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Increased Expression of the Long Non-coding RNA LINC01503, Regulated by TP63, in Squamous Cell Carcinoma and Effects on Oncogenic Activities of Cancer Cell Lines. (Gastroenterology, Feb 2018)

Xie JJ1, Jiang YY2, Jiang Y2, Li CQ3, Chee LM2, An O2, Mayakonda A2, Ding LW2, Long L4, Sun C4, Lin LH5, Chen L5, Wu JY4, Wu ZY6, Cao Q5, Fang WK4, Yang W7, Meltzer SJ8, Yang H2, Fullwood M9, Xu LY10, Li EM11, Lin DC12, Koeffler HP13.

1 Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou, China; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, USA.

2 Cancer Science Institute of Singapore, National University of Singapore, Singapore.

3 School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China.

4 Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou, China.

5 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, USA.

6 Department of Oncologic Surgery, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou, China.

7 Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, USA.

8 Departments of Medicine and Oncology, the Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, USA.

9 Cancer Science Institute of Singapore, National University of Singapore, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore.

10 Institute of Oncologic Pathology, Medical College of Shantou University, Shantou, China.

11 Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou, China.

12 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, USA.

13 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, USA; Cancer Science Institute of Singapore, National University of Singapore, Singapore; National University Cancer Institute, National University Hospital Singapore, Singapore.

Abstract

BACKGROUND & AIMS:

Long non-coding RNAs (lncRNAs) are expressed in tissue-specific pattern, but it is not clear how these are regulated. We aimed to identify squamous cell carcinoma (SCC)-specific lncRNAs and investigate mechanisms that control their expression and function.  METHODS: We studied expression patterns and functions of 4 SCC-specific lncRNAs. We obtained 113 esophageal SCC (ESCC) and matched non-tumor esophageal tissues from a hospital in Shantou City, China, and performed quantitative reverse transcription PCR assays to measure expression levels of LINC01503. We collected clinical data from patients and compared expression levels with survival times. LINC01503 was knocked down using small interfering RNAs and oligonucleotides in TE7, TE5 and KYSE510 cell lines and overexpressed in KYSE30 cells. Cells were analyzed by chromatin immunoprecipitation sequencing, luciferase reporter assays, colony formation, migration and invasion, and mass spectrometry analyses. Cells were injected into nude mice and growth of xenograft tumors was measured. LINC01503 interaction with proteins was studied using fluorescence in situ hybridization, RNA pulldown, and RNA immunoprecipitation analyses.

RESULTS:

We identified a lncRNA, LINC01503, which is regulated by a super-enhancer and is expressed at significantly higher levels in esophageal and head and neck SCCs than in non-tumor tissues. High levels in SCCs correlated with shorter survival times of patients. The transcription factor TP63 bound to the super-enhancer at the LINC01503 locus and activated its transcription. Expression of LINC01503 in ESCC cell lines increased their proliferation, colony formation, migration and invasion. Knockdown of LINC01503 in SCC cells reduced their proliferation, colony formation, migration and invasion, and growth of xenograft tumors in nude mice. Expression of LINC01503 in ESCC cell lines reduced ERK2 dephosphorylation by DUSP6, leading to activation of ERK signaling via MAPK. LINC01503 disrupted the interaction between EBP1 and the p85 subunit of PI3K, increasing AKT signaling.

CONCLUSIONS:

We identified a lncRNA, LINC01503, that is increased in SCC cells compared with non-tumor cells. Increased expression of LINC01503 promotes ESCC cell proliferation, migration, invasion, and growth of xenograft tumors. It might be developed as a biomarker of aggressive SCCs in patients.

Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

epigenetic regulation; gene regulation; oncongenesis; signal transduction

PMID: 29454790