Pseudogene RACGAP1P activates RACGAP1/Rho/ERK signalling axis as a competing endogenous RNA to promote hepatocellular carcinoma early recurrence

Wang, Mengyao; Chen, Dongping; Qi, Bin; Li, Mingyi; Zhu, Yan-Yi; Yin, Wenwu; Hé, Lǚ; Yi, Yu; Li, Zhouyu; Li, Gang; Yang, Fang; Lin, Zhi-Rui; Liu, Jinquan

doi:10.1038/s41419-019-1666-2

Cited by 30 publications

(31 citation statements)

References 35 publications

(33 reference statements)

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“…The RACGAP gene is also the first gene reported as an independent biomarker for HCC recurrence. Wang et al discovered the significant up-regulation of the RACGAP1P pseudogene in HCC, which was related to shortened survival, larger tumor size, elevated AFP level and advanced clinical stage [147]. Luciferase assays and in vivo assays demonstrated that miR-15-5p was sequestered from its endogenous target RACGAP by RACGAP1P, causing increased RACGAP expression and contributing to the RACGAP oncogenic network (Fig.…”

Section: Pseudogenes As Cernasmentioning

confidence: 99%

The emerging roles of non-coding competing endogenous RNA in hepatocellular carcinoma

Xiao

et al. 2020

Cancer Cell Int

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Accumulating evidence has emerged revealing that noncoding RNAs (ncRNAs) play essential roles in the occurrence and development of hepatocellular carcinoma (HCC). However, the complicated regulatory interactions among various ncRNAs in the development of HCC are not entirely understood. The newly discovered mechanism of competing endogenous RNAs (ceRNAs) uncovered regulatory interactions among different varieties of RNAs. In recent years, a growing number of studies have suggested that ncRNAs, including long ncRNAs, circular RNAs and pseudogenes, play major roles in the biological functions of the ceRNA network in HCC. These ncRNAs can share microRNA response elements to affect microRNA affinity with target RNAs, thus regulating gene expression at the transcriptional level and both physiological and pathological processes. The ncRNAs that function as ceRNAs are involved in diverse biological processes in HCC cells, such as tumor cell proliferation, epithelial-mesenchymal transition, invasion, metastasis and chemoresistance. Based on these findings, ncRNAs that act as ceRNAs may be promising candidates for clinical diagnosis and treatments. In this review, we discuss the mechanisms and research methods of ceRNA networks. We also reviewed the recent advances in studying the roles of ncRNAs as ceRNAs in HCC and highlight possible directions and possibilities of ceRNAs as diagnostic biomarkers or therapeutic targets. Finally, the limitations, gaps in knowledge and opportunities for future research are also discussed.

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Section: Pseudogenes As Cernasmentioning

confidence: 99%

The emerging roles of non-coding competing endogenous RNA in hepatocellular carcinoma

Xiao

et al. 2020

Cancer Cell Int

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“…Other groups and our team previously showed that competing endogenous RNA (ceRNA) mechanism is a key action mode of pseudogene-derived RNA. 15 , 18 To ascertain whether RP11-480I12.5-004 exerts its roles in breast cancer by ceRNA mechanism, we performed a series of studies. First of all, we investigated the subcellular location of RP11-480I12.5-004 using the lncLocator ( http://www.csbio.sjtu.edu.cn/bioinf/lncLocator/ ).…”

Section: Resultsmentioning

confidence: 99%

“…MS2-RIP assay was employed to determine whether endogenous miR-29c-3p could bind to RP11-480I12.5-004, CDK6, and AKT3 according to the previous reports using EZ-Magna RIP kit (Millipore) in accordance with the manufacturers' instructions. 18,46…”

Section: Ms2-rip Assaymentioning

confidence: 99%

“…5 Â 10 6 of pre-transfected MCF-7 cells and 2 Â 10 6 of pre-transfected MDA-MB-231 cells were subcutaneously injected into the right back of nude mice (5 mice/group). Tumor volumes were calculated as the formula of 0.5 Â length Â width2 at 6,9,12,15,18,21,24,27, and 30 days post-injection. Finally, these mice were sacrificed and the tumors were isolated and weighted.…”

Section: Animal Studiesmentioning

confidence: 99%

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RP11-480I12.5-004 Promotes Growth and Tumorigenesis of Breast Cancer by Relieving miR-29c-3p-Mediated AKT3 and CDK6 Degradation

