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A lncRNA HAR1B has a potential as a predictive marker for pazopanib therapy in patients with sarcoma

ABSTRACT: Bone and soft tissue sarcomas are rare and highly heterogeneous mesenchymal malignancies. Their rarity makes it difficult to acquire clinical data of patients with specific histological subtypes of sarcoma from large clinical trials. The diagnoses and treatment of sarcomas need to be further developed. We show that a long non-coding RNA (lncRNA) HAR1B may serve as predictive biomarkers for pazopanib treatment in bone and soft tissue sarcomas. Multiplex real-time reverse transcription polymerase chain reaction and microarray analyses revealed that HAR1B and HOTAIR were differentially expressed in pazopanib-sensitive cells and responders. We further clarified this mechanism by showing that siRNA-knockdown of HAR1B led to an increased resistance to pazopanib in sarcoma cell lines. Gene expression profiles related to pazopanib sensitivity included cellular molecular pathways, including genes involved in von-Willebrand factor-related signaling. Our study demonstrates that lncRNA HAR1B expression affects cellular sensitivity to pazopanib in sarcoma cell lines and in patients with sarcoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156344 | GEO | 2021/04/28

REPOSITORIES: GEO

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Project description:Background: The determination of altered expression of genes in specific tumor types and their effect upon cellular processes may create insight in tumorigenesis and help to design better treatments. The Flatcoated retriever is a dog breed with an exceptionally high incidence of histiocytic sarcomas. The breed develops two distinct entities of histiocytic neoplasia, a soft tissue form and a visceral form. Gene expression studies of these tumors has value for comparable human diseases such as histiocytic/dendritic cell sarcoma for which knowledge is difficult to accrue due to their rare occurrence. In addition, such studies may help in the search for genetic aberrations underlying the genetic predisposition in this dog breed. Methods: Microarray analysis and pathway analyses were performed on fresh-frozen tissues obtained from Flatcoated retrievers with localized, soft tissue histiocytic sarcomas (STHS) and disseminated, visceral histiocytic sarcomas (VHS) and on normal canine spleens from various breeds. Expression differences of nine genes were validated with quantitative real-time PCR (qPCR) analyses. Results: QPCR analyses identified the significantly altered expression of nine genes; PPBP, SpiC, VCAM1, ENPEP, ITGAD (down-regulated), and GTSF1, Col3a1, CD90 and LUM (up-regulated) in the comparison of both the soft tissue and the visceral form with healthy spleen. DAVID pathway analyses revealed 24 pathways that were significantly involved in the development of HS in general, most of which were involved in the DNA repair and replication process. Conclusions: This study identified altered expression of nine genes not yet implicated in histiocytic sarcoma manifestations in the dog nor in comparable human histiocytic/dendritic sarcomas. Extraploration of this downside effect of canine inbreeding strategies for the study of similar sarcomas in humans might also lead to the identification of genes related to these rare malignancies in the human. Microarray expression dataset including STHS: Soft Tissue (localized) Histiocytic Sarcoma; VHS: Visceral (disseminated)Histiocytic Sarcoma; together with normal spleen (NS) samples. Comparisons were analysed in dyeswap on a 2-color platform against a common reference sample, consisting of a multitude of canine organs, including liver, spleen, kidney, lung, hart, intestine and bone.

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A lncRNA HAR1B has a potential as a predictive marker for pazopanib therapy in patients with sarcoma

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