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

Published on Mar 26, 2020in Cells4.366
· DOI :10.3390/CELLS9040801
Wonkyun Ronny Im2
Estimated H-index: 2
,
Hyun-Sung Lee25
Estimated H-index: 25
(BCM: Baylor College of Medicine)
+ 10 AuthorsYong Sun Lee19
Estimated H-index: 19
Sources
Abstract
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.
📖 Papers frequently viewed together
20193.70Cell Cycle
9 Authors (Yue Du, ..., Quancheng Kan)
6 Citations
12 Authors (Jia Liu, ..., Wei Cao)
3 Citations
8 Authors (Wen-Chun Lin, ..., Mong-Hsun Tsai)
17 Citations
References31
Newest
#1Ji Hye Ahn (Kyung Hee University)H-Index: 1
#2Hyun-Sung Lee (BCM: Baylor College of Medicine)H-Index: 25
Last. Yong Sun Lee (UTMB: University of Texas Medical Branch)H-Index: 19
view all 16 authors...
Transforming growth factor-β (TGF-β) signaling and microRNAs (miRNAs) are important gene regulatory components in cancer. Usually in advanced malignant stages, TGF-β signaling is elevated but global miRNA expression is suppressed. Such a gene expression signature is well illustrated in a fibrosis (or mesenchymal) subtype of ovarian cancer (OC) that is of poor prognosis. However, the interplay between the two pathways in the OC subtype has not yet been elucidated. nc886 is a recently identified n...
24 CitationsSource
#1Jing-Wen Bai (Ha Tai: Xiamen University)H-Index: 12
#2Yao-Chen Li (Ha Tai: Xiamen University)H-Index: 7
Last. Guo-Jun Zhang (Ha Tai: Xiamen University)H-Index: 29
view all 3 authors...
Cellular growth, development, and differentiation are tightly controlled by a conserved biological mechanism: the cell cycle. Thiscycle is primarily regulated by cyclin-dependent kinase (CDK)-cyclin complexes, checkpoint kinases, and CDK inhibitors.Deregulation of the cell cycle is a hallmark of the transformation of normal cells into tumor cells. Given its importance intumorigenesis, several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers-both as s...
84 CitationsSource
#1J-L ParkH-Index: 1
#2Y-S LeeH-Index: 4
Last. Yong Sun Lee (UTMB: University of Texas Medical Branch)H-Index: 19
view all 13 authors...
RNA polymerase III (Pol III) transcribes medium-sized non-coding RNAs (collectively termed Pol III genes). Emerging diverse roles of Pol III genes suggest that individual Pol III genes are exquisitely regulated by transcription and epigenetic factors. Here we report global Pol III expression/methylation profiles and molecular mechanisms of Pol III regulation that have not been as extensively studied, using nc886 as a representative Pol III gene. In a human mammary epithelial cell system that rec...
17 CitationsSource
#1Liang Chen (JNU: Jinan University)H-Index: 1
#2Jingxuan Pan (JNU: Jinan University)H-Index: 1
Background and Purpose Aberrant activation of the cyclin D1-cyclin-dependent kinase 4/6 (CDK4/6)-Rb signalling pathway is common in oesophageal squamous cell carcinoma (ESCC). PD-0332991, a highly specific inhibitor of CDK4/6, has potent antitumour activity against many types of cancer. The purpose of this study was to examine the in vitro and in vivo antineoplastic effect of PD-0332991 against the growth and metastasis of ESCC cells. Experimental Approach Cell viability and any synergy between ...
22 CitationsSource
#1Brendan D. Manning (Harvard University)H-Index: 65
#2Alex Toker (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 77
The Ser and Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of AKT, and the complex circuitry of this dynamically branching and looping signaling network that is...
1,289 CitationsSource
#1Hee Jin Jang (SNU: Seoul National University)H-Index: 16
#2Hyun-Sung LeeH-Index: 25
Last. Ju Seog Lee (University of Texas MD Anderson Cancer Center)H-Index: 62
view all 26 authors...
