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Next Generation Sequencing Facilitates Analysis of Fangchinoline Treatment and Control SamplesTranscriptomes

ABSTRACT: Conjunctival melanoma (CM) is a rare and potentially deadly ocular tumor with poor prognosis. Thus, effective drugs to kill CM are urgently needed. Herein, we reported the discovery of a novel potential therapeutic target for CM. Through phenotypic screening of our in-house library, fangchinoline was discovered to potently inhibit the growth of CM cell lines including CM-AS16, CRMM1, CRMM2 and CM2005.1. Further mechanistic experiments indicated that fangchinoline could suppress homologous recombination (HR)-directed DNA repair through binding to far upstream element binding protein 2 (FUBP2) and downregulating expression of the HR factors BRCA1 and RAD51. In vitro and in vivo antitumor experiments revealed that fangchinoline increased the efficacy of cisplatin by blocking HR factors and diminished the drug dose and toxicity. In summary, our work provides a promising therapeutic strategy for the treatment of CM that is worthy of extensive preclinical investigation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164340 | GEO | 2021/01/07

REPOSITORIES: GEO

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Project description:Purpose: To characterize the transcriptome and cellular the tumor microenvi-ronment of conjunctival melanoma (CM) compared to healthy conjunctiva and to analyze the transcriptional differences between CM with good and poor clinical outcome. Methods: Twelve formalin-fixed and paraffin-embedded (FFPE) CM of twelve patients were analyzed by Massive Analysis of cDNA Ends (MACE) RNA se-quencing. Six samples each with good and poor clinical outcome were exam-ined, the latter being defined by local recurrence or systemic metastases with a follow-up of at least 24 months. Eight age-matched healthy FFPE conjunctival specimens from eight patients who underwent retinal detachment surgery served as controls. Bioinformatic cell type enrichment analysis with xCell was used to characterize the tumor microenvironment (TME). Differentially expressed genes (DEG) and the associated biological processes were analyzed between CM and control conjunctiva. Additionally, a prognostic transcription profile was identified by comparing melanoma of good and poor clinical outcome. Results: The TME of conjunctival melanoma was characterized by the enrich-ment of melanocytes, pericytes and especially several immune cell types. Among them, plasmacytoid dendritic cells (pDC), natural killer T cells (NKT), B cells and mast cells were most significantly increased in CM compared to healthy conjunc-tiva. DEG between CM and control were mainly involved in biological processes such as inhibition of apoptosis, proteolysis and response to growth factors. POU3F3, BIRC5 and 7 were among the top expressed genes associated with inhibition of apoptosis. Twenty genes, among them CENPK, INHA, USP33 and CASP3, were identified as prognostically relevant factors reaching high classifi-cation accuracy (AUC: 1.0). Conclusions: The present study provides new insights into the TME and the transcriptional profile of CM and additionally identifies new prognostic bi-omarkers. These results might lead to new diagnostic and therapeutic options for CM.

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Next Generation Sequencing Facilitates Analysis of Fangchinoline Treatment and Control SamplesTranscriptomes

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