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Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities [ASOseries]

ABSTRACT: Long noncoding RNAs (lncRNAs) are widely dysregulated in cancer, yet their functional roles in cellular disease hallmarks remain unclear. Here we employ pooled CRISPR deletion to perturb 831 lncRNAs detected in KRAS-mutant non-small cell lung cancer (NSCLC), and measure their contribution to proliferation, chemoresistance and migration across two cell backgrounds. Integrative analysis of this data outperforms conventional “dropout” screens in identifying cancer genes, while prioritising disease-relevant lncRNAs with pleiotropic and background-independent roles. Altogether 80 high-confidence oncogenic lncRNAs are active in NSCLC, the majority identified here for the first time, and which tend to be amplified and overexpressed in tumours. A follow-up antisense oligonucleotide (ASO) screen shortlisted two candidates, Cancer Hallmarks in Lung LncRNA 1 (CHiLL 1) and GCAWKR, whose knockdown consistently suppressed cancer hallmarks in a variety of two- and three-dimension tumour models. Molecular phenotyping reveals that CHiLL 1 and GCAWKR control cellular-level phenotypes via distinct transcriptional networks converging on common oncogenic pathways. In summary, this work reveals a multi-dimensional functional lncRNA landscape underlying NSCLC that contains potential therapeutic vulnerabilities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207227 | GEO | 2022/07/05

REPOSITORIES: GEO

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Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities [CRISPRseries]

Project description:Long noncoding RNAs (lncRNAs) are widely dysregulated in cancer, yet their functional roles in cellular disease hallmarks remain unclear. Here we employ pooled CRISPR deletion to perturb 831 lncRNAs detected in KRAS-mutant non-small cell lung cancer (NSCLC), and measure their contribution to proliferation, chemoresistance and migration across two cell backgrounds. Integrative analysis of this data outperforms conventional “dropout” screens in identifying cancer genes, while prioritising disease-relevant lncRNAs with pleiotropic and background-independent roles. Altogether 80 high-confidence oncogenic lncRNAs are active in NSCLC, the majority identified here for the first time, and which tend to be amplified and overexpressed in tumours. A follow-up antisense oligonucleotide (ASO) screen shortlisted two candidates, Cancer Hallmarks in Lung LncRNA 1 (CHiLL 1) and GCAWKR, whose knockdown consistently suppressed cancer hallmarks in a variety of two- and three-dimension tumour models. Molecular phenotyping reveals that CHiLL 1 and GCAWKR control cellular-level phenotypes via distinct transcriptional networks converging on common oncogenic pathways. In summary, this work reveals a multi-dimensional functional lncRNA landscape underlying NSCLC that contains potential therapeutic vulnerabilities.

2022-07-05 | GSE207228 | GEO

lncRNAs expression signatures of gastric cancer

Project description:Long noncoding RNAs (LncRNAs) are an important class if pervasive genes involved in a variety of biological functions. LncRNAs have been recently implicated as having oncogenic and tumor suppressor roles. To further investigate the function of lncRNA in gastric cancer, we use lncRNA microarray to describe LncRNAs profiles in 6 pairs of human gastric adenocarcinoma and the corresponding adjacent nontumorous tissues. The experimental samples are divided into two groups(normal and tumor) to compare lncRNA expression profiling of those

2013-12-09 | E-GEOD-53137 | biostudies-arrayexpress

Identification of long non-coding RNAs associated with aberrant LKB1 signaling

Project description:The LKB1 tumor suppressor gene is frequently mutated and inactivated in many cancers, particularly non-small cell lung carcinoma (NSCLC). LncRNAs are a novel class of gene regulators with newly discovered roles in cancer development and progression. LncRNA involvement in altered LKB1 signaling in lung cancer is currently unknown. To investigate whether lncRNAs contribute to loss of LKB1 tumor suppression in lung tumorigenesis and maintenance, we performed genome-wide lncRNA transcriptional profiling to identify lncRNAs associated with aberrant LKB1 signaling.

2016-12-31 | GSE73414 | GEO

Identification of a Four-lncRNA Signature Predicting Prognosis of Patients with NSCLC

Project description:LncRNA expression profiles were sucessfully contructed in 370 patients with NSCLC and 198 corresponding adjacent noncancerous tissues using a custom microarray containing probes for 2412 lncRNAs and an outcome prediction of lncRNA signature was successfully identified for predicting prognosis in NSCLC.

2020-08-31 | GSE143018 | GEO

Oncogenic BRAFV600E remodels the melanocyte transcriptome and induces BANCR to regulate melanoma cell migration [HT-seq]

Project description:Most cancer genomics papers to date have focused on aberrations in genomic DNA and protein-coding transcripts. However, around 50% of transcripts have no coding potential and may exist as non-coding RNA. We performed RNA-seq in BRAFv600e melanoma skin cancer and on melanocytes over-expressing oncogenic BRAF to catalog transcriptome remodeling. We discovered that BRAF regulates expression of 1027 protein coding transcripts, 39 annotated lncRNAs and 70 novel transcripts. Many of the novel transcripts are lncRNAs. We used an indepenedent dataset to interrogate our novel transcripts and found that the novel lncRNA BANCR is a BRAF-regulated lncRNA recurrently upregulated in melanoma. Knockdown of BANCR impairs melanoma cell migration. Whole transcriptome RNA-seq followed assembly to Refseq/Gencode and de novo transcript assembly. RNA-seq performed on: 2 BRAFv600e melanomas, melanocytes+RFP control and melanocytes + BRAFv600e. We discovered protein-coding transcripts, annotated ncRNAs and novel transcripts (including lncRNAs) regulated by BRAFv600e also coordinately expressed in melanoma.

