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Infiltrated pre-adipocytes increase prostate cancer metastasis via modulation of the miR-301a/androgen receptor (AR)/TGF-β1/Smad/MMP9 signals.

Xie H, Li L, Zhu G, Dang Q, Ma Z, He D, Chang L, Song W, Chang HC, Krolewski JJ, Nastiuk KL, Yeh S, Chang C - Oncotarget (2015)

Bottom Line: Mechanism dissection revealed infiltrating pre-adipocytes might function through down-regulation of the androgen receptor (AR) via modulation of miR-301a, and then increase PCa cell invasion via induction of TGF-β1/Smad/MMP9 signals.The mouse model with orthotopically xenografted PCa CWR22Rv1 cells with pre-adipocytes also confirmed that infiltrating pre-adipocytes could increase PCa cell invasion via suppressing AR signaling.Targeting this newly identified signaling may help us to better inhibit PCa metastasis.

View Article: PubMed Central - PubMed

Affiliation: Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.

ABSTRACT
High fat dietary intake may increase the risk of prostate cancer (PCa). Pre-adipocytes, one of the basic components in the tumor microenvironment (TME), are capable of differentiating into adipose tissues and play key roles to affect PCa progression. Here we found the pre-adipocytes could be recruited more easily to PCa than its surrounding normal prostate tissue. In vitro co-culture system also confirmed PCa has a better capacity than normal prostate to recruit pre-adipocytes. The consequences of recruiting more pre-adipocytes may then increase PCa cell invasion. Mechanism dissection revealed infiltrating pre-adipocytes might function through down-regulation of the androgen receptor (AR) via modulation of miR-301a, and then increase PCa cell invasion via induction of TGF-β1/Smad/MMP9 signals. The mouse model with orthotopically xenografted PCa CWR22Rv1 cells with pre-adipocytes also confirmed that infiltrating pre-adipocytes could increase PCa cell invasion via suppressing AR signaling. Together, our results reveal a new mechanism showing pre-adipocytes in the prostate TME can be recruited to PCa to increase PCa metastasis via modulation of the miR-301a/AR/TGF-β1/Smad/MMP9 signals. Targeting this newly identified signaling may help us to better inhibit PCa metastasis.

No MeSH data available.


Related in: MedlinePlus

Recruited pre-adipocytes enhanced PCa cell invasion via alteration of AR/TGF-β1/Smad/MMP9 signalingA. mRNA level shows AR is down-regulated, TGF-β1 and MMP-9 are up-regulated after co-culture with pre-adipocytes (pre-adi). B. AR protein level is down-regulated, TGF-β1, p-Smad3 and MMP-9 protein levels are up-regulated in PCa cells after co-culture with pre-adipocytes (pre-adi). The right panels are the quantitative data for western-blot. ***p < 0.005, ns, no statistical differences. C. The representative and quantitative invasion abilites of PCa cells after co-culture with pre-adipocytes following knocking-down PCa cells AR. ***p < 0.005, ns, no statistical differences. D. Knocking down AR in PCa cells can decrease AR protein levels, and increase TGF-β1, p-Smad3 and MMP-9 protein levels. The right panels are the quantitative data for western-blot. ***p < 0.005, ns, no statistical differences. E. TGF-β1 type I receptor inhibitor, SB-431542 interrupts pre-adipocyte mediated PCa invasion. F. Targeting MMP9 by specific inhibitor interrupts pre-adipocyte mediated PCa invasion. G. The recruitment effect for pre-adipocytes by knocking down AR or adding anti-androgen enzalutamide in C4-2 and CWR22Rv1 (22Rv1) cells.
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Figure 3: Recruited pre-adipocytes enhanced PCa cell invasion via alteration of AR/TGF-β1/Smad/MMP9 signalingA. mRNA level shows AR is down-regulated, TGF-β1 and MMP-9 are up-regulated after co-culture with pre-adipocytes (pre-adi). B. AR protein level is down-regulated, TGF-β1, p-Smad3 and MMP-9 protein levels are up-regulated in PCa cells after co-culture with pre-adipocytes (pre-adi). The right panels are the quantitative data for western-blot. ***p < 0.005, ns, no statistical differences. C. The representative and quantitative invasion abilites of PCa cells after co-culture with pre-adipocytes following knocking-down PCa cells AR. ***p < 0.005, ns, no statistical differences. D. Knocking down AR in PCa cells can decrease AR protein levels, and increase TGF-β1, p-Smad3 and MMP-9 protein levels. The right panels are the quantitative data for western-blot. ***p < 0.005, ns, no statistical differences. E. TGF-β1 type I receptor inhibitor, SB-431542 interrupts pre-adipocyte mediated PCa invasion. F. Targeting MMP9 by specific inhibitor interrupts pre-adipocyte mediated PCa invasion. G. The recruitment effect for pre-adipocytes by knocking down AR or adding anti-androgen enzalutamide in C4-2 and CWR22Rv1 (22Rv1) cells.

Mentions: To dissect the molecular mechanisms why increased infiltrating pre-adipocytes could enhance PCa cells invasion, we focused on the influence of the AR, the key player controlling PCa cells invasion [2, 3, 5, 7]. As shown in Fig. 3A-B, the recruitment of pre-adipocytes to PCa cells decreased AR expression at both mRNA (Fig. 3A) and protein (Fig. 3B) levels.


