miR-200c inhibits melanoma progression and drug resistance through down-regulation of BMI-1.

MicroRNAs (miRNAs) are short noncoding RNAs that play crucial roles in tumorigenesis and tumor progression. Melanoma is the most aggressive skin cancer that is resistant or rapidly develops resistance to a variety of chemotherapeutic agents. The role of miRNAs in melanoma progression and drug resistance has not been well studied. Herein, we demonstrate that miR-200c is down-regulated in melanomas (primary and metastatic) compared with melanocytic nevi. Overexpression of miR-200c in melanoma cells resulted in significantly decreased cell proliferation and migratory capacity as well as drug resistance. miR-200c overexpression resulted in significant down-regulation of BMI-1, ABCG2, ABCG5, and MDR1 expression and in a concomitant increase in E-cadherin levels. Knockdown of BMI-1 showed similar effects as miR-200c overexpression in melanoma cells. In addition, miR-200c overexpression significantly inhibited melanoma xenograft growth and metastasis in vivo, and this correlated with diminished expression of BMI-1 and reduced levels of E-cadherin in these tumors. The effects of miR-200c on melanoma cell proliferation and migratory capacity and on self-renewal were rescued by overexpression of Bmi-1, and the reversal of these phenotypes correlated with a reduction in E-cadherin expression and increased levels of ABCG2, ABCG5, and MDR1. Taken together, these findings demonstrate a key role for miR-200c in melanoma progression and drug resistance. These results suggest that miR-200c may represent a critical target for increasing melanoma sensitivity to clinical therapies.

Liu S ，Tetzlaff MT ，Cui R ，Xu X ... -  《-》

miR-200c inhibits invasion, migration and proliferation of bladder cancer cells through down-regulation of BMI-1 and E2F3.

Liu L ，Qiu M ，Tan G ，Liang Z ，Qin Y ，Chen L ，Chen H ，Liu J ... -  《Journal of Translational Medicine》

miR-200c/Bmi1 axis and epithelial-mesenchymal transition contribute to acquired resistance to BRAF inhibitor treatment.

Resistance to BRAF inhibitors (BRAFi) is one of the major challenges for targeted therapies for BRAF-mutant melanomas. However, little is known about the role of microRNAs in conferring BRAFi resistance. Herein, we demonstrate that miR-200c expression is significantly reduced whereas miR-200c target genes including Bmi1, Zeb2, Tubb3, ABCG5, and MDR1 are significantly increased in melanomas that acquired BRAFi resistance compared to pretreatment tumor biopsies. Similar changes were observed in BRAFi-resistant melanoma cell lines. Overexpression of miR-200c or knock-down of Bmi1 in resistant melanoma cells restores their sensitivities to BRAFi, leading to deactivation of the PI3K/AKT and MAPK signaling cascades, and acquisition of epithelial-mesenchymal transition-like phenotypes, including upregulation of E-cadherin, downregulation of N-cadherin, and ABCG5 and MDR1 expression. Conversely, knock-down of miR-200c or overexpression of Bmi1 in BRAFi-sensitive melanoma cells activates the PI3K/AKT and MAPK pathways, upregulates N-cadherin, ABCG5, and MDR1 expression, and downregulates E-cadherin expression, leading to BRAFi resistance. Together, our data identify miR-200c as a critical signaling node in BRAFi-resistant melanomas impacting the MAPK and PI3K/AKT pathways, suggesting miR-200c as a potential therapeutic target for overcoming acquired BRAFi resistance.

Liu S ，Tetzlaff MT ，Wang T ，Yang R ，Xie L ，Zhang G ，Krepler C ，Xiao M ，Beqiri M ，Xu W ，Karakousis G ，Schuchter L ，Amaravadi RK ，Xu W ，Wei Z ，Herlyn M ，Yao Y ，Zhang L ，Wang Y ，Zhang L ，Xu X ... -  《-》

MicroRNA-200c Inhibits Epithelial-Mesenchymal Transition by Targeting the BMI-1 Gene Through the Phospho-AKT Pathway in Endometrial Carcinoma Cells In Vitro.

Li F ，Liang A ，Lv Y ，Liu G ，Jiang A ，Liu P ... -  《MEDICAL SCIENCE MONITOR》

Neuropilin-2 Inhibits Drug Resistance and Progression of Melanoma Involving the MiR-331-3p Regulated Cascade.

MicroRNAs (miRs) are small noncoding RNAs that are crucial in the development and progression of tumours. Melanoma is an aggressive form of skin cancer and is resistant to most of the chemotherapeutic agents. However, the role of miRs in melanoma remains poorly studied. The work aimed to demonstrate that miR-331-3p is downregulated in melanoma against the benign melanocytic nevi. RT-PCR analysis was performed for the expression of proteins; cell proliferation and wound healing assays were carried out. Flow cytometry study was conducted for cell cycle analysis; colony formation assay was performed by soft agar method. For developing a tumour xenograft model, nu/nu mice were selected. Up-regulation of miR-331-3p in melanoma cells decreased cell proliferation, cell migration, and also drug resistance. Over-expression of miR-331-3p resulted in suppression of NRP2 and up-regulation of E-cadherin levels. Moreover, the levels of MDR1, ABCG-2, and ABCG-5 were decreased. However, the knockdown of NRP2 demonstrated similar effects as that of miR- 331-3p overexpression in tumour cells. Overexpression of miR-331-3p caused significant inhibition of tumour growth and its metastasis in mice model of melanoma, which was associated with depletion of NRP2 protein and increased expression of E-cadherin. However, the effects of miR- 331-3p on the migration, cell proliferation, and self-renewal were overturned by the upregulation of NRP2, which also resulted in the inhibition of E-cadherin and overexpression of MDR-1, ABCG-2, and ABCG-5. The findings point out the key role of miR-331-3p in the progression and drug resistance of melanoma involving NRP2.

Xie Q ，Zhang R ，Liu D ，Yang J ，Hu Q ，Shan C ，Li X ... -  《-》