Roles of long noncoding RNAs in colorectal cancer metastasis

Abstract

Colorectal cancer (CRC) is the 3rd most common malignancies worldwide. Metastasis is responsible for more than 90% CRC patients' death. Long noncoding RNAs (lncRNAs) are an important class of transcribed RNA molecules greater than 200 nucleotides in length. With the development of whole genome sequencing technologies, they have been gained more attention. Accumulating evidences suggest that abnormal expression of lncRNAs in diverse diseases are involved in various biological functions such as proliferation, apoptosis, metastasis and differentiation by acting as epigenetic, splicing, transcriptional or post-transcriptional regulators. Aberrant expression of lncRNAs has also been found in CRC. Besides, recent studies have indicated that lncRNAs play important roles in tumourigenesis and cancer metastasis. They participate in the process of metastasis by activing or inhibiting the metastatic pathways. However, their functions on the development of cancer metastasis are poorly understood. In this review, we highlight the findings of roles for lncRNAs in CRC metastasis and review the metastatic pathways of lncRNAs leading to cancer metastasis in CRC, including escape of apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis and invasion, migration and proliferation. Furthermore, we also discuss the potential clinical application of lncRNAs in CRC as diagnostic markers and therapeutic targets.

Keywords: colorectal cancer; lncRNAs; metastasis; review.

Figure 1. Regulation of apoptosis in CRC by lncRNAs

UCA1, PRNCR1 and CCAL could regulate the apoptosis pathway in CRC. High expression levels of PVT-1 response to 8q24 copy-number gain inhibited apoptosis pathway. Low expression levels of Loc554202 inhibited apoptosis pathway by down-regulation of Bcl-2. DQ786243 down-regulated Bcl-2 expression and led cell cycle arrest, leading to repressing apoptosis pathway. GHE1, GAS5 and AFAP1-AS1 influenced apoptosis by regulating cell cycle progression. HOTTIP modified apoptosis pathway and cell cycle progression by inducing expression of p21. BANCR, regulated by Est-1 mildly effected proliferation by promoting G1 arrest and causing p21 mediated- apoptosis. lincRNA-p21 regulates the G1/S the checkpoint and proliferation by promoting p53-dependent transcription of p21. ZFAS1 may influence cell cycle progress and inhibit apoptosis via destabilization of p53

Figure 2. Regulation of EMT in CRC by lncRNAs

BANCR, GHET1, HOTAIR and TUG1 induced EMT phenotypes by repressing the expression of vimentin and promoting the expression of E-cadherin. The expression of long non-coding RNA-activated by TGF-β (lncRNA-ATB) mediated epithelial markers (E-cadherin, ZO-1) repression and increased the expression of mesenchymal markers ZEB1 and N-cadherin through sequestering miR-200a. Besides, H19 significantly promoted EMT progression by functioning as a ceRNA for miR-138 and miR-200a. Moreover, CTD903 induced EMT-like phenotypes.

Figure 3. Regulation of proliferation, invasion and migration in CRC by lncRNAs

MALAT1 and lncRNA-p21 were supposed to promote cell proliferation, invasion and migration by activating Wnt/β-catenin signal pathway. CCAL enhanced cell proliferation by activated AP-2α-mediated Wnt/β-catenin signaling. CASC11 and CCAT2 activated Wnt/β-catenin signal pathway by directly targeting hnRNP-K and TCF7L2, respectively. CTD903, Loc285195 and H19 promoted proliferation through sequestering miR-204-5p, miR-211 and miR-675, respectively. Besides, the binding of eIF4A3 to H19 decreased the recruiting of eIF4A3 to the cell-cycle gene mRNA, resulting in the promotion of cell proliferation.