LncRNA PVT1 up-regulation is a poor prognosticator and serves as a therapeutic target in esophageal adenocarcinoma
Authors: Chengcao Sun
Brian Weston
Longfei Huo
Manoop S Bhutani
Zhenning Wang
Yan Xu
A Robert MacLeod
Jiankang Jin
Christopher Vellano
Jeffrey H Lee
Ailing Scott
Jaffer A Ajani
Linghua Wang
Liuqing Yang
Chunru Lin
Melissa Pool Pizzi
Lang Ma
Youngsoo Kim
Yuan Li
Shumei Song
Guangchun Han
Ying Wang
Journal: Molecular Cancer (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Antisense oligonucleotides; Esophageal adenocarcinoma; Lnc RNA; PVT1; YAP1.
Affiliations: Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA., Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, 110001, People's Republic of China., Departments of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Departments of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Departments of Gastroenterology&Hepatology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Center for Co-Clinical Trial, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Ionis Pharmaceuticals, Inc. 2855 Gazelle Court, Carlsbad, CA, 92010, USA., Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, 110001, People's Republic of China. ., Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. .

Abstract:  Background: PVT1 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. Methods: PVT1 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. Results: PVT1 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. Conclusions: Our 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. 

Retracted: No

PubPeer comments:
 In Figure 3D, a micrograph has been duplicated and presented as something else. ![file] , 
 #1 Thank you for your notifying the discrepant results in our paper. We inadvertently included two identical figures. The error is now noted and acknowledged. We are planning to submit the corrected Figure to the Journal as an addendum. We sincerely apologize for this error. As a result of this error, our team is changing the entire standard operating procedure, which will now include an independent review of all figures to avoid accidental and unintentional duplications. We are appreciative of what you do. ,