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Abstract
Soft 3D-fibrin-gel selected tumor repopulating cells (TRCs) from the B16F1 melanoma cell line exhibit extraordinary self-renewal and tumor-regeneration capabilities. However, their biomarkers and gene regulatory features remain largely unknown. Here, we utilized the next-generation sequencing-based RNA sequencing (RNA-seq) technique to discover novel biomarkers and active gene regulatory features of TRCs. Systems biology analysis of RNA-seq data identified differentially expressed gene clusters, including the cell adhesion cluster, which subsequently identified highly specific and novel biomarkers, such as Col2a1, Ncam1, F11r, and Negr1. We validated the expression of these genes by real-time qPCR. The expression level of Col2a1 was found to be relatively low in TRCs but twenty-fold higher compared to the parental control cell line, thus making the biomarker very specific for TRCs. We validated the COL2A1 protein by immunofluorescence microscopy, showing a higher expression of COL2A1 in TRCs compared to parental control cells. KEGG pathway analysis showed the JAK/STAT, hypoxia, and Akt signaling pathways to be active in TRCs. Besides, the aerobic glycolysis pathway was found to be very active, indicating a typical Warburg Effect on highly tumorigenic cells. Together, our study revealed highly specific biomarkers and active cell signaling pathways of melanoma TRCs that can potentially target and neutralize TRCs.
Highlights
IntroductionCells from the primary tumor spread to distant secondary sites in the body
Cancer metastasis is the leading cause of cancer-related deaths [1,2,3]
After looking into the set of genes belonging to the regeneration term, we find that the genes belong to the Notch signaling pathway, which are found to be downregulated in tumor repopulating cells (TRCs), and are consistent with a previous study [30]
Summary
Cells from the primary tumor spread to distant secondary sites in the body. Within the primary confinement of the tumor, there exists a heterogeneous tumor cell population [4,5,6,7,8]. Biomedicines 2020, 8, 360 the primary tumor can sustain the journey to successfully repopulate in distant secondary sites. It is widely believed that “stem-cell-like” cancer cells or highly tumorigenic cells within the tumor possess unlimited self-renewal capacity and replicative immortality [9,10,11]. These self-renewing cancer cells, present in low numbers within the tumor, have the capacity to survive and repopulate secondary sites
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