A genome-wide expression profile of noncoding RNAs in human osteosarcoma cells as they acquire resistance to cisplatin

Harshita Sharma,Divya Niveditha,Shibasish Chowdhury,Rajdeep Chowdhury,Sudeshna Mukherjee

doi:10.1007/s12672-021-00441-6

Harshita Sharma, Divya Niveditha + Show 3 more

Open Access

https://doi.org/10.1007/s12672-021-00441-6

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Abstract

BackgroundRecurrence 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).ResultIn 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.ConclusionTo 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.

Highlights

Osteosarcoma (OS) is the primary malignant tumor of the bone with the highest incidence rate in adults and children [1, 2]
Comparative transcriptomic profiling was performed in four groups of cells, which are as follows—OS, untreated parental osteosarcoma cells which consisted of 25,016 mRNA transcripts, 1488 miRNA transcripts and 1312 long noncoding RNAs (lncRNAs) transcripts; OS-P, representing cells surviving cisplatin shock contained 24,021 mRNA transcripts, 1290 miRNA transcripts and 1165 lncRNA transcripts; OS-EP, representing proliferating cells after drug insult comprised of 25,482 mRNA transcripts, 1382 miRNA transcripts and 1378 lncRNA transcripts; OS-EP and drug-resistant (OS-R), representing acquired resistant cells consisted of 25,239 mRNA transcripts, 1499 miRNA transcripts and 1362 lncRNA transcripts (Fig. 1a)
Among the dysregulated lncRNAs, more lncRNA transcripts were downregulated in both OS-P and OS-R cells than in the untreated control (Fig. 1c), whereas in the other two sets, the opposite trend was observed

Summary

Introduction

Osteosarcoma (OS) is the primary malignant tumor of the bone with the highest incidence rate in adults and children [1, 2]. Despite aggressive local surgery, OS eventually metastasizes, leading to associated complications and death [3]. This despondency necessitated the development of an alternate arsenal or a belligerent chemotherapeutic regimen for the treatment of OS [4]. Pre- and postoperative chemotherapy is an integral part of the OS treatment strategy Despite such an aggressive treatment regimen, chemotherapy often fails, resulting in acquired drug. Conclusion 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

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