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Cordycepin (3'-deoxyadenosine) suppressed HMGA2, Twist1 and ZEB1-dependent melanoma invasion and metastasis by targeting miR-33b.

Zhang P, Huang C, Fu C, Tian Y, Hu Y, Wang B, Strasner A, Song Y, Song E - Oncotarget (2015)

Bottom Line: Cordycepin, the active component of Cordyceps spp., has been identified to have anti-metastatic effect on tumor progression and thus possesses pharmacological and therapeutic potentials.Cordycepin-mediated miR-33b expression was dependent on LXR-RXR heterodimer activation. miR-33b directly binds to HMGA2, Twist1 and ZEB1 3'-UTR to suppress their expression.In spontaneous metastasis models, cordycepin suppressed tumor metastasis without altering primary tumor growth.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.

ABSTRACT
Malignant melanoma, the most deadly form of skin cancer, has a high propensity for metastatic spread and is notoriously chemotherapy-resistant. Cordycepin, the active component of Cordyceps spp., has been identified to have anti-metastatic effect on tumor progression and thus possesses pharmacological and therapeutic potentials. However, the mechanisms of anti-metastatic effects of cordycepin at cellular levels remain elusive. We analyzed the effect of cordycepin on human melanoma miRNA expression profiles by miRNAarray and found that miR-33b was upregulated in highly-metastatic melanoma cell lines following cordycepin exposure. Cordycepin-mediated miR-33b expression was dependent on LXR-RXR heterodimer activation. miR-33b directly binds to HMGA2, Twist1 and ZEB1 3'-UTR to suppress their expression. The negative correlations between miR-33b levels and HMGA2, Twist1 or ZEB1 expression were detected in 72 patient melanoma tissue samples. By targeting HMGA2 and Twist1, miR-33b attenuated melanoma migration and invasiveness upon cordycepin exposure. miR-33b knockdown or ZEB1 overexpression reverted cordycepin-mediated mesenchymal-epithelial transition (MET), triggering the expression of N-cadherin. In spontaneous metastasis models, cordycepin suppressed tumor metastasis without altering primary tumor growth. We showed for the first time that targeting miRNA by cordycepin indicates a new mechanism of cordycepin-induced suppression of tumor metastasis and miR-33b/HMGA2/Twist1/ZEB1 axis plays critical roles in regulating melanoma dissemination.

No MeSH data available.


Related in: MedlinePlus

miR-33b levels in melanoma patient tissue samples were negatively correlated with those of HMGA2, Twist1 and ZEB1(A) Relationship of miR-33b, HMGA2, Twist1 and ZEB1 relative expression and melanoma clinicopathological features. miR-33b expression levels in FFPE melanoma tissue samples from 72 patients with clinical TNM stage 0–IV were detected with in situ hybridization and quantified by ImageJ for grey value. HMGA2, Twist1 and ZEB1 expression levels in these FFPE melanoma tissue samples were detected with IHC and quantified by ImageJ for grey value. Relative expression levels of target molecules were compared among different TNM stages with ANOVA. P value is shown. Color circles represent outliers in each group. (B–D) The correlation between miR-33b relative expression levels (log transformed) and HMGA2 (B), Twist1 (C) or ZEB1 (D) relative expression levels (log transformed) in FFPE melanoma tissue samples from 72 patients with clinical TNM stage 0–IV. Pearson correlation coefficients and R2-values were calculated as indicated.
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Figure 3: miR-33b levels in melanoma patient tissue samples were negatively correlated with those of HMGA2, Twist1 and ZEB1(A) Relationship of miR-33b, HMGA2, Twist1 and ZEB1 relative expression and melanoma clinicopathological features. miR-33b expression levels in FFPE melanoma tissue samples from 72 patients with clinical TNM stage 0–IV were detected with in situ hybridization and quantified by ImageJ for grey value. HMGA2, Twist1 and ZEB1 expression levels in these FFPE melanoma tissue samples were detected with IHC and quantified by ImageJ for grey value. Relative expression levels of target molecules were compared among different TNM stages with ANOVA. P value is shown. Color circles represent outliers in each group. (B–D) The correlation between miR-33b relative expression levels (log transformed) and HMGA2 (B), Twist1 (C) or ZEB1 (D) relative expression levels (log transformed) in FFPE melanoma tissue samples from 72 patients with clinical TNM stage 0–IV. Pearson correlation coefficients and R2-values were calculated as indicated.

Mentions: To assess whether there is an association between the levels of HMGA2, Twist1 or ZEB1 and miR-33b in melanoma, we analyzed their levels in 72 melanoma patient samples. The 72 melanoma patient samples were categorized according to their clinical stages (TNM) with stage 0 being the carcinoma in situ and stage IV being metastatic cancer. miR-33b levels were detected with in situ hybridization and HMGA2, Twist1 and ZEB1 expression levels were assessed with immunohistochemistry. miR-33b was negatively correlated with the grading of malignancy of melanoma (Figure 3A). Patients whose tumors express low miR-33b levels had reduced metastasis and relapse-free survival. HMGA2, Twist1 and ZEB1 expressions were significantly higher in samples with poor prognosis with stage IV tumor expressing highest levels of HMGA2, Twist1 and ZEB1. Using linear regression analysis, miR-33b displayed a significant negative correlation with the expressions of HMGA2, Twist1 and ZEB1, consistent with these genes being regulated by miR-33b in melanoma (Figure 3B–3D). Altogether, these data suggest that the loss of miR-33b leading to the upregulation of HMGA2, Twist1 and ZEB1 expressions may contribute to metastasis.


