PMID- 36077039
OWN - NLM
STAT- MEDLINE
DCOM- 20220912
LR  - 20230817
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 17
DP  - 2022 Aug 25
TI  - Downregulation of miR-99b-5p and Upregulation of Nuclear mTOR Cooperatively 
      Promotes the Tumor Aggressiveness and Drug Resistance in African American 
      Prostate Cancer.
LID - 10.3390/ijms23179643 [doi]
LID - 9643
AB  - Mammalian target of rapamycin (mTOR) regulates various fundamental cellular 
      events including cell proliferation, protein synthesis, metabolism, apoptosis, 
      and autophagy. Tumor suppressive miR-99b-5p has been implicated in regulating 
      PI3K/AKT/mTOR signaling in a variety of types of cancer. Our previous study 
      suggested the reciprocal miR-99b-5p/MTOR (downregulated/upregulated) pairing as a 
      key microRNA-mRNA regulatory component involved in the prostate cancer (PCa) 
      disparities. In this study, we further validated the expression profiles of mTOR 
      and miR-99b-5p in the PCa, colon, breast, and lung cancer specimens and cell 
      lines. The immunohistochemistry (IHC), immunofluorescence, Western blot, and 
      RT-qPCR assays have confirmed that mTOR is upregulated while miR-99b-5p is 
      downregulated in different patient cohorts and a panel of cancer cell lines. 
      Intriguingly, elevated nuclear mTOR expression was observed in African American 
      PCa and other advanced cancers. Transfection of the miR-99b-5p mimic resulted in 
      a significant reduction in nuclear mTOR and androgen receptor (AR), while a 
      slight/moderate to no decrease in cytoplasmic mTOR and AR in PCa and other cancer 
      cells, suggesting that miR-99b-5p inhibits mTOR and AR expression and their 
      nuclear translocation. Moreover, overexpression of miR-99b-5p targets/inhibits 
      AR-mTOR axis, subsequently initiating cell apoptosis and sensitizing 
      docetaxel-induced cytotoxicity in various cancers. In conclusion, our data 
      suggest that reciprocal miR-99b-5p/nuclear mTOR pairing may be a more precise 
      diagnostic/prognostic biomarker for aggressive PCa, than miR-99b-5p/MTOR pairing 
      or mTOR alone. Targeting the AR-mTOR axis using miR-99b-5p has also been 
      suggested as a novel therapeutic strategy to induce apoptosis and overcome 
      chemoresistance in aggressive PCa.
FAU - Gujrati, Himali
AU  - Gujrati H
AD  - Department of Pharmaceutical Sciences, University of Maryland Eastern Shore 
      School of Pharmacy, Princess Anne, MD 21853, USA.
FAU - Ha, Siyoung
AU  - Ha S
AD  - Department of Pharmaceutical Sciences, University of Maryland Eastern Shore 
      School of Pharmacy, Princess Anne, MD 21853, USA.
FAU - Waseem, Mohammad
AU  - Waseem M
AUID- ORCID: 0000-0002-1708-0137
AD  - Department of Pharmaceutical Sciences, University of Maryland Eastern Shore 
      School of Pharmacy, Princess Anne, MD 21853, USA.
FAU - Wang, Bi-Dar
AU  - Wang BD
AUID- ORCID: 0000-0002-2530-7020
AD  - Department of Pharmaceutical Sciences, University of Maryland Eastern Shore 
      School of Pharmacy, Princess Anne, MD 21853, USA.
AD  - Hormone Related Cancers Program, University of Maryland Greenebaum Comprehensive 
      Cancer Center, Baltimore, MD 21201, USA.
LA  - eng
GR  - SC1 GM127256/GM/NIGMS NIH HHS/United States
GR  - SC1GM127256/NH/NIH HHS/United States
PT  - Journal Article
DEP - 20220825
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (MIRN99 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Black or African American
MH  - Cell Line, Tumor
MH  - Cell Proliferation/genetics
MH  - Down-Regulation/genetics
MH  - Drug Resistance
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Male
MH  - MicroRNAs/genetics/*metabolism
MH  - Phosphatidylinositol 3-Kinases/genetics/metabolism
MH  - *Prostatic Neoplasms/drug therapy/genetics/metabolism
MH  - Sirolimus
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Up-Regulation/genetics
PMC - PMC9455949
OTO - NOTNLM
OT  - miR-99b-5p
OT  - nuclear pmTOR
OT  - precision prognostic biomarker
OT  - reciprocal miRNA-mRNA pairing
COIS- These authors declare no conflict of interest.
EDAT- 2022/09/10 06:00
MHDA- 2022/09/14 06:00
PMCR- 2022/08/25
CRDT- 2022/09/09 01:06
PHST- 2022/08/07 00:00 [received]
PHST- 2022/08/19 00:00 [revised]
PHST- 2022/08/23 00:00 [accepted]
PHST- 2022/09/09 01:06 [entrez]
PHST- 2022/09/10 06:00 [pubmed]
PHST- 2022/09/14 06:00 [medline]
PHST- 2022/08/25 00:00 [pmc-release]
AID - ijms23179643 [pii]
AID - ijms-23-09643 [pii]
AID - 10.3390/ijms23179643 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Aug 25;23(17):9643. doi: 10.3390/ijms23179643.