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A switch from CD44⁺ cell to EMT cell drives the metastasis of prostate cancer.

Shang Z, Cai Q, Zhang M, Zhu S, Ma Y, Sun L, Jiang N, Tian J, Niu X, Chen J, Sun Y, Niu Y - Oncotarget (2015)

Bottom Line: Our results also suggested ADT might go through promoting TGFβ1-CD44 signaling to enhance swift to EMT.Targeting CD44 with salinomycin and siRNA could inhibit cell transition and decrease PCa invasion.Combined therapy of ADT with anti-CD44 may become a new potential therapeutic approach to battle later stage PCa.

View Article: PubMed Central - PubMed

Affiliation: Sex Hormone Research Center, Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Tianjin, China.

ABSTRACT
Epithelial-mesenchymal transition (EMT) has been linked to cancer stem-like (CD44+) cell in the prostate cancer (PCa) metastasis. However, the molecular mechanism remains elusive. Here, we found EMT contributed to metastasis in PCa patients failed in androgen deprivation therapy (ADT). Castration TRAMP model also proved PCa treated with ADT promoted EMT with increased CD44+ stem-like cells. Switched CD44+ cell to EMT cell is a key step for luminal PCa cell metastasis. Our results also suggested ADT might go through promoting TGFβ1-CD44 signaling to enhance swift to EMT. Targeting CD44 with salinomycin and siRNA could inhibit cell transition and decrease PCa invasion. Together, cancer stem-like (CD44+) cells could be the initiator cells of EMT modulated by TGFβ1-CD44 signaling. Combined therapy of ADT with anti-CD44 may become a new potential therapeutic approach to battle later stage PCa.

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Related in: MedlinePlus

TGFβ1 altered EMT with enhanced PCa invasion via modulating CD44(a) After 5ng/ml TGFβ1 treatment, the decrease expression of E-Cadherin and the increase expression of vimentin were detected in LNCaP and CWR22rv1 cells in a time dependent manner by Western blot. (b) EMT transition induced by TGFβ1 could be blocked by CD44 siRNA in LNCaP and CWR22rv1 cells. LNCaP and CWR22rv1 cells were treated with 5ng/ml TGFβ1 with or without CD44 siRNA for 12hrs and 24hrs. The expressions of CD44, E-Cadherin and Vimentin of different treatments were detected by Western blot assay. (c) Invasion ability of LNCaP and CWR22rv1 cells treated with TGFβ1 (5ng/ml), CD44 siRNA and both treatments were analyzed in Transwell Chamber assay. Quantitation was shown on the right. Significance was defined as p<0.05(*).
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Figure 4: TGFβ1 altered EMT with enhanced PCa invasion via modulating CD44(a) After 5ng/ml TGFβ1 treatment, the decrease expression of E-Cadherin and the increase expression of vimentin were detected in LNCaP and CWR22rv1 cells in a time dependent manner by Western blot. (b) EMT transition induced by TGFβ1 could be blocked by CD44 siRNA in LNCaP and CWR22rv1 cells. LNCaP and CWR22rv1 cells were treated with 5ng/ml TGFβ1 with or without CD44 siRNA for 12hrs and 24hrs. The expressions of CD44, E-Cadherin and Vimentin of different treatments were detected by Western blot assay. (c) Invasion ability of LNCaP and CWR22rv1 cells treated with TGFβ1 (5ng/ml), CD44 siRNA and both treatments were analyzed in Transwell Chamber assay. Quantitation was shown on the right. Significance was defined as p<0.05(*).

Mentions: From above results, we demonstrated that TGFβ1 could alter CD44 expression and CD44+ stem-like cell population, we were interested to see if TGFβ1 signaling could modulate EMT and cell invasion via alternation of CD44 expression. We found that addition of 5ng/ml TGFβ1 led to EMT markers changed including increased vimentin and decreased E-Cadherin both in LNCaP and CWR22RV2 cell lines (Fig.4a). To confirm CD44 is a key regulating molecular in EMT induced by TGFβ1/pSmad2 signaling. We firstly found addition of 5ng/ml TGFβ1 led to increase the expression of CD44 and vimentin and decreased the expression of E-Cadherin in LNCaP and CWR22RV1 (Fig. 4b). We also found the invasion ability increased in LNCaP and CWR22RV1 cells with TGFβ1 treatment compared to those cells without TGFβ1 treatment (Fig. 4c). In contrast, TGFβ1 treatment in LNCaP and CWR22RV1 cells with knocked-down CD44 expression with CD44-siRNA led to little change in the expression of E-Cadherin (Fig. 4b) as well as the invasion ability of LNCaP and CWR22RV1 (Fig. 4c), suggesting TGFβ1 may need to go through modulation CD44 to alter the EMT and invasion ability of PCa.


