Long noncoding RNA PANDA promotes esophageal squamous carcinoma cell progress by dissociating from NF-YA but interact with SAFA
Introduction
Esophageal cancer (EC) is the eighth most common malignant tumor worldwide and the sixth most common cause of death from cancer [1]. Esophageal cancer, derived from epithelia, consists of two subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma, which have different etiologic and pathologic characteristics [2]. In Asia, the predominant pathological type is ESCC, which is often diagnosed at the advanced stage, and China is one of the high-risk esophageal cancer areas [3]. To date, the prognosis for ESCC patients is not well improved with a rate of less than 10% 5-year survival [4]. Therefore, it is urgent to understand the detailed interactions and regulatory mechanisms of key pathways involved in the tumor-genesis and progression of ESCC and find molecular markers for early detection and diagnosis.
Recent studies have revealed that epigenetic regulation also participates in cancer development and progression [5]. Long noncoding RNAs (LncRNAs), which occupy the majority of human genome, have been shown to play an important role in the regulation of gene transcription, translation and widespread regulators involved in cell proliferation, migration and apoptosis [[6], [7], [8], [9], [10]]. Mounting evidence indicate that lncRNAs expression is misregulated and contributes to the development and progression of multiple cancers. Their dysregulation has been found in various types of carcinomas, including breast cancer, colon cancer, hepatocellular carcinoma and lung cancer. LncRNAs are often up-regulated and down-regulated, and may serve as oncogenes or tumor suppressors in cancers [[11], [12], [13]]. However, the roles of lncRNAs in ESCC are still not well documented and needed to be further explored.
LncRNA PANDA (PANDA), a 5-capped and polyadenylated non-spliced lncRNA, is transcripted from approximately 5 kb upstream of the CDKN1A transcriptional start site. PANDA expression could be induced by DNA damage and limit expression of pro-apoptotic genes by interacting with the transcription factor NF-YA in a p53-dependent manner [14]. Moreover, PANDA deletion could increase human fibroblasts cells sensitivity to doxorubicin and induce cell apoptosis. However, its expression and biological function in ESCC remain poorly understood. In this study, the expression pattern and biological functions of PANDA in ESCC development were explored. The correlations between PANDA and the clinical outcomes of ESCC patients were evaluated, and the effects of PANDA on proliferation and apoptosis of ESCC cells were also investigated both in vitro and in vivo. Moreover, knockdown of PANDA could affect multiple gene expression involved in regulating phase checkpoints of cell cycle, such as E2F1. This study might provide a novel mechanism and potential therapeutic target for ESCC.
Section snippets
Tissue sample collection and patient data
All samples were collected from informed consent individuals according to protocols approved by the ethics committee of Nanjing Hospital affiliated with Nanjing Medical University. A total of 134 paired samples of ESCC (TNM Stage 0 to IV), including cancer tissues and corresponding adjacent non-cancer tissues were obtained from patients who underwent surgery in our hospital from 2005 to 2012. Only 76 cases of 134 patients had follow-up materials of 5 yrs used for survival analysis for 5 yrs. No
LncRNA PANDA is up-regulated in of ESCC tissues
To validate levels of PANDA expression, we conducted qRT-PCR analysis to measure the PANDA expression in 134 paired cancerous and adjacent noncancerous tissues of ESCC. PANDA expression was up-regulated in 67.5% ESCC sample (91 of 134 cases, p < 0.05) 91 cancerous tissues and down-regulated in 43 cancerous tissues compared with their paired adjacent noncancerous tissues (Fig. 1A and 1B). All ESCC sample were classified into two groups based on the median value of relative PANDA expression. The
Discussion
The human genome contains a large number of lncRNAs that are dynamically expressed in a tissue-, differentiation-, cell type- or developmental stage-specific manner, indicating specific functions of lncRNAs in the development of diseases [[25], [26], [27]]. The cellular functions of most recently discovered lncRNAs then needed to be elucidated. For each individual molecule, it needs to be established whether it executes important functions or just represents “transcriptional noise” or
Conclusions
In this study, we figured out the lncRNA PANDA who could promote the ESCC progression in vitro and in vivo. We reported that PANDA drifted away from NF-YA to promote the expression of NF-YA-E2F1 coregulated proliferation-promoting genes, and to limit the ESCC cell apoptosis. In addition, PANDA binding SAFA to switch on the tumor proliferation programme though CyclinD1/2-Cyclin E1 and Bcl-2 pathways in ESCC.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Funding
This work was supported by Suzhou Science and Technology Development Project (SNG201607, SNG2017049), and 2018 Municipal Industrial Development Guidance Fund (Technology Innovation Special Project) (s201808).
Declaration of Competing Interest
The authors declare that they have no competing interests
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Contributed to the work equally.