Long noncoding RNA (lncRNA) plays a crucial role in the regulation of various cellular processes and human diseases. However, little is known about the role of lncRNAs in colorectal liver metastasis (CLM). In the present study, we aimed to determine whether lncRNAs are differentially expressed in CLM tissue and to further assess their clinical value. lncRNA arrays were employed to screen for differentially expressed lncRNAs in colorectal cancer (CRC) tissues with synchronous, metachronous, or nonliver metastasis. Based on bioinformatics data, a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay was performed to identify target lncRNAs in an expanded set of CRC samples with various subtypes of liver metastasis. The relationships between the target lncRNAs and the clinical characteristics and patient prognosis were further analyzed. After determining the expression profile of lncRNAs (n = 1332) in CLM tissue, 40 differentially expressed lncRNAs that were potentially related to CLM were selected for further examination in an expanded set of clinical samples, and three novel target lncRNAs, termed lncRNA-CLMAT1-3, were verified. High lncRNA-CLMAT3 expression strongly correlated with liver metastasis (P = 0.03) and lymph node metastasis (P = 0.009). Moreover, patients displaying high lncRNA-CLMAT3 expression exhibited a shorter median overall survival duration than those displaying low lncRNA-CLMAT3 expression (30.7 vs. 35.2 months, P = 0.007). Multivariate analysis demonstrated that the lncRNA-CLMAT3 expression level is an independent prognostic factor (hazard ratio 2.05, P = 0.02) after adjusting for other known prognostic factors. lncRNA-CLMAT3 over-expression was significantly associated with CLM and was an independent predictor of poor survival for patients with CRC.
Colorectal liver metastasis Long noncoding RNA lncRNA-CLMAT3
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We thank the National Natural Science Foundation of China (No. 81372315), Shanghai medical guide project (134119a4800) and Shanghai Scientific Research Plan Project (No. 13JC1401601) for providing funding supports.
Conflicts of interest
Le-chi Ye and Li Ren performed the molecular genetics experiments, participated in the sequence alignment, and drafted the manuscript. Jun-jun Qiu participated in the sequence alignment. Tao Chen, De-xiang Zhu, and Wen-ju Chang participated in the design of the study and performed the statistical analysis. Jianmin Xu, Li Ren, and Ye Wei conceived of the study, participated in its design and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.
Overview of the lncRNA microarray analysis results. Heat maps were generated based on hierarchical cluster analysis to display the differentially expressed lncRNAs (>2 fold-change in expression and P < 0.01) between the SLM and NCR samples (A), the MLM and NLM samples (B), the SLM and MLM samples (C), or the SLM and NLM samples (D). Abbreviations: CRC, colorectal cancer; NCR, normal colorectum; NLM, CRC with no liver metastasis; MLM, CRC with metachronous liver metastasis; SLM, CRC with synchronous liver metastasis. (JPEG 185 kb)
Chuang SC, Su YC, Lu CY, Hsu HT, Sun LC, Shih YL, et al. Risk factors for the development of metachronous liver metastasis in colorectal cancer patients after curative resection. World J Surg. 2011;35:424–9.CrossRefPubMedGoogle Scholar
Mekenkamp LJ, Koopman M, Teerenstra S, van Krieken JH, Mol L, Nagtegaal ID, et al. Clinicopathological features and outcome in advanced colorectal cancer patients with synchronous vs metachronous metastases. Br J Cancer. 2010;103:159–64.CrossRefPubMedPubMedCentralGoogle Scholar
