SET contributes to the epithelial-mesenchymal transition of pancreatic cancer

Abstract

Pancreatic cancer has a devastating prognosis due to 80-90% of diagnostic cases occurring when metastasis has already presented. Activation of the epithelial-mesenchymal transition (EMT) is a prerequisite for metastasis because it allows for the dissemination of tumor cells to blood stream and secondary organs. Here, we sought to determine the role of SET oncoprotein, an endogenous inhibitor of PP2A, in EMT and pancreatic tumor progression. Among the two major isoforms of SET (isoform 1 and isoform 2), higher protein levels of SET isoform 2 were identified in aggressive pancreatic cancer cell lines. Overexpressing SET isoform 2, and to a lesser extent SET isoform 1, in epithelial cell lines promoted EMT-like features by inducing mesenchymal characteristics and promoting cellular proliferation, migration, invasion, and colony formation. Consistently, knockdown of SET isoforms in the mesenchymal cell line partially resisted these characteristics and promoted epithelial features. SET-induced EMT was likely facilitated by increased N-cadherin overexpression, decreased PP2A activity and/or increased expression of key EMT-driving transcription factors. Additionally, SET overexpression activated the Rac1/JNK/c-Jun signaling pathway that induced transcriptional activation of N-cadherin expression. In vivo, SET isoform 2 overexpression significantly correlated with increased N-cadherin in human PDAC and to tumor burden and metastatic ability in an orthotopic mouse tumor model. These findings identify a new role for SET in cancer and have implications for the design and targeting of SET for intervening pancreatic tumor progression.

MiR-200c-3p inhibits cell migration and invasion of clear cell renal cell carcinoma via regulating SLC6A1

“…Activation of the epithelial-mesenchymal transition (EMT) is a prior condition for tumor metastasis because it makes it possible for the dissemination of oncocytes to other organs via blood stream. 31 EMT has been observed in several human cancers previously. For example, EMT was induced by SET in pancreatic cancer, lung cancer, 32 prostatic carcinoma and cervical cancer.…”

<p>Upregulated SET Promotes Cell Survival Through Activating Akt/NF-κB Signal in Colorectal Carcinoma</p>

“…A number of studies reported that SET increased the proliferation ability and inhibited cell apoptosis in kinds of malignant tumors. 6,9,16 Sobral et al reported that SET promoted cell proliferation, survival and resistance to cell death in heads and neck squamous cell carcinoma. 16 Liu et al reported that knockdown of SET in NSCLC cells resulted in attenuated proliferative and invasive ability.…”

“…5 Overexpression of SET was characterized as being tumor-specific and was associated with the worse clinical outcomes in many human malignant carcinomas. 4,6 Moreover, SET had been proven to be associated with the development of therapeutic resistance in several kinds of carcinomas. 7 Mody et al reported that SET isoform 2 was overexpressed in aggressive pancreatic cancer cell lines and overexpressing SET isoform 2 promoted cellular proliferation, migration, invasion, and colony formation in pancreatic cancer.…”

“…7 Mody et al reported that SET isoform 2 was overexpressed in aggressive pancreatic cancer cell lines and overexpressing SET isoform 2 promoted cellular proliferation, migration, invasion, and colony formation in pancreatic cancer. 6 Jiang et al reported that SET mRNA expression was up-regulated in colorectal carcinoma, and SET promoted cellular proliferation and inhibited cell apoptosis in colorectal adenocarcinoma cells and oral squamous cells. 4 However, the potential roles of SET remained unclear in colorectal carcinoma.…”

Comment on ‘MicroRNA-199b-5p attenuates TGF-β1-induced epithelial–mesenchymal transition in hepatocellular carcinoma’

“…In fact, SET overexpression positively correlated with N-Cadherin levels. 4 These observations would indicate that the direct miR-199b-induced N-cadherin regulation would be indirectly reinforced by modulating SET.…”