miR‐124 exhibits antiproliferative and antiaggressive effects on prostate cancer cells through PACE4 pathway

Kang, Sunhee; Zhao, Yansheng; Hu, Kaimeng; Xu, Chen; Wang, Lei; Liu, Jian; Yao, Anliang; Zhang, Hongmei; Cao, Fenghong

doi:10.1002/pros.22822

Cited by 25 publications

(31 citation statements)

References 52 publications

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“…The overexpression of PACE4 in prostate cancer has been documented; however, no correlations with clinical parameters, such as Gleason grading, have been reported (6,13,14). New molecular markers with relevance to prostate cancer progression should show a positive correlation with the established histologic prognostic indicator, that is, Gleason grading, to be considered of prognostic usefulness.…”

Section: Resultsmentioning

confidence: 99%

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

et al. 2017

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Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and its growth-inhibitory effects are mitigated and uncertain. Here, we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3 0 untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced autoactivating process and a distinct intracellular routing that prevented its extracellular secretion. Together, these events led to a dramatic increase in processing of the progrowth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this proenzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer. Cancer Res; 77(24); 6863-79. Ó2017 AACR.

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Section: Resultsmentioning

confidence: 99%

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

et al. 2017

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“…miR-124 is also reported to participate in regulating angiogenesis, chemosensitivity and proliferation of cancers [14, 36, 37]. Whether miR-124 participates in regulating other hallmarks of CCA by targeting GATA6 needs to be investigated further.…”

Section: Discussionmentioning

confidence: 99%

miR-124 targets GATA6 to suppress cholangiocarcinoma cell invasion and metastasis

et al. 2017

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BackgroundOur previous study showed that GATA6 plays important roles in cholangiocarcinoma (CCA) cell invasion and metastasis. However, the regulation mechanism of GATA6 in CCA is not clear. In this study, we studied the potential function of miR-124 in CCA and the mechanism of GATA6 regulation.MethodsThe expression levels of miR-124 and GATA6 in cancerous tissues from 57 CCA patients was detected by RT-PCR and IHC. The impact of miR-124 on GATA6 expression in CCA cells was evaluated using cell transfection, xenotransplantation into nude mice and a luciferase reporter assay.ResultsmiR-124 was decreased in 57 cancerous tissue samples compared with 38 matched paracancerous samples. The miR-124 level was inversely associated with lymph node involvement and distant metastasis. miR-124 significantly inhibited invasion and migration of CCA cells in vitro. Furthermore, miR-124 inhibited CCA cell metastasis in nude mice. miR-124 inhibited the luciferase activity of reporter genes containing the wild-type GATA6 3′-UTR, which was abrogated by mutation of the binding site. The protein levels of GATA6 were negatively regulated by miR-124. miR-124 expression was inversely associated with GATA6 in 57 cancerous samples. The miR-124-induced suppression of CCA invasion was abrogated by remedial expression of GATA6. GATA6 expression was decreased by miR-124 overexpression in liver masses from nude mice.ConclusionsOur data suggested that miR-124 decreases GATA6 expression by targeting its 3′-UTR, which in turn inhibits CCA invasion and metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3166-z) contains supplementary material, which is available to authorized users.

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“…So far, functions of miRNAs in PCa occurrence and development are innumerably reported, among which miRNAs regulating invasion and chemoresistance still highlights in recent several years, such as miR-21, miR-221, miR-181, miR-34a and miR-124 (20)(21)(22)(23)(24)(25). And miRNAs possessed invasion and chemoresistance functions were thought to be a promising target for PCa management.…”

Section: Discussionmentioning

confidence: 99%

miR-128 modulates chemosensitivity and invasion of prostate cancer cells through targeting ZEB1

Sun

et al. 2015

Japanese Journal of Clinical Oncology

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Objective: Recent reports strongly suggest the profound role of miRNAs in cancer therapeutic response and progression, including invasion and metastasis. The sensitivity to therapy and invasion is the major obstacle for successful treatment in prostate cancer. We aimed to investigate the regulative effect of miR-128/zinc-finger E-box-binding homeobox 1 axis on prostate cancer cell chemosensitivity and invasion. Methods: The miR-128 expression pattern of prostate cancer cell lines and tissues was detected by real-time reverse transcriptase-polymerase chain reaction, while the mRNA and protein expression levels of zinc-finger E-box-binding homeobox 1 were measured by real-time reverse transcriptasepolymerase chain reaction and western blot assay, respectively. Dual-luciferase reporter gene assay was used to find the direct target of miR-128. Furthermore, prostate cancer cells were treated with miR-128 mimic or zinc-finger E-box-binding homeobox 1-siRNA, and then the cells' chemosensitivity and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and transwell assay, respectively. Results: We found miR-128 expression obviously decreased in prostate cancer tissues compared with paired normal tissues. Restored miR-128 expression sensitized prostate cancer cells to cisplatin and inhibited the invasion. Furthermore, there was an inverse expression pattern between miR-128 and zinc-finger E-box-binding homeobox 1 in prostate cancer cells and tissues, and zinc-finger E-boxbinding homeobox 1 was identified as a direct target of miR-128 in prostate cancer. Knockdown of zinc-finger E-box-binding homeobox 1 expression efficiently sensitized prostate cancer cells to cisplatin and inhibited the invasion. However, ectopic zinc-finger E-box-binding homeobox 1 expression impaired the effects of miR-128 on chemosensitivity and invasion in prostate cancer cells. Conclusions: miR-128 functions as a potential cancer suppressor in prostate cancer progression and rational therapeutic strategies for prostate cancer would be developed based on miR-128/zinc-finger E-box-binding homeobox 1 axis.

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miR‐124 exhibits antiproliferative and antiaggressive effects on prostate cancer cells through PACE4 pathway

Abstract: It was clear that PACE4 level was closely associated with malignancy and invasiveness of PCa in vivo or in vitro MiR-124, played a crucial role inhibiting PACE4 transcription thus exhibiting obvious effects of antiproliferation and antiaggression of PCa.

Cited by 25 publications

References 52 publications

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

miR-124 targets GATA6 to suppress cholangiocarcinoma cell invasion and metastasis

miR-128 modulates chemosensitivity and invasion of prostate cancer cells through targeting ZEB1

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