Objective Oesophageal squamous cell carcinoma (ESCC) is a heterogeneous disease with variable outcomes that are challenging to predict. A better understanding of the biology of ESCC recurrence is needed to improve patient care. Our goal was to identify small non-coding RNAs (sncRNAs) that could predict the likelihood of recurrence after surgical resection and to uncover potential molecular mechanisms that dictate clinical heterogeneity. Design We developed a robust prediction model for recurrenc...
22 CitationsSource
#3BC Cancer AgencyH-Index: 1
#4BrighamH-Index: 1
Last. Ontario Tumour BankH-Index: 1
view all 11 authors...
This work was supported by the Intramural Research Program and the following grants from the United States National Institutes of Health: 5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, and U54HG003273, P30CA16672
770 CitationsSource
#1Nene N. Kalu (University of Texas MD Anderson Cancer Center)H-Index: 8
#1Nene N. Kalu (University of Texas MD Anderson Cancer Center)H-Index: 10
Last. Faye M. JohnsonH-Index: 37
view all 2 authors...
ABSTRACTIntroduction Dysregulation of cell cycle progression has an established link to neoplasia and cancer progression. Components of the cyclin D-CDK4/6-INK4-Rb pathway are frequently altered in squamous cell carcinomas (SCCs) by diverse mechanisms, including viral oncogene–induced degradation, mutation, deletion, and amplification. Activation of the CDK4/6 pathway may predict response to CDK4/6 inhibitors and provide clinical biomarkers. Recently, the CDK4/6 inhibitor palbociclib showed clin...
9 CitationsSource
#1Shuo Qie (MUSC: Medical University of South Carolina)H-Index: 9
#2J. Alan Diehl (MUSC: Medical University of South Carolina)H-Index: 68
Mammalian cells encode three D cyclins (D1, D2, and D3) that coordinately function as allosteric regulators of cyclin-dependent kinase 4 (CDK4) and CDK6 to regulate cell cycle transition from G1 to S phase. Cyclin expression, accumulation, and degradation, as well as assembly and activation of CDK4/CDK6 are governed by growth factor stimulation. Cyclin D1 is more frequently dysregulated than cyclin D2 or D3 in human cancers, and as such, it has been more extensively characterized. Overexpression...
234 CitationsSource
The phosphorylation of ribosomal protein S6 (rpS6) has been described for the first time about four decades ago. Since then, numerous studies have shown that this modification occurs in response to a wide variety of stimuli on five evolutionarily conserved serine residues. However, despite a large body of information on the respective kinases and the signal transduction pathways, the physiological role of rpS6 phosphorylation remained obscure until genetic manipulations were applied in both yeas...
125 CitationsSource
Cited By4
Newest
#1Rafael Sebastián Fort (University of the Republic)H-Index: 6
#2María Ana Duhagon (University of the Republic)H-Index: 12
Background: The vault RNAs (vtRNAs) are a class of 84-141-nt eukaryotic non-coding RNAs transcribed by RNA polymerase III, associated to the ribonucleoprotein complex known as vault particle. Of the four human vtRNA genes, vtRNA1-1, vtRNA1-2 and vtRNA1-3, clustered at locus 1, are integral components of the vault particle, while vtRNA2-1 is a more divergent homologue located in a second locus. Gene expression studies of vtRNAs in large cohorts have been hindered by their unsuccessful sequencing ...
Source
Source
#1Shobha DagamajaluH-Index: 2
#2Manavalan Vijayakumar (Yenepoya University)
Last. T. S. Keshava PrasadH-Index: 36
view all 6 authors...
Introduction: Esophageal squamous cell carcinoma (ESCC), a histopathologic subtype of esophageal cancer is a major cause of cancer-related morbidity and mortality worldwide. This is primarily becau...
Source