Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness

Gong, Xing; Yi, Jing; Carmon, Kendra S.; Crumbley, Christine; Xiong, Wei; Thomas, Anthony; Fan, Xuejun; Guo, Shan; An, Zhiqiang; Chang, Jeffrey T.; Liu, Qingyun J.

doi:10.1038/onc.2014.417

Cited by 59 publications

(64 citation statements)

References 56 publications

(87 reference statements)

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“…When we searched PubMed (http://www.ncbi.nlm.nih.gov/pubmed) to identify reported functions for these differentially expressed genes, we found that only 4 genes (RSPO3, ADAMTS8, DMBT1, and DOCK8) were reported to be associated with NSCLC. RSPO3 was reported to promote tumor aggressiveness in Keap1-deficient lung adenocarcinomas [22]. ADAMTS8 was related to promoter hyper methylation in early-stage NSCLCs [23, 24].…”

Section: Resultsmentioning

confidence: 99%

“…Several studies have reported the functions of these genes and pathways. Gong et al [22] found that RSPO3 was aberrantly overexpressed in half of Keap1-deficient lung adenocarcinomas and that RSPO3 overexpression resulted in much poorer survival. In vitro experiments verified that RSPO3 overexpression was related to cell proliferation and migration.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive analysis of the long noncoding RNA HOXA11-AS gene interaction regulatory network in NSCLC cells

Zhang

Dang

et al. 2016

Cancer Cell Int

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BackgroundLong noncoding RNAs (lncRNAs) are related to different biological processes in non-small cell lung cancer (NSCLC). However, the possible molecular mechanisms underlying the effects of the long noncoding RNA HOXA11-AS (HOXA11 antisense RNA) in NSCLC are unknown.MethodsHOXA11-AS was knocked down in the NSCLC A549 cell line and a high throughput microarray assay was applied to detect changes in the gene profiles of the A549 cells. Bioinformatics analyses (gene ontology (GO), pathway, Kyoto Encyclopedia of Genes and Genomes (KEGG), and network analyses) were performed to investigate the potential pathways and networks of the differentially expressed genes. The molecular signatures database (MSigDB) was used to display the expression profiles of these differentially expressed genes. Furthermore, the relationships between the HOXA11-AS, de-regulated genes and clinical NSCLC parameters were verified by using NSCLC patient information from The Cancer Genome Atlas (TCGA) database. In addition, the relationship between HOXA11-AS expression and clinical diagnostic value was analyzed by receiver operating characteristic (ROC) curve.ResultsAmong the differentially expressed genes, 277 and 80 genes were upregulated and downregulated in NSCLC, respectively (fold change ≥2.0, P < 0.05 and false discovery rate (FDR) < 0.05). According to the degree of the fold change, six upregulated and three downregulated genes were selected for further investigation. Only four genes (RSPO3, ADAMTS8, DMBT1, and DOCK8) were reported to be related with the development or progression of NSCLC based on a PubMed search. Among all possible pathways, three pathways (the PI3K-Akt, TGF-beta and Hippo signaling pathways) were the most likely to be involved in NSCLC development and progression. Furthermore, we found that HOXA11-AS was highly expressed in both lung adenocarcinoma and squamous cell carcinoma based on TCGA database. The ROC curve showed that the area under curve (AUC) of HOXA11-AS was 0.727 (95% CI 0.663–0.790) for lung adenocarcinoma and 0.933 (95% CI 0.906–0.960) for squamous cell carcinoma patients. Additionally, the original data from TCGA verified that ADAMTS8, DMBT1 and DOCK8 were downregulated in both lung adenocarcinoma and squamous cell carcinoma, whereas RSPO3 expression was upregulated in lung adenocarcinoma and downregulated in lung squamous cell carcinoma. For the other five genes (STMN2, SPINK6, TUSC3, LOC100128054, and C8orf22), we found that STMN2, TUSC3 and C8orf22 were upregulated in squamous cell carcinoma and that STMN2 and USC3 were upregulated in lung adenocarcinoma. Furthermore, we compared the correlation between HOXA11-AS and de-regulated genes in NSCLC based on TCGA. The results showed that the HOXA11-AS expression was negatively correlated with DOCK8 in squamous cell carcinoma (r = −0.124, P = 0.048) and lung adenocarcinoma (r = −0.176, P = 0.005). In addition, RSPO3, ADAMTS8 and DOCK8 were related to overall survival and disease-free survival (all P < 0.05) of lung adenocarcinoma patients in TCGA.Conclus...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of the long noncoding RNA HOXA11-AS gene interaction regulatory network in NSCLC cells