Cordycepin (3'-deoxyadenosine) suppressed HMGA2, Twist1 and ZEB1-dependent melanoma invasion and metastasis by targeting miR-33b.

Zhang P, Huang C, Fu C, Tian Y, Hu Y, Wang B, Strasner A, Song Y, Song E - Oncotarget (2015)

miR-33b levels in melanoma patient tissue samples were negatively correlated with those of HMGA2, Twist1 and ZEB1(A) Relationship of miR-33b, HMGA2, Twist1 and ZEB1 relative expression and melanoma clinicopathological features. miR-33b expression levels in FFPE melanoma tissue samples from 72 patients with clinical TNM stage 0–IV were detected with in situ hybridization and quantified by ImageJ for grey value. HMGA2, Twist1 and ZEB1 expression levels in these FFPE melanoma tissue samples were detected with IHC and quantified by ImageJ for grey value. Relative expression levels of target molecules were compared among different TNM stages with ANOVA. P value is shown. Color circles represent outliers in each group. (B–D) The correlation between miR-33b relative expression levels (log transformed) and HMGA2 (B), Twist1 (C) or ZEB1 (D) relative expression levels (log transformed) in FFPE melanoma tissue samples from 72 patients with clinical TNM stage 0–IV. Pearson correlation coefficients and R2-values were calculated as indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496401&req=5

Figure 3: miR-33b levels in melanoma patient tissue samples were negatively correlated with those of HMGA2, Twist1 and ZEB1(A) Relationship of miR-33b, HMGA2, Twist1 and ZEB1 relative expression and melanoma clinicopathological features. miR-33b expression levels in FFPE melanoma tissue samples from 72 patients with clinical TNM stage 0–IV were detected with in situ hybridization and quantified by ImageJ for grey value. HMGA2, Twist1 and ZEB1 expression levels in these FFPE melanoma tissue samples were detected with IHC and quantified by ImageJ for grey value. Relative expression levels of target molecules were compared among different TNM stages with ANOVA. P value is shown. Color circles represent outliers in each group. (B–D) The correlation between miR-33b relative expression levels (log transformed) and HMGA2 (B), Twist1 (C) or ZEB1 (D) relative expression levels (log transformed) in FFPE melanoma tissue samples from 72 patients with clinical TNM stage 0–IV. Pearson correlation coefficients and R2-values were calculated as indicated.
Mentions: To assess whether there is an association between the levels of HMGA2, Twist1 or ZEB1 and miR-33b in melanoma, we analyzed their levels in 72 melanoma patient samples. The 72 melanoma patient samples were categorized according to their clinical stages (TNM) with stage 0 being the carcinoma in situ and stage IV being metastatic cancer. miR-33b levels were detected with in situ hybridization and HMGA2, Twist1 and ZEB1 expression levels were assessed with immunohistochemistry. miR-33b was negatively correlated with the grading of malignancy of melanoma (Figure 3A). Patients whose tumors express low miR-33b levels had reduced metastasis and relapse-free survival. HMGA2, Twist1 and ZEB1 expressions were significantly higher in samples with poor prognosis with stage IV tumor expressing highest levels of HMGA2, Twist1 and ZEB1. Using linear regression analysis, miR-33b displayed a significant negative correlation with the expressions of HMGA2, Twist1 and ZEB1, consistent with these genes being regulated by miR-33b in melanoma (Figure 3B–3D). Altogether, these data suggest that the loss of miR-33b leading to the upregulation of HMGA2, Twist1 and ZEB1 expressions may contribute to metastasis.

Bottom Line: Cordycepin, the active component of Cordyceps spp., has been identified to have anti-metastatic effect on tumor progression and thus possesses pharmacological and therapeutic potentials.Cordycepin-mediated miR-33b expression was dependent on LXR-RXR heterodimer activation. miR-33b directly binds to HMGA2, Twist1 and ZEB1 3'-UTR to suppress their expression.In spontaneous metastasis models, cordycepin suppressed tumor metastasis without altering primary tumor growth.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.

ABSTRACT
Malignant melanoma, the most deadly form of skin cancer, has a high propensity for metastatic spread and is notoriously chemotherapy-resistant. Cordycepin, the active component of Cordyceps spp., has been identified to have anti-metastatic effect on tumor progression and thus possesses pharmacological and therapeutic potentials. However, the mechanisms of anti-metastatic effects of cordycepin at cellular levels remain elusive. We analyzed the effect of cordycepin on human melanoma miRNA expression profiles by miRNAarray and found that miR-33b was upregulated in highly-metastatic melanoma cell lines following cordycepin exposure. Cordycepin-mediated miR-33b expression was dependent on LXR-RXR heterodimer activation. miR-33b directly binds to HMGA2, Twist1 and ZEB1 3'-UTR to suppress their expression. The negative correlations between miR-33b levels and HMGA2, Twist1 or ZEB1 expression were detected in 72 patient melanoma tissue samples. By targeting HMGA2 and Twist1, miR-33b attenuated melanoma migration and invasiveness upon cordycepin exposure. miR-33b knockdown or ZEB1 overexpression reverted cordycepin-mediated mesenchymal-epithelial transition (MET), triggering the expression of N-cadherin. In spontaneous metastasis models, cordycepin suppressed tumor metastasis without altering primary tumor growth. We showed for the first time that targeting miRNA by cordycepin indicates a new mechanism of cordycepin-induced suppression of tumor metastasis and miR-33b/HMGA2/Twist1/ZEB1 axis plays critical roles in regulating melanoma dissemination.

No MeSH data available.


Related in: MedlinePlus