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Long noncoding RNA CCAT2 as a novel biomaker of metastasis and prognosis in human cancer: a meta-analysis.

ABSTRACT: Colon cancer-associated transcript2 (CCAT2), a long noncoding RNA (LncRNA), has been found to function as an oncogene in various cancers. However, the clinical value of CCAT2 in cancers remains unclear. Therefore, we performed this meta-analysis to investigate the association between CCAT2 level and metastasis & prognosis in malignant tumors. The meta analysis was performed by using a systematic search in PubMed, Web of Science, and Cochrane Library from inception to NOV 17, 2016. According to the inclusion and exclusion criteria,9 studies with 1084 patients were included in the meta-analysis.The result showed that overexpression of CCAT2 is positively correlated with lymph node metastasis (Odds ratio,OR=3.57, 95 % confidence interval(CI): 1.79-7.13, p<0.001) in a random-effects model (I2=71%, p=0.008) and distant metastasis(OR=7.68, 95 % CI: 3. 29-17.96, p<0.001) in a random-effects model (I2=41.9%, p=0.16).Likewise,we also found that high CCAT2 expression could predict unfavourable overall survival with pooled hazard ratio (HR) of 2.23 (95 % CI 1.68-2.96, p<0.00001) by a random-effects model (I2=37.5%, p=0.143) and poor metastasis-free survival in cancer patients (HR= 2.08, 95%CI:1.37-3.18 p=0.001) by a fixed-effects model (I2=0.0%, p=0.807). In conclusion,CCAT2 might be served as a novel molecular marker for predicting metastasis and prognosis in various human-cancers.

SUBMITTER: Wang D

PROVIDER: S-EPMC5650455 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Long noncoding RNA CCAT2 as a novel biomaker of metastasis and prognosis in human cancer: a meta-analysis.

Wang Dailian D Chen Zhicong Z Xu Haidan H He Anbang A Liu Yuchen Y Huang Weiren W

Oncotarget 20170524 43

Colon cancer-associated transcript2 (CCAT2), a long noncoding RNA (LncRNA), has been found to function as an oncogene in various cancers. However, the clinical value of CCAT2 in cancers remains unclear. Therefore, we performed this meta-analysis to investigate the association between CCAT2 level and metastasis & prognosis in malignant tumors. The meta analysis was performed by using a systematic search in PubMed, Web of Science, and Cochrane Library from inception to NOV 17, 2016. According to t ...[more]

PMID: 29088900

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Project description:Background & aimsChromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer-associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic.MethodsWe performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, γ-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2'-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients.ResultsHigh expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients.ConclusionsWe found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors.

Dataset Information

Long noncoding RNA CCAT2 as a novel biomaker of metastasis and prognosis in human cancer: a meta-analysis.

Publications

Long noncoding RNA CCAT2 as a novel biomaker of metastasis and prognosis in human cancer: a meta-analysis.

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