Comprehensive Analysis of Tumor Microenvironment Reveals Prognostic ceRNA Network Related to Immune Infiltration in Sarcoma

Abstract

Abstract Purpose: Sarcoma is the second most common solid tumor type in children and adolescents. The high level of tumor heterogeneity as well as aggressive behavior of sarcomas brings serious difficulties to developing effective therapeutic strategies for clinical application. Therefore, it is of great importance to identify accurate biomarkers for early detection and prognostic prediction of sarcomas. Experimental Design: In this study, we characterized three subtypes of sarcomas based on tumor immune infiltration levels (TIIL), and constructed a prognosis-related competing endogenous RNA (ceRNA) network to investigate molecular regulations in the sarcoma tumor microenvironment (TME). We further built a subnetwork consisting of mRNAs and lncRNAs that are targets of key miRNAs and strongly correlated with each other in the ceRNA network. After validation using public data and experiments in vivo and in vitro, we deeply dug the biological role of the miRNAs and lncRNAs in a subnetwork and their impact on TME. Results: Altogether, 5 miRNAs (hsa-mir-125b-2, hsa-mir-135a-1, hsa-mir92a-2, hsa-mir-181a-2, and hsa-mir-214), 3 lncRNAs (LINC00641, LINC01146, and LINC00892), and 10 mRNAs (AGO2, CXCL10, CD86, CASP1, IKZF1, CD27, CD247, CD69, CCR2, and CSF2RB) in the subnetwork were identified as vital regulators to shape the TME. On the basis of the systematic network, we identified that trichostatin A, a pan-HDAC inhibitor, could potentially regulate the TME of sarcoma, thereby inhibiting the tumor growth. Conclusions: Our study identifies a ceRNA network as a promising biomarker for sarcoma. This system provides a more comprehensive understanding and a novel perspective of how ceRNAs are involved in shaping sarcoma TME.