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Open AccessArticle

A Regulatory Noncoding RNA, nc886, Suppresses Esophageal Cancer by Inhibiting the AKT Pathway and Cell Cycle Progression

1
Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea
2
Department of Life Science and Multidisciplinary Genome Institute, Hallym University, Chuncheon 24252, Korea
3
Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
4
Rare Cancer Branch, Research Institute, National Cancer Center, Goyang 10408, Korea
5
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
6
Medical Genomics Research Center, KRIBB, Daejeon 34141, Korea
7
Center for Lung Cancer, National Cancer Center, Goyang 10408, Korea
*
Authors to whom correspondence should be addressed.
Co-first authors.
Cells 2020, 9(4), 801; https://doi.org/10.3390/cells9040801
Received: 17 March 2020 / Accepted: 23 March 2020 / Published: 26 March 2020
(This article belongs to the Section Cellular Pathology)
nc886 is a regulatory non-coding RNA (ncRNA) whose expression is frequently silenced in malignancies. In the case of esophageal squamous cell carcinoma (ESCC), nc886 silencing is associated with shorter survival of patients, suggesting nc886′s tumor suppressor role in ESCC. However, this observation has not been complemented by an in-detail study about nc886′s impact on gene expression and cellular phenotypes. Here we have shown that nc886 inhibits AKT, a key protein in a renowned pro-survival pathway in cancer. nc886-silenced cells (nc886- cells) have activated AKT and altered expression of cell cycle genes. nc886- cells tend to have lower expression of CDKN2A and CDKN2C, both of which are inhibitors for cyclin-dependent kinase (CDK), and higher expression of CDK4 than nc886-expressing cells. As a result, nc886- cells are hyperactive in the progression of the G1 to S cell cycle phase, proliferate faster, and are more sensitive to palbociclib, which is a cancer therapeutic drug that targets CDK4/6. Experimentally by nc886 expression and knockdown, we have determined the AKT target genes and cell cycle genes that are controlled by nc886 (nc886-associated gene sets). These gene sets, in combination with pathologic staging and nc886 expression levels, are a vastly superior predictor for the survival of 108 ESCC patients. In summary, our study has elucidated in ESCC how nc886 inhibits cell proliferation to explain its tumor suppressor role and identified gene sets that are of future clinical utility, by predicting patient survival and responsiveness to a therapeutic drug.
Keywords: nc886; esophageal cancer; cell cycle; AKT; prognosis nc886; esophageal cancer; cell cycle; AKT; prognosis
MDPI and ACS Style

Im, W.R.; Lee, H.-S.; Lee, Y.-S.; Lee, J.-S.; Jang, H.-J.; Kim, S.-Y.; Park, J.-L.; Lee, Y.; Kim, M.S.; Lee, J.M.; Kim, I.-H.; Jeon, S.H.; Lee, Y.S. A Regulatory Noncoding RNA, nc886, Suppresses Esophageal Cancer by Inhibiting the AKT Pathway and Cell Cycle Progression. Cells 2020, 9, 801.

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