PVT1 Long Non-coding RNA in Gastrointestinal Cancer

Abstract

Whole genome and transcriptome sequencing technologies have led to the identification of many long non-coding RNAs (lncRNAs) and stimulated the research of their role in health and disease. LncRNAs participate in the regulation of critical signaling pathways including cell growth, motility, apoptosis, and differentiation; and their expression has been found dysregulated in human tumors. Thus, lncRNAs have emerged as new players in the initiation, maintenance and progression of tumorigenesis. PVT1 (plasmacytoma variant translocation 1) lncRNA is located on chromosomal 8q24.21, a large locus frequently amplified in human cancers and predictive of increased cancer risk in genome-wide association studies (GWAS). Combined, colorectal and gastric adenocarcinomas are the most frequent tumor malignancies and also the leading cause of cancer-related deaths worldwide. PVT1 expression is elevated in gastrointestinal tumors and correlates with poor patient prognosis. In this review, we discuss the mechanisms of action underlying PVT1 oncogenic role in colorectal and gastric cancer such as MYC upregulation, miRNA production, competitive endogenous RNA (ceRNA) function, protein stabilization, and epigenetic regulation. We also illustrate the potential role of PVT1 as prognostic biomarker and its relationship with resistance to current chemotherapeutic treatments.

Keywords: Myc; PVT1; ceRNA; colorectal/gastric cancer; lncRNA; siRNA.

Figure 1

Expression of PVT1 isoforms in normal and tumor tissue from the gastrointestinal tract. Eleven of the twenty-five predicted PVT1 isoforms are expressed in the gastrointestinal tract. Transcripts variants are ranked from top to bottom according to their expression abundance (%) both in colon and stomach. Purple histograms illustrate the expression in normal tissue samples from GTEX database (colon n = 204 and stomach n = 204). Blue histograms illustrate the expression in tumor tissue samples from TCGA repository (colon adenocarcinoma n = 723 and stomach adenocarcinoma n = 453). Exon display for each PVT1 transcript variant is shown. Data was extracted using UCSC Xena Browser.

Figure 2

Chromosome 8q24.21 amplification and PVT1 gene structure and regulation. 8q24.21 chromosomal region is frequently amplified in colorectal and gastric cancers (upper). This region contains MYC as the only protein-coding gene (yellow boxes) and several lncRNAs. Those lncRNA involved in MYC or WNT regulation have been depicted (blue and black boxes) (middle). PVT1 lncRNA expression is regulated by FOXM1, STAT3, and p53 transcription factors. PVT1 promoter exhibits four enhancer regions that in normal conditions (WT) boost its own expression. Due to PVT1 promoter mutations and rearrangements (MUT), which are frequently found in cancers, enhancer elements preferentially interact with MYC promoter enhancing the transcription of the oncogene. PVT1 encodes for four miRNAs. miR-1204 has been show to stabilize p53 protein, while miR-1207 has been proven to modulate TERT protein at the post-transcriptional level and expression of stemness and EMT genes by mechanisms currently unknown (lower). Pictograms in purple and green illustrate evidences obtained in colorectal and gastric cancer, respectively. Dark gray boxes indicate gene promoters. Dark blue boxes indicate enhancer regions. Green and red arrows indicate up- and down-regulation, respectively.

Figure 3

PVT1 and MYC expression in gastrointestinal tumors and cell lines. PVT1 and MYC copy number variation (A,B) and RNAseq expression (C,D) in tumor samples from colorectal (n = 616) and stomach (n = 441) adenocarcinomas (A,C) and established cell lines from colorectal (n = 58) and gastric tumors (n = 38) (B,D). The name of cell lines used in studies investigating the role of PVT1 in gastrointestinal cancer are shown. Gray boxes indicate no alteration. Light blue boxes indicate gene amplification. Dark blue boxes indicate gene deletion. RNAseq expression units: RPKM (Reads Per Kilobase Million). Pearson and Spearman correlation coefficients and associated p-value (Spearman) are shown.

Figure 4

miRNAs encoded by PVT1 transcript variants. PTV1 isoforms are ranked according to expression abundance (%) in gastrointestinal normal tissues and tumors. Gray and blue boxes indicate absence and presence of the indicated miRNA, respectively. Nucleotide sequence, length, and location within PVT1 introns or exons is indicated for all miRNAs.

Figure 5

PVT1 interaction with miRNAs and proteins. PVT1 interacts with multiple miRNAs and proteins in cancer cells, leading to post-transcriptional (1) and post-translational (2) regulation of gene expression. PVT1-miRNA interactions promote efficient de-repression of miRNA targets. Specifically, PVT1 hinders miRNAs binding in the 3′ untranslated region of target transcripts, preventing their degradation by the RISC complex and thus increasing protein levels. PVT1-protein interactions stabilize proteins and prevent their degradation. Pictograms in purple and green illustrate PVT1-miRNAs/proteins interactions identified in colorectal and gastric cancer, respectively.

Figure 6

Predicted sponge capacity of miRNAs by PVT1 transcript variants. PTV1 isoforms are ranked according to their relative expression abundance (%) in gastrointestinal normal tissues and tumors. Gray and solid blue boxes indicate absence and presence of the nucleotide sequence complementary to the different miRNA, respectively. Patterned blue boxes indicate complementarity with miR-128 principal binding motif, but lack of the additional contact sites and/or difference in length from the main interacting core. Nucleotide sequence of the miRNA binding site is specified.

Figure 7

Epigenetic regulation by PVT1. PVT1 recruits EZH2 polycomb group protein leading to promoter methylation and transcriptional repression of CDKN2A (p16) and CDKN2B (p15).