Hayashi N, Ito I, Yanagisawa A, Kato Y, Nakamori S, Imaoka S, et al. Genetic diagnosis of lymph-node metastasis in colorectal cancer. Lancet. 1995;345:1257–9.CrossRefPubMedGoogle Scholar
Mercer TR, Mattick JS. Structure and function of long noncoding RNAs in epigenetic regulation. Nat Struct Mol Biol. 2013;20:300–7.CrossRefPubMedGoogle Scholar
Xue Y, Ma G, Gu D, Zhu L, Hua Q, Du M, et al. Genome-wide analysis of long noncoding RNA signature in human colorectal cancer. Gene. 2015;556:227–34.CrossRefPubMedGoogle Scholar
Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T, et al. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 2011;71:6320–6.CrossRefPubMedGoogle Scholar
Matouk IJ, Abbasi I, Hochberg A, Galun E, Dweik H, Akkawi M. Highly upregulated in liver cancer noncoding RNA is overexpressed in hepatic colorectal metastasis. Eur J Gastroenterol Hepatol. 2009;21:688–92.CrossRefPubMedGoogle Scholar
Sorin V, Ohana P, Mizrahi A, Matouk I, Birman T, Hochberg A, et al. Regional therapy with DTA-H19 vector suppresses growth of colon adenocarcinoma metastases in the rat liver. Int J Oncol. 2011;39:1407–12.PubMedGoogle Scholar
Zheng HT, Shi DB, Wang YW, Li XX, Xu Y, Tripathi P, et al. High expression of lncRNA MALAT1 suggests a biomarker of poor prognosis in colorectal cancer. Int J Clin Exp Pathol. 2014;7:3174–81.PubMedPubMedCentralGoogle Scholar
Chen H, Xu J, Hong J, Tang R, Zhang X, Fang JY. Long noncoding RNA profiles identify five distinct molecular subtypes of colorectal cancer with clinical relevance. Mol Oncol. 2014;8:1393–403.CrossRefPubMedGoogle Scholar
Nissan A, Stojadinovic A, Mitrani-Rosenbaum S, Halle D, Grinbaum R, Roistacher M, et al. Colon cancer associated transcript-1: a novel RNA expressed in malignant and pre-malignant human tissues. Int J Cancer. 2012;130:1598–606.CrossRefPubMedGoogle Scholar
Dexiang Z, Li R, Ye W, Haifu W, Yunshi Z, Qinghai Y, et al. Outcome of patients with colorectal liver metastasis: analysis of 1,613 consecutive cases. Ann Surg Oncol. 2012;19:2860–8.CrossRefPubMedGoogle Scholar
Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, Hung G, et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 2013;73:1180–9.CrossRefPubMedGoogle Scholar
Zoratto F, Rossi L, Verrico M, Papa A, Basso E, Zullo A, et al. Focus on genetic and epigenetic events of colorectal cancer pathogenesis: implications for molecular diagnosis. Tumour Biol. 2014;35:6195–206.CrossRefPubMedGoogle Scholar
Ji Q, Liu X, Fu X, Zhang L, Sui H, Zhou L, et al. Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated Wnt/beta-catenin signal pathway. PLoS One. 2013;8:e78700.CrossRefPubMedPubMedCentralGoogle Scholar
Ling H, Spizzo R, Atlasi Y, Nicoloso M, Shimizu M, Redis RS, et al. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res. 2013;23:1446–61.CrossRefPubMedPubMedCentralGoogle Scholar
Feng J, Bi C, Clark BS, Mady R, Shah P, Kohtz JD. The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes Dev. 2006;20:1470–84.CrossRefPubMedPubMedCentralGoogle Scholar
Yoshimura T, Nagahara M, Kuo C, Turner RR, Soon-Shiong P, Hoon DS. Lymphovascular invasion of colorectal cancer is correlated to SPARC expression in the tumor stromal microenvironment. Epigenetics. 2011;6:1001–11.CrossRefPubMedGoogle Scholar
Heitzer E, Artl M, Filipits M, Resel M, Graf R, Weissenbacher B, et al. Differential survival trends of stage II colorectal cancer patients relate to promoter methylation status of PCDH10, SPARC, and UCHL1. Mod Pathol. 2014;27:906–15.CrossRefPubMedGoogle Scholar
Yusuf N, Inagaki T, Kusunoki S, Okabe H, Yamada I, Matsumoto A, et al. SPARC was overexpressed in human endometrial cancer stem-like cells and promoted migration activity. Gynecol Oncol. 2014;134:356–63.CrossRefPubMedGoogle Scholar