Hypoxia and RAS-signaling pathways converge on, and cooperatively downregulate, the RECK tumor-suppressor protein through microRNAs

Abstract

Cancer cells show characteristic gene expression profiles. Recent studies support the potential importance of micro-RNA (miRNA) expression signatures as biomarkers and therapeutic targets. The membrane-anchored protease regulator RECK is downregulated in many cancers, and forced expression of RECK in tumor cells results in decreased malignancy in animal models. RECK is also essential for mammalian development. In this study, we found that RECK is a target of at least three groups of miRNAs (miR-15b/16, miR-21 and miR-372/373); that RECK mutants lacking the target sites for these miRNA show augmented tumor/metastasis-suppressor activities; and that miR-372/373 are upregulated in response to hypoxia through HIF1a and TWIST1, whereas miR-21 is upregulated by RAS/ERK signaling. These data indicate that the hypoxia-and RAS-signaling pathways converge on RECK through miRNAs, cooperatively downregulating this tumor suppressor and thereby promoting malignant cell behavior.

Up-regulation of miR-21 Mediates Resistance to Trastuzumab Therapy for Breast Cancer

“…Because the miR-21 promoter contains highly conserved regions with consensus binding sites for several transcription factors, including STAT3 (38, 39), AP-1 (40), and factors of the forkhead family (FOXO), such as FOXO3a (41), transcription of primary miR-21 (pri-miR-21) can be regulated via various pathways. Among them, activation of the RAS/ MEK/MAPK pathway due to increased homodimerization of EGFR or heterodimerization of EGFR/HER3 potentially may lead to enhanced transcription of pri-miR-21 via AP-1 (42,43). Additionally, phosphorylated activation of AKT may also upregulate miR-21 expression by relieving the repression of FOXO transcription factors on its promoter activity (41).…”

MicroRNA-21: A novel therapeutic target in human cancer

“…Of these, various components of the p53 network, 61 the PTEN/AKT signaling pathway, [33][34][35] antagonists of the RAS pathway (i.e., PDCD4, 41,62-66 BTG2, 67 and SPRY2 56,68 ), FasL, 44 Cdc25A, 69 NFIB, 48 TPM1, maspin 64 and regulators of matrix metalloproteinase (i.e., TIMP3, 11,70 and RECK 11,37,56,71 ) are all involved in tumorigenesis, cell cycle control, apoptosis and metastasis. In addition, indirect regulation of Bcl-2 by miR-21 has also been shown in breast cancer.…”

Reversion-inducing cysteine-rich protein with Kazal motifs interferes with epidermal growth factor receptor signaling

“…In this study, mutual suppression between RECK and RAS signaling was demonstrated (Supplementary Figure S6b). In addition, many of retroviral oncogenes , oncogenic DNA virus products (Liu et al, 2003) and the so-called 'oncomir' (oncogenic microRNA) miR-21 (Gabriely et al, 2008;Hu et al, 2008;Zhang et al, 2008;reviewed in Nicoloso et al, 2009;Loayza-Puch et al, 2010) were demonstrated to negatively regulate RECK transcription. These findings indicate that these oncogenic signals may commonly impact on RAS signaling from the extracellular space through transcriptional regulation of RECK.…”

“…The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene is a negative transcriptional target of various viral oncogenes including activated K-RAS Sasahara et al, 1999;Liu et al, 2003;Hsu et al, 2006), and a negative post-transcriptional target of oncogenic microRNAs including miR-21 (Hu et al, 2008;Gabriely et al, 2008;Zhang et al, 2008;reviewed in Nicoloso et al, 2009;Loayza-Puch et al, 2010). Furthermore, histone modification and DNA methylation have also been reported to be involved in the transcriptional regulation of RECK (Chang et al, 2004(Chang et al, , 2007.…”