A novel LncRNA PTH-AS upregulates interferon-related DNA damage resistance signature genes and promotes metastasis in human breast cancer xenografts

Long noncoding RNAs (lncRNAs) are important tissue-specific regulators of gene expression, and their dysregulation can induce aberrant gene expression leading to various pathological conditions, including cancer. Although many lncRNAs have been discovered by computational analysis, most of these are as yet unannotated. Herein, we describe the nature and function of a novel lncRNA detected downstream of the human parathyroid hormone (PTH) gene in both extremely rare ectopic PTH-producing retroperitoneal malignant fibrous histiocytoma and parathyroid tumors with PTH overproduction. This novel lncRNA, which we have named “PTH-AS,” has never been registered in a public database, and here, we investigated for the first time its exact locus, length, transcription direction, polyadenylation, and nuclear localization. Microarray and Gene Ontology analyses demonstrated that forced expression of PTH-AS in PTH–nonexpressing human breast cancer T47D cells did not induce the ectopic expression of the nearby PTH gene but did significantly upregulate Janus kinase–signal transducer and activator of transcription pathway–related genes such as cancer-promoting interferon-related DNA damage resistance signature (IRDS) genes. Importantly, we show that PTH-AS expression not only enhanced T47D cell invasion and resistance to the DNA-damaging drug doxorubicin but also promoted lung metastasis rather than tumor growth in a mouse xenograft model. In addition, PTH-AS–expressing T47D tumors showed increased macrophage infiltration that promoted angiogenesis, similar to IRDS-associated cancer characteristics. Although the detailed molecular mechanism remains imperfectly understood, we conclude that PTH-AS may contribute to tumor development, possibly through IRDS gene upregulation.