MicroRNA-21 Targets the Tumor Suppressor Gene Tropomyosin 1 (TPM1)*

By Shuomin Zhu, M-L Si, Hailong Wu, Yin-yuan Mo. Journal of Biological Chemistry, 2007

1,123 citations recorded by the source corpus.

MicroRNAs are small noncoding RNA molecules that control expression of target genes. Our previous studies show that mir-21 is overexpressed in tumor tissues compared with the matched normal tissues. Moreover, suppression of mir-21 by antisense oligonucleotides inhibits tumor cell growth both in vitro and in vivo. However, it remains largely unclear as to how mir-21 affects tumor growth, because our understanding of mir-21 targets is limited. In this study, we performed two-dimensional differentiation in-gel electrophoresis of tumors treated with anti-mir-21 and identified the tumor suppressor tropomyosin 1 (TPM1) as a potential mir-21 target. In agreement with this, there is a putative mir-21 binding site at the 3′-untranslated region (3′-UTR) of TPM1 variants V1 and V5. Thus, we cloned the 3′-UTR of TPM1 into a luciferase reporter and found that although mir-21 down-regulated the luciferase activity, anti-mir-21 up-regulated it. Moreover, deletion of the mir-21 binding site abolished the effect of mir-21 on the luciferase activity, suggesting that this mir-21 binding site is critical. Western blot with the cloned TPM1-V1 plus the 3′-UTR indicated that TPM1 protein level was also regulated by mir-21, whereas real-time quantitative reverse transcription-PCR revealed no difference at the mRNA level, suggesting translational regulation. Finally, overexpression of TPM1 in breast cancer MCF-7 cells suppressed anchorage-independent growth. Thus, down-regulation of TPM1 by mir-21 may explain, at least in part, why suppression of mir-21 can inhibit tumor growth, further supporting the notion that mir-21 functions as an oncogene.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/53699f1ed244de07a43e794699d7a09b11b210e5

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Citations in the corpus

MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. (2008, background): “Studies in human cell lines have shown miR-21 can also target the tumor suppressor genes, phosphatase and tensin homolog (PTEN)(39) and tropomyosin 1 (TPM1).(40) These data, taken together, support a causal role for altered microRNA expression during tumorigenesis.”
MicroRNAs in development and disease. (2011, background): “Consistent with a tumor-promoting function, miR-21 was found to target and inhibit TPM1 (716), PDCD4 (184, 391), and maspin (717).”
MicroRNA function in cancer: oncogene or a tumor suppressor? (2009, background): “A binding site for miR-21 was identified in the 3’ UTR of the TPM1 transcript [65].”
OncomiRs: the discovery and progress of microRNAs in cancers (2007, background): “Downregulation of tropomyosin 1 in breast cancer by miR-21 might explain why suppression of miR-21 could inhibit tumor growth, further supporting the notion that miR-21 functions as an oncogene [20].”
MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene (2008, background): “, 2006); and the TCGAATG sequence, which is proposed to be crucial to the miR-21/TPM1 (human) interaction (Zhu et al., 2007), is not present in the mouse TPM1 30-UTR.”
MicroRNA: Biogenesis, Function and Role in Cancer (2010, background): “It is hypothesized that miR-21 repression of TMP1 leads to cytoskeleton changes that promote neoplastic transformation, cell invasion and metastasis [282].”
MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. (2008, background): “It is noteworthy that TPM1 has recently been shown to be a target of miR- 21 ( Zhu et al. 2007 ), which is not shown in any of the four target predictors.”
MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death (2008, background): “Further work identified PTEN and tropomyosin 1 as direct targets of miR-21 in cancer cell lines (Zhu et al., 2007; Meng et al., 2007a).”