Lou

Ding

Zhong

et al. 2020

Molecular Therapy - Nucleic Acids

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Pseudogenes have been reported to exert oncogenic or tumorsuppressive functions in cancer. However, the expression, role, and mechanism of pseudogene-derived RNAs in breast cancer remain unclear. The RNA levels and prognostic values of pseudogenes in breast cancer were determined. The levels of RP11-480I12.5 in cell lines and clinical samples were validated by quantitative real-time PCR. In vitro effects of RP11-480I12.5 on cell growth were measured by cell counting kit-8 (CCK-8) assay, colony formation assay, cell counting assay, and flow cytometry analysis. Xenograft model was established to detect its in vivo effect. The potential mechanism of RP11-480I12.5 was also studied by a combination of bioinformatic analysis and experimental confirmation. Finally, the possible functional parental genes of RP11-480I12.5 in breast cancer were explored. After a series of bioinformatic analyses, RP11-480I12.5 was selected as the most potential pseudogene in breast cancer. RP11-480I12.5 expression was significantly upregulated in breast cancer cell lines and clinical breast cancer tissues. Knockdown of RP11-480I12.5 markedly suppressed cell proliferation and colony formation, induced cell apoptosis of breast cancer in vitro, and inhibited tumor growth in vivo. Four transcripts of RP11-480I12.5 (001/002/003/004) were identified. Only overexpression of RP11-480I12.5-004 significantly enhanced cell growth of breast cancer both in vitro and in vivo. RP11-480I12.5-004 mainly located in cytoplasm and increased AKT3 and CDK6 mRNA expression, at least in part, by competitively binding to miR-29c-3p. Six parental genes of RP11-480I12.5 were found, among which TUBA1B and TUBA1C were statistically linked to RP11-480I12.5 expression, possessed prognostic values, and were upregulated in breast cancer. Our findings suggested that pseudogene-derived long non-coding RNA (lncRNA) RP11-480I12.5-004 promoted growth and tumorigenesis of breast cancer via increasing AKT3 and CDK6 expression by competitively binding to miR-29c-3p.

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“…The protein interaction network identified nine key genes [RAD51 (29), KIF4A (30), RACGAP1 (31), SPAG5 (32), HMMr (33), cdc25c (34), cKS2 (35), SHcBP1 (36) and ERCC6L (37)] that interacted strongly with CENPM mRNA. Subsequently, the functions of these nine genes (38)(39)(40)(41)(42)(43)(44)(45)(46) were profiled in various types of cancer and it was identified that all of them have been reported to accelerate the progression of cancer, including BC and hepatocellular carcinoma (29)(30)(31)(32)(33)(34)(35)(36)(37). RT-qPCR demonstrated that the expression levels of five of the nine genes, ERCC6L, CKS2, KIF4A, SPAG5 and CDC25C, were increased in MCF7 cells with elevated CENPM expression, implying that cenPM may promote tumor progression by controlling the expression of these five genes.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of centromere protein�M promotes tumorigenesis: A potential predictive target for cancer in humans

Liu

Ren

et al. 2020

Mol Med Rep

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centromere protein M (cenPM), a protein required for chromosome separation, is involved in in mitosis. However, little has been reported about the roles of cenPM in various types of cancer. The present study identified that the mRNA expression levels of CENPM were significantly upregulated in 14 types of human cancer and identified a positive association between cenPM mrna expression and patient mortality using the oncomine, Gene expression Profiling interactive analysis, Human Protein atlas and Kaplan-Meier Plotter databases. a protein interaction network constructed with cenPM-interacting genes obtained from the cBio-Portal demonstrated that nine genes participating in the cell cycle served key roles in the function of cenPM. cell cycle analysis, reverse transcription-quantitative polymerase chain reaction, a cell counting Kit-8-based proliferation assay and a terminal deoxynucleotidyl transferase duTP nick end labelling assay further revealed the tumorigenic and carcinogenic roles of cenPM in vitro. In addition, it was identified that the mRNA expression levels of five of the nine identified genes were significantly associated with CENPM in MCF7 cells and that cenPM was rarely mutated among various types of human cancer. in conclusion, the data from the present study revealed that cenPM exerted its pro-tumorigenic function by regulating cell cycle-associated protein expression and suggested that cenPM could be used as a prognostic marker for breast cancer.

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Pseudogene RACGAP1P activates RACGAP1/Rho/ERK signalling axis as a competing endogenous RNA to promote hepatocellular carcinoma early recurrence

Cited by 30 publications

References 35 publications

The emerging roles of non-coding competing endogenous RNA in hepatocellular carcinoma

The emerging roles of non-coding competing endogenous RNA in hepatocellular carcinoma

RP11-480I12.5-004 Promotes Growth and Tumorigenesis of Breast Cancer by Relieving miR-29c-3p-Mediated AKT3 and CDK6 Degradation

Upregulation of centromere protein�M promotes tumorigenesis: A potential predictive target for cancer in humans

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