Published online May 21, 2020. doi: 10.3748/wjg.v26.i19.2349
Peer-review started: November 18, 2019
First decision: January 19, 2020
Revised: February 20, 2010
Accepted: April 18, 2020
Article in press: April 18, 2020
Published online: May 21, 2020
Pancreatic cancer (PC) continues to be a leading cause of cancer-related death 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 PC cells and facilitates metastasis; however, the mechanisms remain elusive.
This study aimed to investigate the key regulators and signaling pathways in hypoxia-induced EMT in PC cells. This study may enrich the mechanism of PC metastasis and provide a target for the treatment of PC.
The objectives of this research was to explore the role and the mechanism of miR-301a in hypoxia-induced EMT in PC cells. Realizing these objectives will provide strong evidence that miR-301a can be used as a new molecular marker for the prognosis of patients with PC.
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 and knockout. 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 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.
MiR-301a was increased in a HIF-2α dependent manner in the process of hypoxia-induced EMT in PC cells. MiR-301a promoted EMT of PC cells by inhibiting the expression of TP63. 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. These results are helpful to enrich the metastasis mechanism of PC and provide targets for clinical treatment. How to develop an effective drug to inhibit miRNAs in PC patient is an urgent problem to be solved.
MiR-301a regulated by HIF-2α plays an important role in the process of hypoxia-induced EMT in PC cells. In addition, TP63 as a new target gene of miR-301a, is involved in the EMT and metastasis of PC. Therefore, the results of this study showed that miR-301a may be a new therapeutic target for patients with PC.
A prospective study is expected to confirm the role of miR-301a in PDAC patients with advanced metastases. It is worth further studying whether dysfunctions of the miR-301a by effective drugs could prevent PDAC metastasis.