MiR-301a transcriptionally activated by HIF-2α promotes hypoxia-induced epithelial-mesenchymal transition by targeting TP63 in pancreatic cancer.

Pancreatic cancer (PC) is one of the deadliest cancers worldwide. PC metastasis involves a complex set of events, including epithelial-mesenchymal transition (EMT), that increase tumor cell invasiveness. Recent evidence has shown that hypoxia is a major EMT regulator in pancreatic cancer cells and facilitates metastasis; however, the mechanisms remain elusive. To investigate the role of miR-301a in hypoxia-induced EMT in PC cells. Real-time PCR and Western blot analysis were used to detect the expression of miR-301a and EMT markers in PDAC cells cultured in hypoxic and normoxic conditions. Western blot analysis was used to detect the expression of EMT markers in PDAC cells with miR-301a overexpression. Wound healing assay and Transwell assay were used to detect the migration capabilities of PDAC cells with miR-301a overexpression and knockout. Luciferase assay was used to detect the miR-301a promoter and the 3' untranslated region activity of TP63. Orthotopic PC mouse models were used to study the role of miR-301a in metastasis of PDAC cells in vivo. In situ hybridization assay was used to detect the expression of miR-301a in PDAC patient samples (adjacent paratumor and paired tumor tissues).  . Hypoxic environment could directly promote the EMT of PC cells. The expression level of miR-301a was increased in a HIF2α dependent manner in hypoxia-cultured CFPAC-1 and BxPC-3 cells. Overexpression of miR-301a enhanced the hypoxia-induced EMT of PC cells, while knocking out miR-301a result in the suppression of hypoxia-induced EMT. TP63 was a direct target of miR-301a and involved in the metastatic process of PC cells. Furthermore, miR-301a upregulation facilitated PDAC distant metastasis and lymph node metastasis in vivo. Additionally, miR-301a overexpression was indicative of aggressive clinicopathological behaviors and poor prognosis. The newly identified HIF-2α-miR301a-TP63 signaling pathway may play a crucial role in hypoxia-induced EMT in PDAC cells.

Zhang KD ，Hu B ，Cen G ，Yang YH ，Chen WW ，Guo ZY ，Wang XF ，Zhao Q ，Qiu ZJ ... -  《-》

MiR-361-3p regulates ERK1/2-induced EMT via DUSP2 mRNA degradation in pancreatic ductal adenocarcinoma.

Hu J ，Li L ，Chen H ，Zhang G ，Liu H ，Kong R ，Chen H ，Wang Y ，Li Y ，Tian F ，Lv X ，Li G ，Sun B ... -  《Cell Death & Disease》

Knockdown of FOXO3a induces epithelial-mesenchymal transition and promotes metastasis of pancreatic ductal adenocarcinoma by activation of the β-catenin/TCF4 pathway through SPRY2.

Li J ，Yang R ，Dong Y ，Chen M ，Wang Y ，Wang G ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

MicroRNA-301a-3p promotes pancreatic cancer progression via negative regulation of SMAD4.

Xia X ，Zhang K ，Cen G ，Jiang T ，Cao J ，Huang K ，Huang C ，Zhao Q ，Qiu Z ... -  《Oncotarget》

HIF-2α promotes epithelial-mesenchymal transition through regulating Twist2 binding to the promoter of E-cadherin in pancreatic cancer.

Yang J ，Zhang X ，Zhang Y ，Zhu D ，Zhang L ，Li Y ，Zhu Y ，Li D ，Zhou J ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》