The tumor suppressor microRNA let-7 represses the HMGA2 oncogene.

By Yong Sun Lee, Anindya Dutta. Genes & Development, 2007

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HMGA2, a high-mobility group protein, is oncogenic in a variety of tumors, including benign mesenchymal tumors and lung cancers. Knockdown of Dicer in HeLa cells revealed that the HMGA2 gene is transcriptionally active, but its mRNA is destabilized in the cytoplasm through the microRNA (miRNA) pathway. HMGA2 was derepressed upon inhibition of let-7 in cells with high levels of the miRNA. Ectopic expression of let-7 reduced HMGA2 and cell proliferation in a lung cancer cell. The effect of let-7 on HMGA2 was dependent on multiple target sites in the 3' untranslated region (UTR), and the growth-suppressive effect of let-7 on lung cancer cells was rescued by overexpression of the HMGA2 ORF without a 3'UTR. Our results provide a novel example of suppression of an oncogene by a tumor-suppressive miRNA and suggest that some tumors activate the oncogene through chromosomal translocations that eliminate the oncogene's 3'UTR with the let-7 target sites.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/06ce2c2512e70122743d7f400a95ee3d01dc7c43

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Citations in the corpus

MicroRNAs and cancer: short RNAs go a long way. (2009, background): “Functionally, let-7 represses members of the Ras family of oncogenes (Johnson et al., 2005) as well as the oncogene HMGA2 (Lee and Dutta, 2007; Mayr et al., 2007) and even c-Myc itself (Sampson et al., 2007).”
The Imprinted H19 LncRNA Antagonizes Let-7 MicroRNAs (2013, background): “We find that both Hmga2 and Dicer mRNA levels decrease in C2C12 myoblasts transfected with simH19 or let-7 (Figure 6B , 2 nd and 3 rd columns from left, compare green and purple bars with blue bars), consistent with Hmga2 and Dicer being additional downstream effectors of H19/let-7-mediated regulati”
A novel class of small RNAs: tRNA-derived RNA fragments (tRFs). (2009, methodology): “Isolation of RNA, 454 deep sequencing, and measurement of tRFs Isolation of total, nuclear, and cytoplasmic RNA from cell lines was performed as described in Lee and Dutta (2007).”
MicroRNA: Biogenesis, Function and Role in Cancer (2010, background): “This regulation can explain the HMG2A expression pattern as let-7 exhibits a reciprocal expression pattern compared to HMG2A in embryonic and mature tissue [22].”
let-7 regulates self renewal and tumorigenicity of breast cancer cells. (2007, background): “Therefore, let-7 silences RAS and HMGA2 expression by inhibiting translation as previously reported (Johnson et al., 2005; Mayr et al., 2007), rather than by cleaving mRNA (Lee and Dutta, 2007).”
Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. (2008, background): “Let-7 itself has been shown to target the oncogenes Ras, Myc, and HMGA2, and expression of this miRNA inversely correlates with disease severity (Esquela-Kerscher and Slack 2006; Lee and Dutta 2007; Mayr et al. 2007).”
TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation. (2009, background): “By targeting multiple oncogenes such as RAS, HMGA2, and c-MYC, let-7 also functions as a tumor suppressor, most prominently in lung cancer (Johnson et al., 2005; Lee and Dutta, 2007; Mayr et al., 2007; Sampson et al., 2007).”
Hmga2 promotes neural stem cell self-renewal in young, but not old, mice by reducing p16Ink4a and p19Arf expression (2008, background): “Recent studies have demonstrated that let-7 family microRNAs are important negative regulators of Hmga2 expression: loss of the let-7 binding sites in Hmga2 increases Hmga2 expression and promotes tumorigenesis (Lee and Dutta, 2007; Mayr et al., 2007; Yu et al., 2007).”
Suppression of non-small cell lung tumor development by the let-7 microRNA family (2008, background): “Studies of the effect of let-7 on cellular proliferation have used cells containing activating mutations in K-Ras (A549) and N-Ras (H1299 and HepG2) (20, 21).”
The Lin28/let-7 axis regulates glucose metabolism (2011, background): “The let-7 miRNA family members act as tumor suppressors by negatively regulating the translation of oncogenes and cell cycle regulators (Johnson et al., 2005; Lee and Dutta, 2007;Mayr et al., 2007; Kumar et al., 2008).”
MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype (2007, background): “For example, deregulation of the oncogene RAS and HMGA2 by loss of regulation through the let-7 family of miRNAs might contribute to human cancer [59-61].”
MicroRNA signature predicts survival and relapse in lung cancer. (2008, background): “Expression of MicroRNAs Alters Invasiveness of Lung Cancer Cells Two components of this five-microRNA signature, hsa-let-7a and hsa-miR-372, can play opposite roles in tumorigenesis through regulation of cell proliferation (Johnson et al., 2005; Lee and Dutta, 2007; Mayr et al., 2007; Takamizawa et ”