Life science
Molecular-targeted drugs

Development of molecular-targeted therapeutic drugs forcancer
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences
SA Associate Professor Kentaro Jingushi

Researchmap https://researchmap.jp/_kj

Professor Kazutake Tsujikawa

Researchmap https://researchmap.jp/read0014359

Life science

Abstract
Bladder cancer causes an estimated 150,000 deaths per year
worldwide. Although 15% of the recurrent bladder cancer becomesan invasive type, currently used targeted therapy for malignant
bladder cancer is still not efficient. We focused on the miR-130
family (miR-130b, miR-301a, and miR-301b) that was significantly
upregulated in bladder cancer specimens than that of the normal
urothelial specimens. We found that miR-130 family has a crucialrole in malignant progression of bladder cancer, and miR-130 family-targeted LNA oligonucleotides were found to suppress tumor
growth in an in vivo xenograft model. We also found that miR-130
family was also highly expressed in non-small cell lung cancer (NSCLC) and act as an oncomiR, promoting metastasis and invasion
activities in NSCLC cells.

▍ Background & Results
MicroRNAs (miRNAs) are small noncoding RNA molecules
20–25 nucleotides in length. These molecules regulate gene expression through translational repression or degradation of mRNAby binding to the 3′-untranslated region (3′-UTR) of target
mRNAs. Each miRNA typically targets approximately 200 genes.
Because 30–60% of human genes can be regulated by miRNAs,
these molecules have the potential to modulate various cellular
processes, such as cell growth, migration, invasion, apoptosis,and angiogenesis. Our study showed that the miR-130 family, including miR-130b, miR-301a, and miR-301b, is highly expressed inbladder cancer specimens and functions as an oncogenic miRNA(oncomiR) family by promoting the migration and invasion of bladder cancer cells. Moreover, miR-130 family-targeted LNA oligonucleotides were found to suppress tumor growth in an in vivo xenograft model. Furthermore, miR-130 family was found to act as an
oncomiR, promoting metastasis and invasion activities in NSCLCcells.

▍ Significance of the research and Future perspective
Our findings indicated that miR-130 family functioned as an oncogenic miRNA in NSCLC and bladder cancer and could therefore
facilitate the development of molecular-targeted therapeutic drugs
for these cancers.

P a t e n t Japanese Patent Application No. 2013-165600 PCT/JP2014/070811
Monoe, Y; Jingushi, K; Kawase, A et al. Pharmacological inhibition of miR-130 family suppresses bladder tumor growth by targeting various oncogenic pathways via PTPN1. Int J Mol Sci.
2021; 9: 4751. doi: 10.3390/ijms22094751.
Hirono, T; Jingushi, K; Nagata, T et al. MicroRNA-130b functions as an oncomiRNA in non-small cell lung cancer by targeting tissue inhibitor of metalloproteinase-2. Sci Rep. 2019; 1: 6956.
T r e a t i s e doi: 10.1038/s41598-019-43355-8.
Egawa, H; Jingushi, K; Hirono, T et al. The miR-130 family promotes cell migration and invasion in bladder cancer through FAK and Akt phosphorylation by regulating PTEN. Sci Rep. 2016; 6:20574. doi: 10.1038/srep20574.
Egawa, H; Jingushi, K; Hirono, T et al. Pharmacological regulation of bladder cancer by miR-130 family seed-targeting LNA. Integr Mol Med, 2015; 1: 457-463. doi: 10.15761/IMM.1000187.
URLK e y w o r d locked nucleic acid (LNA), miRNA, bladder cancer, non-small cell lung cancer