2012-04-28 | E-GEOD-33092 | biostudies-arrayexpress

lncRNAs expression signatures of gastric cancer

2013-12-09 | GSE53137 | GEO

lncRNA n384546 promotes thyroid papillary cancer proliferation and migration by targeting miR-145-5p to regulate AKT3

Project description:we document a novel lncRNA, n384546, which may exert its oncogenic property in PTC tumorigenesis by sponging miR-145-5p and then regulating its target AKT3.This study reveals that n384546 is an oncogenic lncRNA in human thyroid cancer.

2019-06-16 | GSE124841 | GEO

Oncogenic BRAFV600E remodels the melanocyte transcriptome and induces BLNCR1 to regulate melanoma cell migration [Affymetrix]

Project description:Most cancer genomics papers to date have focused on aberrations in genomic DNA and protein-coding transcripts. However, around 50% of transcripts have no coding potential and may exist as non-coding RNA. We performed RNA-seq in BRAFv600e melanoma skin cancer and on melanocytes over-expressing oncogenic BRAF to catalog transcriptome remodeling. We discovered that BRAF regulates expression of 1027 protein coding transcripts, 39 annotated lncRNAs and 70 novel transcripts. Many of the novel transcripts are lncRNAs. We used an indepenedent dataset to interrogate our novel transcripts and found that the novel lncRNA BLNCR1 is a BRAF-regulated lncRNA recurrently upregulated in melanoma. Knockdown of BLNCR1 impairs melanoma cell migration. To identify genes regulated by BLNCR1 we perrformed shRNA knockdown experiments using 2 independent shRNA sequences in col829 melanoma cells. RNA was then extracted for microarray analysis.

2012-04-27 | E-GEOD-37132 | biostudies-arrayexpress

Genome-wide profiling of long noncoding RNA expression patterns in chemoresistant breast cancer cells

Project description:Long non-coding RNAs (lncRNAs) are involved in cancer progression. In this study, the lncRNA profiling were analyzed in chemoresistant and sensitive breast cancer cells. We found a group of dysregulated lncRNAs in chemoresistant cells. Expression of dysregulated lncRNAs are correlated with dysregulated mRNAs, and enriched in GO and KEGG pathways related with cancer progression and chemoresistance development. Within those lncRNA-mRNA interactions, some lncRNAs may cis-regulate neighboring protein coding genes and involved in chemoresistance. The lncRNA NONHSAT028712 was then validated to regulate nearby CDK2 and interfere with cell cycle and chemoresistance. Furthermore, we identified another group of lncRNAs trans-regulated gene expression via interacting with different transcription factors (TF). Whereby NONHSAT057282 and NONHSAG023333 was found to modulate chemoresistance and most likely interacted with ELF1 and E2F1 respectively. In conclusion, this study reported for the first time the lncRNA expression patterns in chemoresistant breast cancer cells, and provided a group of novel lncRNA targets in mediating chemoresistance development in both cis- and trans- action mode. MCF-7/ADM replication 3 times, MCF-7/WT replication 3 times

2016-05-28 | E-GEOD-81971 | biostudies-arrayexpress

Integrative genomic analyses identify lncRNA regulatory networks across pediatric leukemias and solid tumors

Project description:Long non-coding RNAs (lncRNAs) play an important role in gene regulation and contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the lncRNA landscape across pediatric cancers remains largely uncharted. Here, we curated RNA sequencing data for 1,044 pediatric leukemia and extra-cranial solid tumors and integrated paired tumor whole genome sequencing and epigenetic data in relevant cell line models to explore lncRNA expression, regulation, and association with cancer. A total of 2,657 lncRNAs were robustly expressed across six pediatric cancers, including 1,142 exhibiting histotype-elevated expression. DNA copy number alterations contributed to lncRNA dysregulation at a proportion comparable to protein coding genes. Application of a multi-dimensional framework to identify and prioritize lncRNAs impacting gene networks revealed that lncRNAs dysregulated in pediatric cancer are associated with proliferation, metabolism, and DNA damage hallmarks. Analysis of upstream regulation via cell-type specific transcription factors further implicated distinct histotype-elevated and developmental lncRNAs. Integration of these analyses prioritized lncRNAs for experimental validation, and silencing of TBX2-AS1, the top-prioritized neuroblastoma-specific lncRNA, resulted in significant growth inhibition of neuroblastoma cells, confirming the computational predictions. Taken together, these data provide a comprehensive characterization of lncRNA regulation and function in pediatric cancers and pave the way for future mechanistic studies.

2023-07-31 | GSE238166 | GEO

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