TY - JOUR
T1 - Interplay between ceRNA and Epigenetic Control of microRNA
T2 - Modelling Approaches with Application to the Role of Estrogen in Ovarian Cancer
AU - Huang, Tzy Wei
AU - Cheng, Frank H.C.
AU - Yan, Ching Cher Sanders
AU - Chuang, Yu Ming
AU - Cho, Chien Hong
AU - Lai, Hung Cheng
AU - Shieh, Shih Feng
AU - Chan, Michael W.Y.
AU - Tsai, Je Chiang
N1 - Funding Information:
This study was supported by grants from the Ministry of Science and Technology, Taiwan (MOST 110-2314-B-194-002-MY3 and MOST 109-2115-M-007-013-MY2). This study was also supported by the Center for Innovative Research on Aging Society (CIRAS) and partially supported by MOST, National Center for Theoretical Science (NCTS), and the Brain Research Center (to J.-C.Tsai) from The Featured Areas Research Center Program under the framework of the Higher Education Sprout Project by Ministry of Education, Taiwan.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - MicroRNAs (miRNAs) play an important role in gene regulation by degradation or translational inhibition of the targeted mRNAs. It has been experimentally shown that the way miRNAs interact with their targets can be used to explain the indirect interactions among their targets, i.e., competing endogenous RNA (ceRNA). However, whether the protein translated from the targeted mRNAs can play any role in this ceRNA network has not been explored. Here we propose a deterministic model to demonstrate that in a network of one miRNA interacting with multiple-targeted mRNAs, the competition between miRNA-targeted mRNAs is not sufficient for the significant change of those targeted mRNA levels, while dramatic changes of these miRNA-targeted mRNAs require transcriptional inhibition of miRNA by its target proteins. When applied to estrogen receptor signaling pathways, the miR-193a targets E2F6 (a target of estrogen receptor), c-KIT (a marker for cancer stemness), and PBX1 (a transcriptional activator for immunosuppressive cytokine, IL-10) in ovarian cancer, such that epigenetic silencing of miR-193a by E2F6 protein is required for the significant change of c-KIT and PBX1 mRNA level for cancer stemness and immunoevasion, respectively, in ovarian cancer carcinogenesis.
AB - MicroRNAs (miRNAs) play an important role in gene regulation by degradation or translational inhibition of the targeted mRNAs. It has been experimentally shown that the way miRNAs interact with their targets can be used to explain the indirect interactions among their targets, i.e., competing endogenous RNA (ceRNA). However, whether the protein translated from the targeted mRNAs can play any role in this ceRNA network has not been explored. Here we propose a deterministic model to demonstrate that in a network of one miRNA interacting with multiple-targeted mRNAs, the competition between miRNA-targeted mRNAs is not sufficient for the significant change of those targeted mRNA levels, while dramatic changes of these miRNA-targeted mRNAs require transcriptional inhibition of miRNA by its target proteins. When applied to estrogen receptor signaling pathways, the miR-193a targets E2F6 (a target of estrogen receptor), c-KIT (a marker for cancer stemness), and PBX1 (a transcriptional activator for immunosuppressive cytokine, IL-10) in ovarian cancer, such that epigenetic silencing of miR-193a by E2F6 protein is required for the significant change of c-KIT and PBX1 mRNA level for cancer stemness and immunoevasion, respectively, in ovarian cancer carcinogenesis.
KW - Deterministic model
KW - Epigenetics
KW - Ovarian cancer
KW - Target-translated protein
KW - ceRNA
KW - microRNA
KW - Estrogens/genetics
KW - MicroRNAs/genetics
KW - Epigenomics/methods
KW - Humans
KW - Signal Transduction/genetics
KW - Ovarian Neoplasms/genetics
KW - RNA, Messenger/genetics
KW - Gene Regulatory Networks/genetics
KW - RNA, Long Noncoding/genetics
KW - Cell Line, Tumor
KW - Female
KW - Gene Expression Regulation, Neoplastic/genetics
KW - Epigenesis, Genetic/genetics
KW - Carcinogenesis/genetics
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UR - http://www.scopus.com/inward/citedby.url?scp=85124869946&partnerID=8YFLogxK
U2 - 10.3390/ijms23042277
DO - 10.3390/ijms23042277
M3 - Article
C2 - 35216394
AN - SCOPUS:85124869946
SN - 1661-6596
VL - 23
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 4
M1 - 2277
ER -
