataset confirmed higher ANRIL expression portending poorer prognosis, as evidenced by association with death and metastases at diagnosis. Osteosarcoma has a poor prognosis due to chemo-resistance and/or metastases. Increasing evidence shows that long non-coding RNAs (lncRNAs) can play an important role in drug sensitivity and cancer metastasis. Using osteosarcoma cell lines, we identified a positive correlation between the expression of a lncRNA and ANRIL, and resistance to two of the three standard-of-care agents for treating osteosarcoma—cisplatin and doxorubicin. To confirm the potential role of ANRIL in chemosensitivity, we independently inhibited and over-expressed ANRIL in osteosarcoma cell lines followed by treatment with either cisplatin or doxorubicin. Knocking-down ANRIL in SAOS2 resulted in a significant increase in cellular sensitivity to both cisplatin and doxorubicin, while the over-expression of ANRIL in both HOS and U2OS cells led to an increased resistance to both agents. To investigate the clinical significance of ANRIL in osteosarcoma, we assessed ANRIL expression in relation to clinical phenotypes using the osteosarcoma data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset. Higher ANRIL expression was significantly associated with increased rates of metastases at diagnosis and death and was a significant predictor of reduced overall survival rate. Collectively, our results suggest that the lncRNA ANRIL can be a chemosensitivity and prognosis biomarker in osteosarcoma. Furthermore, reducing ANRIL expression may be a therapeutic strategy to overcome current standard-of-care treatment resistance.
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