Title: MicroRNA21 targets tumor suppressor genes in invasion
1MicroRNA-21 targets tumor suppressor genes in
invasion and metastasis Shuomin Zhu1, Hailong
Wu1, Fangting Wu1, Daotai Nie1, Shijie Sheng2,
Yin-Yuan Mo1 1Department of Medical Microbiology,
Immunology and Cell Biology, Southern Illinois
University School of Medicine, 825 N.
Rutledge, PO Box 19626, Springfield, IL 62794,
USA 2Department of Pathology, The Proteases and
Cancer Program, Karmanos Cancer Institute, Wayne
State University School of Medicine, Detroit, MI
48202, USA
Cell Research (2008) 18350-359.
2MicroRNA
- Small non-coding RNA
- Approximately 22 nucleotides
- Repress translation or cause mRNA degradation
- Target a cluster of genes (1 miRNA may target
more than 100 genes)
3MicroRNA processing pathway
http//www.ambion.com/figs/f01266.gif
MicroRNAs can function as tumor suppressors or
oncogenes, depending on whether they target
oncogenes or tumor suppressor genes. Tumor
suppressor microRNA is usually downregulated in
human tumors, whereas oncogenic microRNA are
overexpressed.
4Searchable databases available to search for
microRNA targets
- MirBase- microrna.sanger.ac.uk
- Miranda- microrna.org
- TargetScan- targetscan.org
- PicTar- pictar.bio.nyu.edu
5microrna.sanger.ac.uk
6Experimental Goals
- Analyze the post-transcriptional miRNA regulation
of tumor suppressor genes TPM1,PDCD4, and maspin
and the effect on invasion and metastasis in
MDA-MB-231 breast cancer cell line.
7MDA-MB-231 cells express a high level of mature
mir-21, which can be suppressed by anti-mir-21
8Effect of anti-mir-21 on MDA-MB-231 cell growth
in vitro and in vivo
MTT
9In vitro cell invasion is suppressed by
anti-mir-21
10Anti-mir-21 suppresses tumor metastasis in vivo
- These data suggest that mir-21 plays an important
role in cell metastasis. - A genetic screening identified TPM1, PDCD4, and
maspin as candidate targets for mir-21
11Mir-21 targets
- Tropomyosin1 (TPM1) is an actin-binding protein
and functions to stabilize microfilaments. TPM1
overexpression suppresses cell invasion. - Programmed cell death 4 (PDCD4) is a tumor
suppressor protein which interacts with EIF4A and
inhibits protein synthesis. - Maspin is a member of the serpin family of
proteases and has tumor-suppressive activity.
Maspin is downregulated in mammary carcinoma.
12Exogenous overexpression of TPM1, PDCD4 or Maspin
suppresses cell invasion
- These results suggest that mir-21 affects cell
invasion and metastasis by regulating multiple
target genes.
13PDCD4 and maspin are direct mir-21 targets
14Breast tumors have lower levels of PDCD4 and
Maspin than normal breast tissue
- There is an inverse correlation between PDCD4
protein and mir-21 in breast tumors.
15Conclusions
- Mir-21 directly interacts with and
post-transcriptionally regulates PDCD4, and
maspin. - Inhibition of mir-21 suppresses invasion and
metastasis in MDA-MB-231 cells. - There is an inverse correlation between the
expression of PDCD4 and mir-21 in breast tumor
samples. - Mir-21 may promote tumor invasion and metastasis
by simultaneously downregulating multiple
metastasis-related tumor suppressor genes.