Abstract
Background: Few oncogenic drivers of long noncoding RNAs (lncRNAs) have been identified and investigated. Identifying noncoding drivers provides potential strategies for novel interventions in lung adenocarcinoma (LUAD). Methods: We constructed a machine learning model for driver gene annotation using pan-cancer and clinical prognosis data from OncoKB and TCGA to predict potential oncogenic drivers of lncRNAs; then, we used zebrafish models to validate the biological function of candidate targets. The full length of FAM83H-AS1 was obtained by rapid amplification of the cDNA ends (RACE) assay. RNA pull-down, RNA immunoprecipitation (RIP), quantative mass spectrometry (QMS) and RNA sequencing (RNA-Seq) assays were utilized to explore the potential mechanisms. Additionally, we used CRISPR interference (CRISPRi) system and patient-derived tumor xenograft (PDTX) model to evaluate the therapeutic potential of targeting FAM83H-AS1 in vivo.Results: The results suggested that FAM83H-AS1 was a potential oncogenic driver from the chromosome 8q24 amplicon; increases in the expression of FAM83H-AS1 resulted in poor prognosis for LUAD patients both in JSCH and TCGA cohorts. Functional assays revealed that FAM83H-AS1 promotes malignant progression and inhibits apoptosis. Mechanistically, FAM83H-AS1 binds with HNRNPK to enhance the translation of oncogenes RAB8B and RAB14. Experiments using CRISPR interference (CRISPRi)-mediated xenografts and patient-derived tumor xenograft (PDTX) models indicated that targeting FAM83H-AS1 inhibited LUAD progression in vivo. Conclusions: Our work demonstrated that FAM83H-AS1 is a potential oncogenic driver that inhibits LUAD-mediated apoptosis via the FAM83H-AS1-HNRNPK-RAB8B/RAB14 axis. Importantly, we suggest targeting of FAM83H-AS1 as a potential therapeutic strategy for LUAD.
Ly6/uPAR-Related Protein C4.4A as a Marker of Solid Growth Pattern and Poor Prognosis in Lung Adenocarcinoma
