PMID- 34890627
OWN - NLM
STAT- MEDLINE
DCOM- 20220621
LR  - 20230703
IS  - 1523-1747 (Electronic)
IS  - 0022-202X (Print)
IS  - 0022-202X (Linking)
VI  - 142
IP  - 7
DP  - 2022 Jul
TI  - miR-181a Promotes Multiple Protumorigenic Functions by Targeting TGFbetaR3.
PG  - 1956-1965.e2
LID - S0022-202X(21)02586-0 [pii]
LID - 10.1016/j.jid.2021.09.040 [doi]
AB  - Cutaneous squamous cell carcinoma (cSCC) comprises 15‒20% of all skin cancers and 
      has a well-defined progression sequence from precancerous actinic keratosis to 
      invasive cSCC. To identify targets for chemoprevention, we previously reported a 
      cross-species analysis to identify the transcriptional drivers of cSCC 
      development and identified miR-181a as a potential oncomiR. We show that the 
      upregulation of miR-181a promotes multiple protumorigenic properties by targeting 
      an understudied component of TGFbeta signaling, TGFbetaR3. miR-181a and TGFbetaR3 are 
      upregulated and downregulated, respectively, in cSCC. miR-181a overexpression 
      (OE) and TGFbetaR3 knockdown (KD) significantly suppresses UV-induced apoptosis in 
      HaCaT cells and in primary normal human epidermal keratinocytes. In addition, OE 
      of miR-181a or KD of TGFbetaR3 by short hairpin RNA enhances anchorage-independent 
      survival. miR-181a OE or TGFbetaR3 KD enhances cellular migration and invasion and 
      upregulation of epithelial‒mesenchymal transition markers. Luciferase reporter 
      assays demonstrate that miR-181a directly targets the 3'-untranslated region of 
      TGFbetaR3. miR-181a upregulates phosphorylated SMAD3 levels after TGFbeta2 
      administration and results in elevated SNAIL and SLUG expression. Finally, we 
      confirm in vivo that miR-181a inhibition compromises tumor growth. Importantly, 
      these phenotypes can be reversed with TGFbetaR3 OE or KD in the context of miR-181a 
      OE or KD, respectively, further highlighting the physiologic relevance of this 
      regulation in cSCC.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Chitsazzadeh, Vida
AU  - Chitsazzadeh V
AD  - Department of Translational Molecular Pathology, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas, USA.
FAU - Nguyen, Tran N
AU  - Nguyen TN
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida, USA.
FAU - de Mingo Pulido, Alvaro
AU  - de Mingo Pulido A
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida, USA.
FAU - Bittencourt, Bruna B
AU  - Bittencourt BB
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida, USA.
FAU - Du, Lili
AU  - Du L
AD  - Department of Translational Molecular Pathology, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas, USA.
FAU - Adelmann, Charles H
AU  - Adelmann CH
AD  - Department of Translational Molecular Pathology, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas, USA.
FAU - Ortiz Rivera, Ivannie
AU  - Ortiz Rivera I
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida, USA.
FAU - Nguyen, Kimberly A
AU  - Nguyen KA
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida, USA.
FAU - Guerra, Leah D
AU  - Guerra LD
AD  - Department of Translational Molecular Pathology, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas, USA.
FAU - Davis, Andrew
AU  - Davis A
AD  - Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida, USA.
FAU - Napoli, Marco
AU  - Napoli M
AD  - Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida, USA.
FAU - Ma, Wencai
AU  - Ma W
AD  - Department of Translational Molecular Pathology, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas, USA; Department of Bioinformatics and 
      Computational Biology, The University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Davis, Richard Eric
AU  - Davis RE
AD  - Department of Translational Molecular Pathology, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas, USA; Department of Lymphoma-Myeloma, The 
      University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
FAU - Rajapakshe, Kimal
AU  - Rajapakshe K
AD  - Department of Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.
FAU - Coarfa, Cristian
AU  - Coarfa C
AD  - Department of Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.
FAU - Flores, Elsa R
AU  - Flores ER
AD  - Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida, USA.
FAU - Tsai, Kenneth Y
AU  - Tsai KY
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida, USA; Department of Pathology, H. Lee Moffitt Cancer Center & 
      Research Institute, Tampa, Florida, USA. Electronic address: 
      Kenneth.Tsai@moffitt.org.
LA  - eng
GR  - P30 CA076292/CA/NCI NIH HHS/United States
GR  - R01 CA194062/CA/NCI NIH HHS/United States
GR  - R01 CA194617/CA/NCI NIH HHS/United States
GR  - R35 CA197452/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20211208
PL  - United States
TA  - J Invest Dermatol
JT  - The Journal of investigative dermatology
JID - 0426720
RN  - 0 (3' Untranslated Regions)
RN  - 0 (MIrn181 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Proteoglycans)
RN  - 0 (Receptors, Transforming Growth Factor beta)
RN  - 145170-29-2 (betaglycan)
SB  - IM
MH  - 3' Untranslated Regions/genetics
MH  - *Carcinoma, Squamous Cell/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/genetics
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - *MicroRNAs/genetics
MH  - *Proteoglycans/genetics
MH  - *Receptors, Transforming Growth Factor beta/genetics
MH  - *Skin Neoplasms/pathology
PMC - PMC9174350
MID - NIHMS1762867
COIS- CONFLICTS OF INTEREST The authors declare no conflict of interest.
EDAT- 2021/12/11 06:00
MHDA- 2022/06/22 06:00
PMCR- 2023/07/01
CRDT- 2021/12/10 20:13
PHST- 2020/08/12 00:00 [received]
PHST- 2021/09/15 00:00 [revised]
PHST- 2021/09/22 00:00 [accepted]
PHST- 2021/12/11 06:00 [pubmed]
PHST- 2022/06/22 06:00 [medline]
PHST- 2021/12/10 20:13 [entrez]
PHST- 2023/07/01 00:00 [pmc-release]
AID - S0022-202X(21)02586-0 [pii]
AID - 10.1016/j.jid.2021.09.040 [doi]
PST - ppublish
SO  - J Invest Dermatol. 2022 Jul;142(7):1956-1965.e2. doi: 10.1016/j.jid.2021.09.040. 
      Epub 2021 Dec 8.