Abstract
BackgroundHead and neck squamous cell carcinoma (HNSCC) represents one of the most common malignancies worldwide with a high mortality rate mainly due to lack of early detection markers, frequent association with metastasis and aggressive phenotype. Recently, long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in human cancers. The lncRNA prostate cancer-associated transcript 1 (PCAT-1) showed potential oncogenic roles in different cancers, however its role in HNSCC is not known. In this study, we evaluated the role of the PCAT-1 in HNSCC.MethodsThe expression of PCAT-1 was measured by quantitative real-time PCR in 23 paired human HNSCC tissues and adjacent non-tumor tissue specimens. Cell proliferation after depleting PCAT-1 was determined. Effect of PCAT-1 depletion in HNSCC cell lines was determined by qRT-PCR and Western blot analyses. Finally, JHU029 HNSCC cells was implanted subcutaneously into athymic nude mice and therapeutic potential of PCAT-1 was investigated.ResultsUp-regulation of PCAT-1 in TCGA dataset of HNSCC was noted. We also observed increased expression of PCAT-1 in archived HNSCC patient samples as compared to adjacent non-tumor tissues. Knockdown of PCAT-1 significantly reduced cell proliferation in HNSCC cell lines. Mechanistic study revealed significant down regulation of c-Myc and AKT1 gene in both RNA and protein levels upon knockdown of PCAT-1. We observed that c-Myc and AKT1 positively correlate with PCAT-1 expression in HNSCC. Further, we observed activation of p38 MAPK and apoptosis signal-regulating kinase 1 upon knockdown of PCAT-1 which induces Caspase 9 and PARP mediated apoptosis. Targeted inhibition of PCAT-1 regresses tumor growth in nude mice.ConclusionTogether our data demonstrated an important role of the PCAT-1 in HNSCC and might serve as a target for HNSCC therapy.
Highlights
Head and neck squamous cell carcinoma (HNSCC) represents one of the most common malignancies worldwide with a high mortality rate mainly due to lack of early detection markers, frequent association with metastasis and aggressive phenotype
We further examined prostate cancer-associated transcript 1 (PCAT-1) expression in a panel of human HNSCC cell lines and detected higher expression of PCAT-1 in JHU029 and JHU022 cells when compared with Normal oral keratinocytes (NOK) cells (Fig. 1c)
When the tumors were palpable, we randomly divided the mice in two Discussion Our study demonstrated that depletion of PCAT-1 in HNSCC cell lines inhibits cell proliferation and induces apoptosis by i) inhibiting c-Myc and AKT1 expression, ii) activating apoptosis signal-regulating kinase 1 (ASK1) mediated p38 Mitogen-activated protein kinase (MAPK) signalling, and iii) inducing Caspase 9 and Poly polymerases (PARP) cleavage
Summary
Head and neck squamous cell carcinoma (HNSCC) represents one of the most common malignancies worldwide with a high mortality rate mainly due to lack of early detection markers, frequent association with metastasis and aggressive phenotype. Long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in human cancers. The lncRNA prostate cancer-associated transcript 1 (PCAT-1) showed potential oncogenic roles in different cancers, its role in HNSCC is not known. The recent discovery of long non-coding RNAs (lncRNAs) has gained widespread attention as a new layer of regulation in biological processes. Numerous cancer-associated lncRNAs are reported to modulate tumour growth, invasion and metastasis, and have been implicated as potential alternative biomarkers and therapeutic targets for cancer [1]. Prostate cancer-associated transcript 1 (PCAT-1) was initially identified in prostate cancer [5, 6]. Overexpression of PCAT-1 was reported in several cancers and its function is associated with cell proliferation, invasion, metastasis, survival, cell cycle, chemoresistance, and homologous recombination. The role of PCAT-1 in HNSCC remains unknown
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