Oncogenic Activities Of UBE2S Mediated By VHL/HIF-1α/STAT3 Signal Via The Ubiquitin-Proteasome System In PDAC

PURPOSE: Ubiquitin-conjugating enzyme E2S (UBE2S) is important for the development and progression of several types of cancer. However, neither the role of UBE2S in pancreatic cancer nor its mechanism is clear. METHODS: We analyzed three GEO datasets to obtain 150 differentially expressed genes (DEGs) between pancreatic ductal adenocarcinoma (PDAC) and non-cancerous samples. Moreover, GSEA and mutation analysis were also done for UBE2S. The UBE2S expression in PDAC was measured by immunohistochemistry and qRT-PCR. Colony formation, scratch wound-healing and tumor growth assays were conducted to examine the effect of UBE2S on PDAC cells. Migration was detected using Transwell assay. UBE2S knockdown pancreatic cells were treated with proteasome inhibitor MG132. Immunofluorescence was undertaken for interaction between UBE2S and VHL. The expression of Snail and Twist1 and the changes of HIF-1α/STAT3 pathway were detected by Western blotting. RESULTS: The mRNA of UBE2S was significantly upregulated in human pancreatic cancer compared to normal tissues. Immunohistochemistry confirmed that the protein level of UBE2S increased in tissue microarrays (TMAs) and was associated with lymph nodes metastasis and distant metastasis. CONCLUSION: UBE2S could enhance EMT by the VHL/HIF-1α/STAT3 pathway via the ubiquitin-proteasome system. Co-expression of CDC20 may represent a novel and promising therapeutic target for the patients with PDAC.