MicroRNA-194 Promotes Prostate Cancer Metastasis by Inhibiting SOCS2

Das, Rajdeep; Gregory, Philip A.; Fernandes, Rayzel C.; Denis, Iza; Wang, Qingqing; Townley, Scott L.; Zhao, Shuang G.; Hanson, Adrienne R.; Pickering, Marie A.; Armstrong, Heather; Lokman, Noor A.; Ebrahimie, Esmaeil; Davicioni, Elai; Jenkins, Robert B.; Karnes, R. Jeffrey; Ross, Ashley E.; Den, Robert B.; Klein, Eric A.; N., Kim; Ramshaw, Hayley S.; Williams, Elizabeth D.; Zoubeidi, Amina; Goodall, Gregory J.; Feng, Felix Y.; Butler, Lisa M.; Tilley, Wayne D.; Selth, Luke A.

doi:10.1158/0008-5472.can-16-2529

Cited by 100 publications

(90 citation statements)

References 59 publications

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“…Whilst this manuscript was in revision, Das and colleagues reported the selective advantage in promoting PCa metastasis upon inhibition of SOCS2 (Das et al, 2017), which is one of the genes we found to be attenuated by MYC overexpression. Furthermore, a re-analysis of a comprehensive study by Taylor and colleagues (Taylor et al, 2010) profiling transcriptomics of PCa showed that the expression of SOCS2 is lowest in metastases found in patients treated with castration (Fig.…”

Section: Discussionmentioning

confidence: 82%

c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks

et al. 2017

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Prostate cancer (PCa) is the most common non-cutaneous cancer in men. The androgen receptor (AR), a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signaling networks have been shown to be altered in patients and to influence AR activity. Amongst these, the oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies and elevated protein levels of c-Myc are commonly observed in PCa. Its impact on AR activity, however, remains elusive. In this study, we assessed the impact of c-Myc overexpression on AR activity and transcriptional output in a PCa cell line model and validated the antagonistic effect of c-MYC on AR-targets in patient samples. We found that c-Myc overexpression partially reprogrammed AR chromatin occupancy and was associated with altered histone marks distribution, most notably H3K4me1 and H3K27me3. We found c-Myc and the AR co-occupy a substantial number of binding sites and these exhibited enhancer-like characteristics. Interestingly, c-Myc overexpression antagonised clinically relevant AR target genes. Therefore, as an example, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 (alias PSA, prostate specific antigen), and Glycine N-Methyltransferase (GNMT), in patient samples. Our findings provide unbiased evidence that MYC overexpression deregulates the AR transcriptional program, which is thought to be a driving force in PCa.

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Section: Discussionmentioning

confidence: 82%

c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks

et al. 2017

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“…Several studies have indicated that the expression of MMP-2 and MMP-9 is associated with EMT, and vimentin is often used as a marker of mesenchymally derived cells or cells undergoing EMT during both normal development and metastatic progression [51,52]. However, the STAT3 signaling pathway has been shown to be involved in tumor EMT [53]. Our results showed that allicin significantly inhibits the migration and invasion capacity of CCA cells and reduces the expression of MMP-2/9 and vimentin, but increases E-cadherin protein levels in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Allicin Inhibits Proliferation and Invasion in Vitro and in Vivo via SHP-1-Mediated STAT3 Signaling in Cholangiocarcinoma

Chen

Zhu

Zhao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cholangiocarcinoma (CCA) is a malignant tumor that is resistant to chemotherapy, so new therapeutic agents are needed. Allicin which is rapidly converted from allin by allinase, is one of the most biologically active compounds in freshly crushed garlic and has been shown to have strong anti-tumor effects. Our aim was to explore the molecular mechanism by which allicin affects the cell proliferation and invasion of CCA. Methods: Cell viability and apoptosis were measured using the CCK-8 assay, colony formation assay, and flow cytometry. Cell migration and invasion were evaluated by wound healing and Transwell assays, respectively. The expression of several proteins involved in cell apoptosis and invasion were assessed by Western blot. The activation of STAT3 signaling was detected by Western blot and immunofluorescence staining. The involvement of SHP-1 was determined using small interfering RNA (siRNA). Moreover, a nude mouse model of human CCA was established to assess the anti-tumor effects of allicin in vivo. Results: Allicin significantly suppressed CCA cell proliferation by activating the caspase cascade, inducing apoptosis, and reducing the expression of proteins downstream of STAT3, such as B-cell lymphoma 2 (Bcl-2), while upregulating Bcl-2-associated X (Bax) protein. In addition, allicin inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of CCA cells. Moreover, the protein expression of MMP-2 and MMP-9 was significantly downregulated in CCA cells treated with allicin compared with CCA cells treated with control. Mechanistic investigations indicated that allicin upregulated SHP-1 expression in CCA, and pervanadate treatment reversed the allicin-induced downregulation of STAT3. Moreover, suppression of SHP-1 by siRNA overturned the effect of allicin on the induction of SHP-1 and inhibition of STAT3 activation. Additionally, treatment with allicin attenuated tumor growth in the nude mouse model of CCA. Conclusions: Our findings suggest that allicin suppresses cell proliferation and invasion via STAT3 signaling and may be a potential therapeutic agent for CCA.

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“…Stable LNCaP-shGRHL2 cell lines were generated using GRHL2-specific shRNA plasmids (TRCN0000015808 and TRCN0000015810) and an shRNA control plasmid (Shc002) from Sigma as described previously (7). …”

Section: Methodsmentioning

confidence: 99%

“…CAM assays were approved by the University of Adelaide Animal Ethics Committee (approval number M-2014_079) and done using the in ovo method as described previously (7). …”

Section: Methodsmentioning

confidence: 99%

Novel Androgen Receptor Coregulator GRHL2 Exerts Both Oncogenic and Antimetastatic Functions in Prostate Cancer

et al. 2017

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Alterations to the expression and activity of androgen receptor (AR) co-regulators in prostate cancer is an important mechanism driving disease progression and therapy resistance. Using a novel proteomic technique, we identified a new AR co-regulator, the transcription factor Grainyhead-like 2 (GRHL2), and demonstrated its essential role in the oncogenic AR signaling axis. GRHL2 colocalized with AR in prostate tumors and was frequently amplified and upregulated in prostate cancer. Importantly, GRHL2 maintained AR expression in multiple prostate cancer model systems, was required for cell proliferation, enhanced AR's transcriptional activity, and co-located with AR at specific sites on chromatin to regulate genes relevant to disease progression. GRHL2 is itself an AR-regulated gene, creating a positive feedback loop between the two factors. The link between GRHL2 and AR also applied to constitutively active truncated AR variants (ARVs), as GRHL2 interacted with and regulated ARVs and vice versa. These oncogenic functions of GRHL2 were counterbalanced by its ability to suppress epithelial-mesenchymal transition and cell invasion. Mechanistic evidence suggested that AR assisted GRHL2 in maintaining the epithelial phenotype. In summary, this study has identified a new AR co-regulator with a multifaceted role in prostate cancer, functioning as an enhancer of the oncogenic AR signaling pathway but also a suppressor of metastasis-related phenotypes.

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MicroRNA-194 Promotes Prostate Cancer Metastasis by Inhibiting SOCS2

Cited by 100 publications

References 59 publications

c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks

c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks

Allicin Inhibits Proliferation and Invasion in Vitro and in Vivo via SHP-1-Mediated STAT3 Signaling in Cholangiocarcinoma

Novel Androgen Receptor Coregulator GRHL2 Exerts Both Oncogenic and Antimetastatic Functions in Prostate Cancer

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