Zhang

Dang

et al. 2016

Cancer Cell Int

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“…RSPO2 with hypermethylation was the top 10 down-regulated DEmRNAs in READ compared to normal control tissues. Dysregulated expression of RSPO2 is closely related to the tumor invasiveness and aggressiveness in papillary thyroid cancer, pancreatic cancer and lung adenocarcinoma [25–27]. However, RSPO2 functions as a tumor driver or suppressor in CRC is still controversial [28–30].…”

Section: Discussionmentioning

confidence: 99%

Abnormal expression of mRNA, microRNA alteration and aberrant DNA methylation patterns in rectal adenocarcinoma

Yang

Liu

et al. 2017

PLoS ONE

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AimRectal adenocarcinoma (READ) is a malignancy cancer with the high morbidity and motility worldwide. Our study aimed to explore the potential pathogenesis of READ through integrated analysis of gene expression profiling and DNA methylation data.MethodsThe miRNA, mRNA expression profiling and corresponding DNA methylation data were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNAs/ miRNAs/methylated regions (DEmRNA/DEmiRNAs) were identified in READ. The negatively correlation of DEmiRNA-DEmRNAs and DNA methylation-DEmRNAs were obtained. DEmRNAs expression was validated through quantitative real-time polymerase chain reaction (qRT-PCR) and microarray expression profiling analyses.Results1192 dysregulated DEmRNAs, 27 dysregulated DEmiRNAs and 6403 aberrant methylation CpG sites were screened in READ compared to normal controls. 1987 negative interaction pairs among 27 DEmiRNAs and 668 DEmRNAs were predicted. 446 genes with aberrant methylation were annotated. Eventually, 50 DEmRNAs (39 down- and 11 up-regulated DEmRNAs) with hypermethylation, synchronously negatively targeted by DEmiRNAs, were identified through the correlation analysis among 446 genes with aberrant methylation and 668 DEmRNAs. 50 DEmRNAs were significantly enriched in cAMP signaling pathway, circadian entrainment and glutamatergic synapse. The validation results of expression levels of DEmRNAs through qRT-PCR and microarray analyses were compatible with our study.Conclusion7 genes of SORCS1, PDZRN4, LONRF2, CNGA3, HAND2, RSPO2 and GNAO1 with hypermethylation and negatively regulation by DEmiRNAs might contribute to the tumorigenesis of READ. Our work might provide valuable foundation for the READ in mechanism elucidation, early diagnosis and therapeutic target identification.

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“…Ectopic expression of Rspo2 was shown to increase tumorigenic and invasive properties of mouse breast cell lines (25). Genomic rearrangements and transcriptional activation in human tumors that result in elevated RSPO expression have been identified, suggesting that RSPO may be functionally important for tumor development (29)(30)(31)(32). However, no direct demonstration of a functional role for RSPO in cancer development and maintenance has been reported to date.…”

Section: Introductionmentioning

confidence: 96%

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types

et al. 2016

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Deregulation of the b-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and b-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate b-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate b-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, geneexpression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited b-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of b-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis. Cancer Res; 76(3); 713-23. Ó2015 AACR.

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Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness

Cited by 59 publications

References 56 publications

Comprehensive analysis of the long noncoding RNA HOXA11-AS gene interaction regulatory network in NSCLC cells

Comprehensive analysis of the long noncoding RNA HOXA11-AS gene interaction regulatory network in NSCLC cells

Abnormal expression of mRNA, microRNA alteration and aberrant DNA methylation patterns in rectal adenocarcinoma

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types

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