bims-lorfki 2021-05-30 papers

Issue of 2021‒05‒30
three papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

EBioMedicine. 2021 May 24. pii: S2352-3964(21)00192-4. [Epub ahead of print]68 103399

Pan-cancer characterization of long non-coding RNA and DNA methylation mediated transcriptional dysregulation.

Zhen Yang, Feng Xu, Haizhou Wang, Andrew E Teschendorff, Feng Xie, Yungang He.

BACKGROUND: Disruption of DNA methylation (DNAm) is one of the key signatures of cancer, however, detailed mechanisms that alter the DNA methylome in cancer remain to be elucidated.METHODS: Here we present a novel integrative analysis framework, called MeLncTRN (Methylation mediated LncRNA Transcriptional Regulatory Network), that integrates genome-wide transcriptome, DNA methylome and copy number variation profiles, to systematically identify the epigenetically-driven lncRNA-gene regulation circuits across 18 cancer types.
FINDING: We show that a significant fraction of the aberrant DNAm and gene expression landscape in cancer is associated with long noncoding RNAs (lncRNAs). We reveal distinct types of regulation between lncRNA modulators and target genes that are operative in either only specific cancers or across cancers. Functional studies identified a common theme of cancer hallmarks that lncRNA modulators may participate in. The coupled lncRNA gene interactions via DNAm also serve as markers for classifications of cancer subtypes with different prognoses.
INTERPRETATION: Our study reveals a vital layer of DNAm and associated expression regulation for many cancer-related genes and we also provide a valuable database resource for interrogating epigenetically mediated lncRNA-gene interactions in cancer.
FUNDING: National Natural Science Foundation of China [91959106, 31871255].

Keywords: DNA methylation; LncRNA; Omics-data integration; Regulatory network; Transcriptional regulation

DOI: https://doi.org/10.1016/j.ebiom.2021.103399

Dis Markers. 2021 ;2021 8849977

A Risk Signature with Autophagy-Related Long Noncoding RNAs for Predicting the Prognosis of Clear Cell Renal Cell Carcinoma: Based on the TCGA Database and Bioinformatics.

Yundong Xuan, Weihao Chen, Kan Liu, Yu Gao, Shidong Zuo, Baojun Wang, Xin Ma, Xu Zhang.

Background: Disorders of autophagic processes have been reported to affect the survival outcome of clear cell renal cell carcinoma (ccRCC) patients. The purpose of our study was to identify and validate the candidate prognostic long noncoding RNA signature of autophagy.Methods: Transcriptome profiles were obtained from The Cancer Genome Atlas. The autophagy gene list was obtained from the Human Autophagy Database. Based on coexpression analysis, we obtained a list of autophagy-related lncRNAs (ARlncRNAs). GO enrichment analysis and KEGG pathway analysis were conducted to explore the functional annotation of these ARlncRNAs. Univariate and multivariate Cox regression analyses were conducted to elucidate the correlation between overall survival and the expression level of each ARlncRNAs. We then established a prognostic signature that was a linear combination of the regression coefficients from the multivariate Cox regression model (β) multiplied by the expression levels of the respective ARlncRNAs in the training cohort. The predictive performance was tested in the validation cohort. Additionally, the independence of the risk signature was assessed, and the relationship between the risk signature and conventional clinicopathological features was explored.
Results: Seven autophagy-related lncRNAs with prognostic value (SNHG3, SNHG17, MELTF-AS1, HOTAIRM1, EPB41L4A-DT, AP003352.1, and AC145423.2) were identified and integrated into a risk signature, dividing patients into low-risk and high-risk groups. The risk signature was independent of conventional clinical characteristics as a prognostic indicator of ccRCC (HR, 1.074, 95% confidence interval: 1.036-1.113, p < 0.001) and was valuable in the prediction of ccRCC progression.
Conclusion: Our risk signature has potential prognostic value in ccRCC, and these ARlncRNAs may play a significant role in ccRCC tumor biology.

DOI: https://doi.org/10.1155/2021/8849977

Exp Ther Med. 2021 Jul;22(1): 754

Long non-coding RNA LUCAT1 promotes the progression of clear cell renal cell carcinoma via the microRNA-375/YAP1 axis.

Xiaojun Wang, Hui Ou, Liangfen Zhou, Hengyu Liu, Xiaobao Liu, Huiyun Zhang.

Clear cell renal cell carcinoma (ccRCC) is a common renal cell carcinoma with a high mortality rate. Lung cancer-associated transcript 1 (LUCAT1) has been reported to be a potential biomarker of prognosis in human ccRCC. However, the underlying mechanism of the function of LUCAT1 in ccRCC remains poorly understood. The present study aimed to investigate the role and underlying mechanism of LUCAT1 in ccRCC. The expression level of LUCAT1, microRNA-375 (miR-375) and yes-associated protein 1 (YAP1) in ccRCC tissues and cells was detected by reverse transcription-quantitative PCR, and the protein level of YAP1 was detected by western blotting. The effects of LUCAT1 on cell proliferation, migration and invasion were analyzed using Cell Counting Kit-8 and Transwell assays. The association between miR-375 and LUCAT1 or miR-375 and YAP1 was predicted by lncBase Predicted v.2 or TargetScan and verified using dual-luciferase reporter assay. The effect of LUCAT1 on ccRCC progression in vivo was evaluated using a xenograft tumor model. The results revealed that LUCAT1 and YAP1 were upregulated and miR-375 was downregulated in ccRCC tissues and cells. LUCAT1 knockdown suppressed cell proliferation, migration and invasion, which were reversed by the inhibition of miR-375. In addition, YAP1 overexpression attenuated the inhibitory effects of miR-375 overexpression on cell proliferation, migration and invasion. Subsequent experiments suggested that LUCAT1 regulated YAP1 expression by sponging miR-375. Therefore, LUCAT1 exerted its role by regulating the miR-375/YAP1 axis in vitro. Moreover, LUCAT1 knockdown suppressed the growth of ccRCC xenograft tumors in vivo. These results collectively revealed that LUCAT1 promoted the proliferation, migration and invasion of ccRCC by the upregulation of YAP1 via sponging miR-375, which may be used as a potential therapeutic target for ccRCC.

Keywords: clear cell renal cell carcinoma; long non-coding RNA LUCAT1; microRNA-375; yes-associated protein 1

DOI: https://doi.org/10.3892/etm.2021.10186