The Role of lncRNAs TAPIR-1 and -2 as Diagnostic Markers and Potential Therapeutic Targets in Prostate Cancer

Abstract

In search of new biomarkers suitable for the diagnosis and treatment of prostate cancer, genome-wide transcriptome sequencing was carried out with tissue specimens from 40 prostate cancer (PCa) and 8 benign prostate hyperplasia patients. We identified two intergenic long non-coding transcripts, located in close genomic proximity, which are highly expressed in PCa. Microarray studies on a larger cohort comprising 155 patients showed a profound diagnostic potential of these transcripts (AUC~0.94), which we designated as tumor associated prostate cancer increased lncRNA (TAPIR-1 and -2). To test their therapeutic potential, knockdown experiments with siRNA were carried out. The knockdown caused an increase in the p53/TP53 tumor suppressor protein level followed by downregulation of a large number of cell cycle- and DNA-damage repair key regulators. Furthermore, in radiation therapy resistant tumor cells, the knockdown leads to a renewed sensitization of these cells to radiation treatment. Accordingly, in a preclinical PCa xenograft model in mice, the systemic application of nanoparticles loaded with siRNA targeting TAPIR-1 significantly reduced tumor growth. These findings point to a crucial role of TAPIR-1 and -2 in PCa.

The noncoding RNA LINC00152 conveys contradicting effects in different glioblastoma cells

“…Since new RNAi based therapies are now entering the clinic 7 , 8 , therapeutic targets based on oncogenic lncRNAs are moving strongly into the medical research focus 10 . Our findings that oncogenic LINC00152 acts as a tumor suppressor in A172 glioblastoma cells point out to a potential yet unknown risk, if lncRNAs were addressed as targets in very heterogeneous tumors.…”

“…This new class of drugs targeting specific cancer-associated RNAs, i.e. ONPATTRO ® (patisiran) 7 and GIVLAARI ® (givosiran) 8 , has recently been approved by the FDA, and in combination with traditional anticancer drugs, synergistic effects are anticipated 4 , 9 , 10 . Furthermore, most recently developed nanoparticle-based delivery systems give hope to major problems of RNA delivery, stability and intracellular release 4 , 9 , 11 , 12 .…”

Developing an immune‐related gene prognostic index associated with progression and providing new insights into the tumor immune microenvironment of prostate cancer

“…Co-stimulatory signals initiated by the interaction between the tumour necrosis factor (TNF) ligand and cognate TNF receptor (TNFR) superfamilies promote clonal expansion, differentiation and survival of antigen-primed CD4+ and CD8+ T cells and play an important role in T-cell-mediated adaptive immunity and diseases [42]. Accumulating evidence in recent years indicates that co-stimulatory signals via the subset of the TNFR superfamily molecules, OX40 (TNFRSF4), 4-1BB (TNFRSF9), CD27, DR3 (TNFRSF25), CD30 (TNFRSF8), GITR (TNFRSF18), TNFR2 (TNFRSF1B), and HVEM (TNFRSF14), which are constitutive or inducible on T cells, play important roles in protective [7]; (h) analysis of progress free survival between high-and low-risk groups, which were determined according to the median of IGPI score for prostate cancer patients in the GSE11 6918 [7]; (i) ROC curve of the IPGI score GSE13 4051 [18]; (j) analysis of progress free survival between high-and low-risk groups, which were determined according to the median of IGPI score for prostate cancer patients in the in GSE13 4051 [18]; (k) meta-analysis of progress free survival in three databases; migration ability, and mature DCs can effectively activate the initial T cells. DC migration is important for the maintenance of immune surveillance and tissue homeostasis, and the pathogenesis of a range of diseases [43].…”

“…Moreover, we confirmed the independently prognostic value of the IGPI score through the COX regression analysis encompassing the IGPI score and clinical features for PCA patients in the TCGA database. For the purpose of external validation, 216 and 248 PCA patients in the http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE134051 [18] and http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE116918 [7] from the Gene Expression Omnibus (GEO) [19] were divided into high‐ and low‐risk groups according to the median of the IGPI score, and the same method was used to confirm its prognostic value for PFS. Meta‐analysis of the PFS including the above three datasets was also conducted via STATA 16.0.…”

Tyrosine-Modification of Polypropylenimine (PPI) and Polyethylenimine (PEI) Strongly Improves Efficacy of siRNA-Mediated Gene Knockdown

“…They are thus also able to target proteins which are otherwise undruggable by small molecules and offer new therapeutic strategies. This also includes the knockdown of non-protein encoding mRNAs such as "long noncoding RNAs" (lncRNA) which are crucial biological regulators [4]. However, siRNAs are large and negatively charged molecules, which impair their cellular delivery and uptake, and are very susceptible to nuclease degradation.…”