Abstract
The reduction of oxygen partial pressure in growing tumors triggers numerous survival strategies driven by the transcription factor complex HIF1 (Hypoxia Inducible Factor-1). Recent evidence revealed that HIF1 promotes rapid and effective phenotypic changes through the induction of non-coding RNAs, whose contribution has not yet been fully described. Here we investigated the role of the hypoxia-induced, long non-coding RNA H19 (lncH19) and its intragenic miRNA (miR-675-5p) into HIF1-Wnt crosstalk. During hypoxic stimulation, colorectal cancer cell lines up-regulated the levels of both the lncH19 and its intragenic miR-675-5p. Loss of expression experiments revealed that miR-675-5p inhibition, in hypoxic cells, hampered β-catenin nuclear localization and its transcriptional activity, while lncH19 silencing did not induce the same effects. Interestingly, our data revealed that miRNA inhibition in hypoxic cells restored the activity of Glycogen Synthase Kinase 3β (GSK-3β) reducing the amount of P-Ser9 kinase, thus unveiling a role of the miR-675-5p in controlling GSK-3β activity. Bioinformatics analyses highlighted the serine/threonine-protein phosphatases PPP2CA, responsible for GSK-3β activation, among the miR-675-5p targets, thus indicating the molecular mediator through which miR-675-5p may control β-catenin nuclear localization. In conclusion, here we demonstrated that the inhibition of the hypoxia-induced non-coding RNA miR-675-5p hampered the nuclear localization of β-catenin by regulating GSK-3β activity, thus proposing the miR-675-5p as a new therapeutic target for the treatment of colorectal cancer.
Highlights
Colorectal cancer (CRC) is a heterogeneous disease with an environmental, genetic and biochemical background
With the aim to identify molecular mechanisms through which the two pathways could reinforce each other, in this study, we investigated the role of hypoxia-induced non-coding RNAs on two different CRC cell lines: the SW620 and the HCT116, that display, respectively, mutation in Adenomatous Polyposis Coli (APC) and β-catenin [5,23,24]
J. pMaotlh. wScai.y20[2301,]21w, 3h8i3le2 not much is known about the role of hypoxia-induced miR-675-5p in colon3 of 17 cancer
Summary
Colorectal cancer (CRC) is a heterogeneous disease with an environmental, genetic and biochemical background. It is the third most commonly diagnosed cancer and the fourth in terms of cancer-related deaths, and it is expected to increase worldwide by 60% with more than 2.2 million new cases and 1.1 million cancer deaths by 2030 [1]. APC constitutes, together with Axin, Glycogen synthase kinase 3β (GSK-3β), and Casein kinase 1 (CK1), the “degradation complex”, a multiprotein complex responsible for β-catenin phosphorylation, poly-ubiquitination and subsequent degradation through proteasome [2]. The binding of canonical Wnt ligand to its receptors inactivates the degradation complex, allowing for β-catenin nuclear translocation and the induction of its targets in cooperation with the TCF/LEF transcription factors. In CRC, Wnt signaling dysregulation is associated with proliferation, invasion, differentiation, and cell resistance both in early stages as well as during cancer progression [3]
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