Expression profiling of microRNAs and isomiRs in conventional central chondrosarcoma

Abstract

Conventional central chondrosarcoma (CCC) is a malignant bone tumor that is characterized by the production of chondroid tissue. Since radiation therapy and chemotherapy have limited effects on CCC, treatment of most patients depends on surgical resection. This study aimed to identify the expression profiles of microRNAs (miRNAs) and isomiRs in CCC tissues to highlight their possible participation to the regulation of pathways critical for the formation and growth of this type of tumor. Our study analyzed miRNAs and isomiRs from Grade I (GI), Grade II (GII), and Grade III (GIII) histologically validated CCC tissue samples. While the different histological grades shared a similar expression profile for the top abundant miRNAs, we found several microRNAs and isomiRs showing a strong different modulation in GII + GIII vs GI grade samples and their involvement in tumor biology could be consistently hypothesized. We then in silico validated these differently expressed miRNAs in a larger chondrosarcoma public dataset and confirmed the expression trend for 17 out of 34 miRNAs. Our results clearly suggests that the contribution of miRNA deregulation, and their targeted pathways, to the progression of CCC could be relevant and strongly indicates that when studying miRNA deregulation in tumors, not only the canonical miRNAs, but the whole set of corresponding isomiRs should be taken in account. Improving understanding of the precise roles of miRNAs and isomiRs over the course of central chondrosarcoma progression could help identifying possible targets for precision medicine therapeutic intervention.

Keywords: Bone cancer; Diagnostic markers.

Fig. 1. Multiple chondroid nodules from GI treated with curetage.

a, b Macroscopic features; c microscopic features showing permeative growth patterns of GI CCC; d hypocellular cartilage and occasional binucleation (Arrow). GII CCC of proximal femoral shaft. e Macroscopic features on cut surface that show cartilaginous tumor with focal chalk-like gritty areas. f, g Microscopic features showing aggressive growth patterns of CCC with permeation of intertrabecular spaces within intramedullary cavity and intermediate power photomicrographs showing mixoid matrix and immature hypercellular cartilage. GIII CCC of femoral shaft. h Macroscopic features on cut surface. i, j Microscopic appearance of aggressive growth patterns with permeation of lamellar bone, showing marked increase in cellularity, nuclear atypia, binucleation, multinucleation, stromal myxoid changes, and spindling of chondrocytes.

Fig. 2. The 20 most abundant miRNAs expressed in Grade I, Grade II, and Grade III central chondrosarcomas.

The colored sectors of the pie-charts identify each miRNA in Grade I (GI), Grade II (GII), and Grade III (GIII) CCC samples. The percentage of expression reported for each miRNA is calculated on the total miRNAs identified in each group.

Fig. 3. In silico validation of the canonical miRNAs found modulated in our GII + GIII vs GI grade samples.

Expression modulation of each miRNA is reported as log2 fold-change value as calculated in GII + GIII vs GI grade cases of our sample collection (black bars) and of a chondrosarcoma public dataset (white bars). *FDR-BH < 0.1.

Fig. 4. Differently modulated isomiRs in our GII + GIII vs GI CCC cases.

Expression modulation of each isomiR is reported as log2 fold-change value. IsomiR names follow nomenclature rules described in Table S2B. *FDR-BH < 0.1.