Identification of the 3-lncRNA Signature as a Prognostic Biomarker for Colorectal Cancer.

Shuzhen Liu,Qing Cao,Bianbian Yan,Guoyan An,Lei Lei

doi:10.3390/ijms21249359

Abstract

Colorectal cancer (CRC) is one of the most common malignant carcinomas in the world, and metastasis is the main cause of CRC-related death. However, the molecular network involved in CRC metastasis remains poorly understood. Long noncoding RNA (lncRNA) plays a vital role in tumorigenesis and may act as a competing endogenous RNA (ceRNA) to affect the expression of mRNA by suppressing miRNA function. In this study, we identified 628 mRNAs, 144 lncRNAs, and 25 miRNAs that are differentially expressed (DE) in metastatic CRC patients compared with nonmetastatic CRC patients from the Cancer Genome Atlas (TCGA) database. Functional enrichment analyses confirmed that the identified DE mRNAs are extensively involved in CRC tumorigenesis and migration. By bioinformatics analysis, we constructed a metastasis-associated ceRNA network for CRC that includes 28 mRNAs, 12 lncRNAs, and 15 miRNAs. We then performed multivariate Cox regression analysis on the ceRNA-related DE lncRNAs and identified a 3-lncRNA signature (LINC00114, LINC00261, and HOTAIR) with the greatest prognostic value for CRC. Clinical feature analysis and functional enrichment analysis further proved that these three lncRNAs are involved in CRC tumorigenesis. Finally, we used Transwell, Cell Counting Kit (CCK)-8, and colony formation assays to clarify that the inhibition of LINC00114 promotes the migratory, invasive, and proliferative abilities of CRC cells. The results of the luciferase assay suggest that LINC00114 is the direct target of miR-135a, which also verified the ceRNA network. In summary, this study provides a metastasis-associated ceRNA network for CRC and suggests that the 3-lncRNA signature may be a useful candidate for the diagnosis and prognosis of CRC.

Highlights

Worldwide, the incidence of colorectal cancer (CRC) ranks third and the mortality rate ranks second
We aim to identify a Long noncoding RNA (lncRNA) signature as a biomarker for the diagnosis and prognosis of CRC
An increasing number of articles have shown that dysregulated lncRNA expression is related to CRC tumorigenesis and metastasis [10,11,12]

Summary

Introduction

The incidence of colorectal cancer (CRC) ranks third and the mortality rate ranks second. Despite a decreasing trend of CRC mortality in many developed countries, the highest CRC incidence rates occur in Europe, Australia, and Northern America. Some developing countries have shown increases in both incidence and mortality in recent decades [1]. Investigating the molecular networks that regulate metastasis is imperative for improving CRC early diagnosis and therapy. LncRNAs are greater than 200 nt in length, act as translational regulators to regulate the degradation and stability of mRNAs, and play critical roles in the progression of many cancers, including CRC [7,8,9]. Increasing evidence indicates that molecular networks play important roles in a wide variety of human diseases [14]. Dysregulation of the competing endogenous RNA (ceRNA) network could promote tumorigenesis, including CRC [15,16]

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