Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

Abstract

Human sarcomas comprise a heterogeneous group of more than 50 subtypes broadly classified into two groups: bone and soft tissue sarcomas. Such heterogeneity and their relative rarity have made them challenging targets for classification, biomarker identification, and development of improved treatment strategies. In this study, we used RNA sequencing to analyze 35 primary human tissue samples representing 13 different sarcoma subtypes, along with benign schwannoma, and normal bone and muscle tissues. For each sarcoma subtype, we detected unique messenger RNA (mRNA) expression signatures, which we further subjected to bioinformatic functional analysis, upstream regulatory analysis, and microRNA (miRNA) targeting analysis. We found that, for each sarcoma subtype, significantly upregulated genes and their deduced upstream regulators included not only previously implicated known players but also novel candidates not previously reported to be associated with sarcoma. For example, the schwannoma samples were characterized by high expression of not only the known associated proteins GFAP and GAP43 but also the novel player GJB6. Further, when we integrated our expression profiles with miRNA expression data from each sarcoma subtype, we were able to deduce potential key miRNA-gene regulator relationships for each. In the Ewing's sarcoma and fibromatosis samples, two sarcomas where miR-182-5p is significantly downregulated, multiple predicted targets were significantly upregulated, including HMCN1, NKX2-2, SCNN1G, and SOX2. In conclusion, despite the small number of samples per sarcoma subtype, we were able to identify key known players; concurrently, we discovered novel genes that may prove to be important in the molecular classification of sarcomas and in the development of novel treatments.

NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes

“…All these genes are well expressed in KBM-7 cells, with BASP1 exhibiting 35-fold up-regulation in NuKO cells. Up-regulation of IFI44L is associated with melanoma and prostate cancer [ 107 , 108 ] while overexpression of NKX2-2 is associated with Ewing’s sarcoma and fibromatosis [ 109 ]. They are down 224- and 125-fold respectively in NuKO cells.…”

Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR

“…To perform a similar analysis in dogs, we used next generation RNA sequencing (RNAseq) data from canine hemangiosarcoma and canine lymphoma samples that were reported previously [24, 25]. RNAseq for 31 canine osteosarcoma samples was performed as described [24, 26, 27]. EGFR and uPAR protein expression were evaluated in a human synovial sarcoma tissue microarray (TMA) [28]; the same methods were used to build a study-specific TMA that included tumors from 15 dogs as well as normal canine spleen, liver and kidney and spleens with nodular lymphoid hyperplasia and associated hematomas as controls.…”

Vascular Smooth Muscle Cell-Derived Exosomal MicroRNAs Regulate Endothelial Cell Migration Under PDGF Stimulation

“…MiR-1246 is known to promote growth and metastasis of colorectal cancer cells and hepatocellular carcinoma by targeting CCNG2 or cell adhesion molecule 1, while miR-1246 inhibits cell invasion and epithelial-mesenchymal transition in prostate cancer and lung cancer cells by inhibiting N-cadherin and vimentin activities or targeting CXCR4 [23][24][25][26]. MiR-182 shows oncogenic features by promoting growth in oral squamous cell carcinoma, hepatocellular carcinoma, gastric cancer cells, and bladder cancer cells through repressing CAMK2N1, FOXO3a, RAB27A, Smad4, or RECK, while miR-182 plays a role as a tumor suppressor in renal cell carcinoma, Ewing's sarcoma, and fibromatosis [27][28][29][30][31]. MiR-486 is known to drive tumorigenesis by targeting multiple negative regulators of PTEN/PI3K/Akt, FOXO, and TGF-β/Smad2 signaling in cervical cancer and prostate cancer cells [32,33].…”