Sharma Harshita, Niveditha Divya, Chowdhury Rajdeep, Mukherjee Sudeshna, Chowdhury Shibasish
Department of Biological Sciences, Birla Institute of Technology and Science (BITS), Pilani Campus, Pilani, Rajasthan, 333031, India.
Discov Oncol. 2021 Oct 20;12(1):43. doi: 10.1007/s12672-021-00441-6.
Recurrence after cisplatin therapy is one of the major hindrances in the management of cancer. This necessitates a deeper understanding of the molecular signatures marking the acquisition of resistance. We therefore modeled the response of osteosarcoma (OS) cells to the first-line chemotherapeutic drug cisplatin. A small population of nondividing cells survived acute cisplatin shock (persisters; OS-P). These cells regained proliferative potential over time re-instating the population again (extended persisters; OS-EP).
In this study, we present the expression profile of noncoding RNAs in untreated OS cells (chemo-naive), OS-P, OS-EP and drug-resistant (OS-R) cells derived from the latter. RNA sequencing was carried out, and thereafter, differential expression (log2-fold ± 1.5; p value ≤ 0.05) of microRNAs (miRNAs) was analyzed in each set. The core set of miRNAs that were uniquely or differentially expressed in each group was identified. Interestingly, we observed that most of each group had their own distinctive set of miRNAs. The miRNAs showing an inverse correlation in expression pattern with mRNAs were further selected, and the key pathways regulated by them were delineated for each group. We observed that pathways such as TNF signaling, autophagy and mitophagy were implicated in multiple groups.
To the best of our knowledge, this is the first study that provides critical information on the variation in the expression pattern of ncRNAs in osteosarcoma cells and the pathways that they might tightly regulate as cells acquire resistance.
顺铂治疗后的复发是癌症治疗中的主要障碍之一。这就需要更深入地了解标志着耐药性产生的分子特征。因此，我们对骨肉瘤（OS）细胞对一线化疗药物顺铂的反应进行了建模。一小部分不分裂的细胞在急性顺铂冲击后存活下来（持久细胞；OS-P）。随着时间的推移，这些细胞恢复了增殖潜力，再次恢复了细胞群体（延长持久细胞；OS-EP）。
在本研究中，我们展示了未经处理的OS细胞（化疗初治）、OS-P、OS-EP以及由后者衍生的耐药（OS-R）细胞中非编码RNA的表达谱。进行了RNA测序，然后分析了每组中微小RNA（miRNA）的差异表达（log2倍数±1.5；p值≤0.05）。确定了在每组中独特表达或差异表达的miRNA核心集。有趣的是，我们观察到每组中的大多数都有其独特的miRNA集。进一步选择了在表达模式上与mRNA呈负相关的miRNA，并为每组描绘了由它们调控的关键途径。我们观察到，TNF信号传导、自噬和线粒体自噬等途径在多个组中都有涉及。
据我们所知，这是第一项提供骨肉瘤细胞中非编码RNA表达模式变化以及细胞获得耐药性时它们可能紧密调控的途径的关键信息的研究。
