Abstract
BackgroundPVT1 has emerged as an oncogene in many tumor types. However, its role in Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) is unknown. The aim of this study was to assess the role of PVT1 in BE/EAC progression and uncover its therapeutic value against EAC.MethodsPVT1 expression was assessed by qPCR in normal, BE, and EAC tissues and statistical analysis was performed to determine the association of PVT1 expression and EAC (stage, metastases, and survival). PVT1 antisense oligonucleotides (ASOs) were tested for their antitumor activity in vitro and in vivo.ResultsPVT1 expression was up-regulated in EACs compared with paired BEs, and normal esophageal tissues. High expression of PVT1 was associated with poor differentiation, lymph node metastases, and shorter survival. Effective knockdown of PVT1 in EAC cells using PVT1 ASOs resulted in decreased cell proliferation, invasion, colony formation, tumor sphere formation, and reduced proportion of ALDH1A1+ cells. Mechanistically, we discovered mutual regulation of PVT1 and YAP1 in EAC cells. Inhibition of PVT1 by PVT1 ASOs suppressed YAP1 expression through increased phosphor-LATS1and phosphor-YAP1 while knockout of YAP1 in EAC cells significantly suppressed PVT1 levels indicating a positive regulation of PVT1 by YAP1. Most importantly, we found that targeting both PVT1 and YAP1 using their specific ASOs led to better antitumor activity in vitro and in vivo.ConclusionsOur results provide strong evidence that PVT1 confers an aggressive phenotype to EAC and is a poor prognosticator. Combined targeting of PVT1 and YAP1 provided the highest therapeutic index and represents a novel therapeutic strategy.
Highlights
Esophageal cancer (ESCA) is one of the most aggressive malignancies and ranks seventh in terms of incidence and sixth in mortality, globally [1]
Overexpression of plasmacytoma variant translocation 1 (PVT1) long non-coding RNA (lncRNA) in esophageal adenocarcinoma (EAC) patients associated with poor prognosis First, genomic alteration of PVT1 was analyzed using the The Cancer Genome Atlas (TCGA) dataset across multiple cancer types; we found that ESCA was the second-ranking cancer type with high PVT1 alterations with 20% PVT1 amplification and around 75% of ESCA cases contained both amplification and duplications (> 3 N) (Fig. 1a)
On further analysis of two major ESCA subtypes EAC and esophageal squamous cell carcinoma (ESCC), we found that EAC patients had relative higher PVT1 amplification and its higher incidence in Western population leading us to focus on EAC (Fig. 1b)
Summary
Esophageal cancer (ESCA) is one of the most aggressive malignancies and ranks seventh in terms of incidence and sixth in mortality, globally [1]. Esophageal adenocarcinoma (EAC), a major subtype of ESCA, has increased dramatically in incidence in recent decades [2, 3]. In Western countries, the incidence of EAC has exceeded that of the previously more common esophageal squamous cell carcinoma (ESCC) [2, 3]. EAC is characterized by frequent somatic DNA structural rearrangements (copy number variations, CNVs) similar to the chromosomal instability (CIN) subtype of gastric adenocarcinoma [4]. Its role in Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) is unknown. The aim of this study was to assess the role of PVT1 in BE/EAC progression and uncover its therapeutic value against EAC
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