Long noncoding RNA PVT1-214 promotes proliferation and invasion of colorectal cancer by stabilizing Lin28 and interacting with miR-128

Abstract

Long noncoding RNAs (lncRNAs) are implicated in human cancer, but their mechanisms of action are largely unknown. In this study, we investigated lncRNA alterations that contribute to colorectal cancer (CRC) through microarray expression profiling in CRC patient samples. Here, we report that the CRC-associated lncRNA PVT1-214 is a key regulator of CRC development and progression; patients with high PVT1-214 expression had a shorter survival and poorer prognosis. In vitro and in vivo investigation of the role of PVT1-214 revealed a complex integrated phenotype affecting cell growth, stem-like properties, migration, and invasion. Furthermore, using RNA pull-down and mass spectrometry, we found that Lin28 (also known as Lin28A), a highly conserved RNA-binding protein, is associated with PVT1-214. Strikingly, we found that PVT1-214 not only upregulated Lin28 protein expression in CRC cells by stabilizing Lin28, but also participated in crosstalk with Lin28 mRNA through competition for miR-128 binding, imposing an additional level of post-transcriptional regulation. In addition, we further show that PVT1-214 repressed expression of let-7 family miRNAs, which was abrogated by Lin28 knockdown. Taken together, our findings support a model in which the PVT1-214/Lin28/let-7 axis serves as a critical regulator of CRC pathogenesis, which may simulate a new direction for CRC therapeutic development.

PVT1 Long Non-coding RNA in Gastrointestinal Cancer

“…In silico analysis identified PVT1 Sv-214 as ceRNA for miR-128, and the initial observation was confirmed experimentally in colorectal cancer cell lines through gain and loss-of-function experiments against PVT1 Sv-214 isoform and further extended to gastric cancer cell line model (68,79). Moreover, the expression of miR-128 showed a significant inverse correlation with the expression of PVT1 Sv-214 in colorectal and gastric primary tumor samples.…”

“…On the other hand, models of PVT1 overexpression do not adequately report the specific isoforms used. The only exception is the study of He et al, where they convincingly demonstrated in HCT116 and SW480 colon cancer cell lines, the ability of PVT1 Sv-214 to promote proliferation, stemness, migration and invasion in vitro; as well as in vivo by establishing tumor xenografts and liver metastasis mouse models in immunodeficient nude mice (68). Importantly, differences in the PVT1 isoforms downregulated in different studies might explain the discrepancies reported regarding the role of PVT1 to regulate apoptosis.…”

“…Unfortunately, very few reports have taken into consideration the large heterogeneity in PVT1 isoform expression and consequently, some of the results described in this review require further investigation. Nonetheless, multiple studies assessing PVT1 expression by means of microarray technology (66-68) or RT-PCR using oligonucleotides amplifying several PVT1 isoforms, have shown a general overexpression of PVT1 in colorectal tumors compared to paired normal tissue samples (66,(68)(69)(70)(71)(72)(73)(74) (68). Similarly, increased PVT1 expression has been described in primary gastric tumors compared to the normal gastric mucosa (75)(76)(77)(78).…”

“…Interestingly, the tumorigenic process does not seem to affect the relative abundance of PVT1 isoforms (Figure 1), being PVT1 Sv-217 the isoform also more abundant in tumors. Unfortunately, the studies investigating the expression and role of PVT1 in gastrointestinal malignancies have not addressed directly or indirectly the expression of this isoform (66,(68)(69)(70)(71)(72)(75)(76)(77)(78). All these observations have been extended to human cancer cell lines.…”

The novel long noncoding RNA CRART16 confers cetuximab resistance in colorectal cancer cells by enhancing ERBB3 expression via miR-371a-5p

“…proliferation and invasion of CRC cells and function as ceRNAs to modulate miRNA-34a expression, subsequently causing the repression of the miR-34a/SIRT1 axis [23,24]. The lncRNA plasmacytoma variant translocation 1 (PVT1)-214 acts as an oncogene that can facilitate proliferation, migration, and invasion in CRC cells by reducing Lin28 protein degradation and enhancing its stability and by increasing Lin28 at the posttranscriptional level by binding to miR-128 [25]. However, there has been little research on the role of lncRNAs in cetuximab resistance.…”