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TR4 nuclear receptor increases prostate cancer invasion via decreasing the miR-373-3p expression to alter TGF?R2/p-Smad3 signals.

ABSTRACT: Testicular nuclear receptor 4 (TR4), a member of the nuclear receptor superfamily, may play important roles to modulate the metabolic diseases and prostate tumorigenesis. Here we found TR4 could increase prostate cancer (PCa) cell invasion. Mechanism dissection revealed that TR4 might increase PCa cell invasion via decreasing the miR-373-3p expression that resulted in the activation of the TGF?R2/p-Smad3 signals. The in vivo mouse model using orthotopically xenografted CWR22Rv1 cell line transfected with luciferase-reporter confirmed in vitro cell line studies showing TR4 increased PCa metastasis via decreasing the miR-373-3p expression. Together, these data suggest that TR4 may increase PCa metastasis via a newly identified signal and targeting these TR4/miR-473-3p/TGF?R2/p-Smad3 signals using TR4 antagonist or TR4-siRNA or miR-373-3p may allow us to develop a new potential therapeutic approach to better suppress PCa metastasis.

SUBMITTER: Qiu X

PROVIDER: S-EPMC4558159 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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TR4 nuclear receptor increases prostate cancer invasion via decreasing the miR-373-3p expression to alter TGFβR2/p-Smad3 signals.

Qiu Xiaofu X Zhu Jin J Sun Yin Y Fan Kun K Yang Dong-Rong DR Li Gonghui G Yang Guosheng G Chang Chawnshang C

Oncotarget 20150601 17

Testicular nuclear receptor 4 (TR4), a member of the nuclear receptor superfamily, may play important roles to modulate the metabolic diseases and prostate tumorigenesis. Here we found TR4 could increase prostate cancer (PCa) cell invasion. Mechanism dissection revealed that TR4 might increase PCa cell invasion via decreasing the miR-373-3p expression that resulted in the activation of the TGFβR2/p-Smad3 signals. The in vivo mouse model using orthotopically xenografted CWR22Rv1 cell line transfe ...[more]

PMID: 25980442

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Project description:BackgroundCircular RNAs (circRNAs) represent a class of non-coding RNAs (ncRNAs) which are widely expressed in mammals and tissue-specific, of which some could act as critical regulators in the atherogenesis of cerebrovascular disease. However, the underlying mechanisms by which circRNA regulates the ectopic phenotype of endothelial cells (ECs) in atherosclerosis remain largely elusive.MethodsCCK-8, transwell, wound healing and Matrigel assays were used to assess cell viability, migration and tube formation. QRT-qPCR and Immunoblotting were used to examine targeted gene expression in different groups. The binding sites of miR-370-3p (miR-370) with TGFβR2 or hsa_circ_0003204 (circ_0003204) were predicted using a series of bioinformatic tools, and validated using dual luciferase assay and RNA immunoprecipitation (RIP) assay. The localization of circ_0003204 and miR-370 in ECs were investigated by fluorescence in situ hybridization (FISH). Gene function and pathways were enriched through Metascape and gene set enrichment analysis (GSEA). The association of circ_0003204 and miR-370 in extracellular vesicles (EVs) with clinical characteristics of patients were investigated using multiple statistical analysis.ResultsCirc_0003204, mainly located in the cytoplasm of human aorta endothelial cells (HAECs), was upregulated in the ox-LDL-induced HAECs. Functionally, the ectopic expression of circ_0003204 inhibited proliferation, migration and tube formation of HAECs exposed to ox-LDL. Mechanically, circ_0003204 could promote protein expression of TGFβR2 and its downstream phosph-SMAD3 through sponging miR-370, and miR-370 targeted the 3' untranslated region (UTR) of TGFβR2. Furthermore, the expression of circ_0003204 in plasma EVs was upregulated in the patients with cerebral atherosclerosis, and represented a potential biomarker for diangnosis and prognosis of cerebrovascular atherogenesis.ConclusionsCirc_0003204 could act as a novel stimulator for ectopic endothelial inactivation in atherosclerosis and a potential biomarker for cerebral atherosclerosis.

Project description:Simple Summary While 90% of cancer patient deaths are caused by cancer dissemination through metastasis, no current therapy selectively targets this process due to the lack of selective inhibitors. Various intratumoral factors are known to promote metastasis, notably low oxygen concentration, called hypoxia, and various growth factors, including transforming growth factor β (TGFβ). Our group previously demonstrated that hypoxia enhances TGFβ-induced cancer cell invasion processes. The present study further characterizes the mechanisms involved in hypoxia-induced cancer cell invasion using in vitro, in vivo and in silico approaches and identifies a HDAC6- SMAD3 pathway that can be pharmacologically targeted to inhibit tumor progression. Abstract Transforming growth factor β (TGFβ) plays a paradoxical role in cancer, first inhibiting then promoting its progression, a duality that poses a real challenge for the development of effective TGFβ-targeted therapies. The major TGFβ downstream effectors, SMAD2 and SMAD3, display both distinct and overlapping functions and accumulating evidence suggests that their activation ratio may contribute to the dual effect of TGFβ. However, the mechanisms responsible for their selective activation remain poorly understood. Here, we provide experimental evidence that hypoxia induces the pro-invasive arm of TGFβ signaling through a selective increase in SMAD3 interaction with SMAD-Anchor for Receptor Activation (SARA). This event relies on HDAC6-dependent SMAD3 bioavailability, as well as increased SARA recruitment to EEA1+ endosomes. A motility gene expression study indicated that SMAD3 selectively increased the expression of ITGB2 and VIM, two genes that were found to be implicated in hypoxia-induced cell invasion and associated with tumor progression and metastasis in cohorts of cancer patients. Furthermore, CAM xenograft assays show the significant benefit of selective inhibition of the SMAD3 signaling pathway as opposed to global TGFβ inhibition in preventing tumor progression. Overall, these results suggest that fine-tuning of the pro-invasive HDAC6-SARA-SMAD3 axis could be a better strategy towards effective cancer treatments.

Dataset Information

TR4 nuclear receptor increases prostate cancer invasion via decreasing the miR-373-3p expression to alter TGF?R2/p-Smad3 signals.

Publications

TR4 nuclear receptor increases prostate cancer invasion via decreasing the miR-373-3p expression to alter TGFβR2/p-Smad3 signals.

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