Infiltrated pre-adipocytes increase prostate cancer metastasis via modulation of the miR-301a/androgen receptor (AR)/TGF-β1/Smad/MMP9 signals.

Xie H, Li L, Zhu G, Dang Q, Ma Z, He D, Chang L, Song W, Chang HC, Krolewski JJ, Nastiuk KL, Yeh S, Chang C - Oncotarget (2015)

Recruited pre-adipocytes enhanced PCa cell invasion via alteration of AR/TGF-β1/Smad/MMP9 signalingA. mRNA level shows AR is down-regulated, TGF-β1 and MMP-9 are up-regulated after co-culture with pre-adipocytes (pre-adi). B. AR protein level is down-regulated, TGF-β1, p-Smad3 and MMP-9 protein levels are up-regulated in PCa cells after co-culture with pre-adipocytes (pre-adi). The right panels are the quantitative data for western-blot. ***p < 0.005, ns, no statistical differences. C. The representative and quantitative invasion abilites of PCa cells after co-culture with pre-adipocytes following knocking-down PCa cells AR. ***p < 0.005, ns, no statistical differences. D. Knocking down AR in PCa cells can decrease AR protein levels, and increase TGF-β1, p-Smad3 and MMP-9 protein levels. The right panels are the quantitative data for western-blot. ***p < 0.005, ns, no statistical differences. E. TGF-β1 type I receptor inhibitor, SB-431542 interrupts pre-adipocyte mediated PCa invasion. F. Targeting MMP9 by specific inhibitor interrupts pre-adipocyte mediated PCa invasion. G. The recruitment effect for pre-adipocytes by knocking down AR or adding anti-androgen enzalutamide in C4-2 and CWR22Rv1 (22Rv1) cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Recruited pre-adipocytes enhanced PCa cell invasion via alteration of AR/TGF-β1/Smad/MMP9 signalingA. mRNA level shows AR is down-regulated, TGF-β1 and MMP-9 are up-regulated after co-culture with pre-adipocytes (pre-adi). B. AR protein level is down-regulated, TGF-β1, p-Smad3 and MMP-9 protein levels are up-regulated in PCa cells after co-culture with pre-adipocytes (pre-adi). The right panels are the quantitative data for western-blot. ***p < 0.005, ns, no statistical differences. C. The representative and quantitative invasion abilites of PCa cells after co-culture with pre-adipocytes following knocking-down PCa cells AR. ***p < 0.005, ns, no statistical differences. D. Knocking down AR in PCa cells can decrease AR protein levels, and increase TGF-β1, p-Smad3 and MMP-9 protein levels. The right panels are the quantitative data for western-blot. ***p < 0.005, ns, no statistical differences. E. TGF-β1 type I receptor inhibitor, SB-431542 interrupts pre-adipocyte mediated PCa invasion. F. Targeting MMP9 by specific inhibitor interrupts pre-adipocyte mediated PCa invasion. G. The recruitment effect for pre-adipocytes by knocking down AR or adding anti-androgen enzalutamide in C4-2 and CWR22Rv1 (22Rv1) cells.
Mentions: To dissect the molecular mechanisms why increased infiltrating pre-adipocytes could enhance PCa cells invasion, we focused on the influence of the AR, the key player controlling PCa cells invasion [2, 3, 5, 7]. As shown in Fig. 3A-B, the recruitment of pre-adipocytes to PCa cells decreased AR expression at both mRNA (Fig. 3A) and protein (Fig. 3B) levels.

Bottom Line: Mechanism dissection revealed infiltrating pre-adipocytes might function through down-regulation of the androgen receptor (AR) via modulation of miR-301a, and then increase PCa cell invasion via induction of TGF-β1/Smad/MMP9 signals.The mouse model with orthotopically xenografted PCa CWR22Rv1 cells with pre-adipocytes also confirmed that infiltrating pre-adipocytes could increase PCa cell invasion via suppressing AR signaling.Targeting this newly identified signaling may help us to better inhibit PCa metastasis.

View Article: PubMed Central - PubMed

Affiliation: Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.

ABSTRACT
High fat dietary intake may increase the risk of prostate cancer (PCa). Pre-adipocytes, one of the basic components in the tumor microenvironment (TME), are capable of differentiating into adipose tissues and play key roles to affect PCa progression. Here we found the pre-adipocytes could be recruited more easily to PCa than its surrounding normal prostate tissue. In vitro co-culture system also confirmed PCa has a better capacity than normal prostate to recruit pre-adipocytes. The consequences of recruiting more pre-adipocytes may then increase PCa cell invasion. Mechanism dissection revealed infiltrating pre-adipocytes might function through down-regulation of the androgen receptor (AR) via modulation of miR-301a, and then increase PCa cell invasion via induction of TGF-β1/Smad/MMP9 signals. The mouse model with orthotopically xenografted PCa CWR22Rv1 cells with pre-adipocytes also confirmed that infiltrating pre-adipocytes could increase PCa cell invasion via suppressing AR signaling. Together, our results reveal a new mechanism showing pre-adipocytes in the prostate TME can be recruited to PCa to increase PCa metastasis via modulation of the miR-301a/AR/TGF-β1/Smad/MMP9 signals. Targeting this newly identified signaling may help us to better inhibit PCa metastasis.

No MeSH data available.


Related in: MedlinePlus