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01.12.2019 | Research | Ausgabe 1/2019 Open Access

Journal of Experimental & Clinical Cancer Research 1/2019

MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway

Zeitschrift:
Journal of Experimental & Clinical Cancer Research > Ausgabe 1/2019
Autoren:
Qing Yang, Chuandong Lang, Zhengquan Wu, Yuhu Dai, Shaofu He, Wei Guo, Shuai Huang, Hong Du, Dong Ren, Xinsheng Peng
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13046-019-1374-x) contains supplementary material, which is available to authorized users.
Qing Yang, Chuandong Lang and Zhengquan Wu contributed equally to this work.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Abstract

Background

Clinically, prostate cancer (PCa) exhibits a high avidity to metastasize to bone. Myc-associated zinc-finger protein (MAZ) is a well-documented oncogene involved in the progression and metastasis of multiple cancer types, even in PCa. However, the clinical significance and biological roles of MAZ in bone metastasis of PCa remain unclear.

Methods

MAZ expression was examined in PCa tissues with bone metastasis, PCa tissues without bone metastasis and metastatic bone tissues by real-time PCR and immunohistochemistry (IHC), respectively. Statistical analysis was performed to evaluate the clinical correlation between MAZ expression and clinicopathological features and bone metastasis-free survival in PCa patients. Biological roles of MAZ in bone metastasis of PCa were investigated both in vitro by transwell assay, and in vivo by a mouse model of left cardiac ventricle inoculation. The bioinformatics analysis, western blot, pull-down assays, chromatin immunoprecipitation (ChIP) and luciferase reporter assays were applied to demonstrate and examine the relationship between MAZ and its potential downstream signalling pathway. TaqMan copy number assay was performed to identify the underlying mechanism responsible for MAZ overexpression in PCa tissues.

Results

MAZ expression is elevated in PCa tissues with bone metastasis compared with that in PCa tissues without bone metastasis, and is further increased in metastatic bone tissues. High expression of MAZ positively correlates with poor overall and bone metastasis-free survival in PCa patients. Upregulating MAZ elevates, while silencing MAZ represses the invasion and migration abilities of PCa cells in vitro and bone metastasis ability in vivo. Our results further reveal that MAZ promotes bone metastasis of PCa dependent on KRas signalling, although MAZ transcriptionally upregulates KRas and HRas expression, where the Ral guanine nucleotide exchange factor (RalGEF) signaling is responsible for the different roles of KRas and HRas in mediating the pro-bone metastasis of MAZ in PCa. Finally, our results indicate that recurrent gains contribute to MAZ overexpression in a small portion of PCa tissues.

Conclusion

These results indicate that the MAZ/Kras/ RalGEF signalling axis plays a crucial role in promoting PCa cell bone metastasis, suggesting a potential therapeutic utility of MAZ in bone metastasis of PCa.
Zusatzmaterial
Additional file 2: Figure S2. Overexpressing enhanced, while silencing MAZ repressed invasion and migration in PCa cells. (A) The real-time PCR analysis of MAZ expression in PC-3 cells transduced with MAZ or sh-MAZ plasmid compared to vector or scramble. (B) The real-time PCR analysis of MAZ expression in VCaP cells transduced with sh-MAZ plasmid compared to vector. Transcript levels were normalized by GAPDH expression. Error bars represent the mean ± s.d. of three independent experiments. *P < 0.05. (C) Western blotting analysis of MAZ expression in MAZ-overexpressing or MAZ-silencing PCa cells. (D, E) Overexpression of MAZ enhanced, while silencing MAZ suppressed invasion and migration abilities in PC-3 cells. Error bars represent the mean ± S.D. of three independent experiments. *P < 0.05. (F, G) Silencing MAZ suppressed invasion and migration abilities in VCaP cells. Error bars represent the mean ± S.D. of three independent experiments. *P < 0.05. (H) Representative BLIs signal of tibia tumor lesion of a mouse from the indicated groups of mice at 12 mins and 6 weeks respectively. (I) Representative radiographic images of bone tumor lesion in the indicated mice (arrows indicate lesions). (J) Representative H&E-stained sections of tibias from the indicated mouse. (K) The sum of bone tumor score for each mouse in tumor-bearing mice inoculated with scramble(n = 10) and sh-MAZ-1# (n = 10) VCaP cells. *P < 0.05 (L) Kaplan-Meyer analysis of mouse bone tumor burden-free survival in the scramble and sh-MAZ-1# groups (Gehan-Breslow-Wilcoxon Test). (TIF 7437 kb)
Literatur
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