A switch from CD44⁺ cell to EMT cell drives the metastasis of prostate cancer.

Shang Z, Cai Q, Zhang M, Zhu S, Ma Y, Sun L, Jiang N, Tian J, Niu X, Chen J, Sun Y, Niu Y - Oncotarget (2015)

TGFβ1 altered EMT with enhanced PCa invasion via modulating CD44(a) After 5ng/ml TGFβ1 treatment, the decrease expression of E-Cadherin and the increase expression of vimentin were detected in LNCaP and CWR22rv1 cells in a time dependent manner by Western blot. (b) EMT transition induced by TGFβ1 could be blocked by CD44 siRNA in LNCaP and CWR22rv1 cells. LNCaP and CWR22rv1 cells were treated with 5ng/ml TGFβ1 with or without CD44 siRNA for 12hrs and 24hrs. The expressions of CD44, E-Cadherin and Vimentin of different treatments were detected by Western blot assay. (c) Invasion ability of LNCaP and CWR22rv1 cells treated with TGFβ1 (5ng/ml), CD44 siRNA and both treatments were analyzed in Transwell Chamber assay. Quantitation was shown on the right. Significance was defined as p<0.05(*).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359227&req=5

Figure 4: TGFβ1 altered EMT with enhanced PCa invasion via modulating CD44(a) After 5ng/ml TGFβ1 treatment, the decrease expression of E-Cadherin and the increase expression of vimentin were detected in LNCaP and CWR22rv1 cells in a time dependent manner by Western blot. (b) EMT transition induced by TGFβ1 could be blocked by CD44 siRNA in LNCaP and CWR22rv1 cells. LNCaP and CWR22rv1 cells were treated with 5ng/ml TGFβ1 with or without CD44 siRNA for 12hrs and 24hrs. The expressions of CD44, E-Cadherin and Vimentin of different treatments were detected by Western blot assay. (c) Invasion ability of LNCaP and CWR22rv1 cells treated with TGFβ1 (5ng/ml), CD44 siRNA and both treatments were analyzed in Transwell Chamber assay. Quantitation was shown on the right. Significance was defined as p<0.05(*).
Mentions: From above results, we demonstrated that TGFβ1 could alter CD44 expression and CD44+ stem-like cell population, we were interested to see if TGFβ1 signaling could modulate EMT and cell invasion via alternation of CD44 expression. We found that addition of 5ng/ml TGFβ1 led to EMT markers changed including increased vimentin and decreased E-Cadherin both in LNCaP and CWR22RV2 cell lines (Fig.4a). To confirm CD44 is a key regulating molecular in EMT induced by TGFβ1/pSmad2 signaling. We firstly found addition of 5ng/ml TGFβ1 led to increase the expression of CD44 and vimentin and decreased the expression of E-Cadherin in LNCaP and CWR22RV1 (Fig. 4b). We also found the invasion ability increased in LNCaP and CWR22RV1 cells with TGFβ1 treatment compared to those cells without TGFβ1 treatment (Fig. 4c). In contrast, TGFβ1 treatment in LNCaP and CWR22RV1 cells with knocked-down CD44 expression with CD44-siRNA led to little change in the expression of E-Cadherin (Fig. 4b) as well as the invasion ability of LNCaP and CWR22RV1 (Fig. 4c), suggesting TGFβ1 may need to go through modulation CD44 to alter the EMT and invasion ability of PCa.

Bottom Line: Our results also suggested ADT might go through promoting TGFβ1-CD44 signaling to enhance swift to EMT.Targeting CD44 with salinomycin and siRNA could inhibit cell transition and decrease PCa invasion.Combined therapy of ADT with anti-CD44 may become a new potential therapeutic approach to battle later stage PCa.

View Article: PubMed Central - PubMed

Affiliation: Sex Hormone Research Center, Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Tianjin, China.

ABSTRACT
Epithelial-mesenchymal transition (EMT) has been linked to cancer stem-like (CD44+) cell in the prostate cancer (PCa) metastasis. However, the molecular mechanism remains elusive. Here, we found EMT contributed to metastasis in PCa patients failed in androgen deprivation therapy (ADT). Castration TRAMP model also proved PCa treated with ADT promoted EMT with increased CD44+ stem-like cells. Switched CD44+ cell to EMT cell is a key step for luminal PCa cell metastasis. Our results also suggested ADT might go through promoting TGFβ1-CD44 signaling to enhance swift to EMT. Targeting CD44 with salinomycin and siRNA could inhibit cell transition and decrease PCa invasion. Together, cancer stem-like (CD44+) cells could be the initiator cells of EMT modulated by TGFβ1-CD44 signaling. Combined therapy of ADT with anti-CD44 may become a new potential therapeutic approach to battle later stage PCa.

Show MeSH
Related in: MedlinePlus