Involvement of SET in the Wnt signaling pathway and the development of human colorectal cancer

Abstract

The SET oncoprotein is involved in cancer progression by modulating multiple cellular processes, including the inhibition of the tumor suppressor, protein phosphatase 2 (PP2A). Based upon these multiple activities, we hypothesized that targeted inhibition of SET is likely to have multiple discrete and measurable effects on cancer cells. In the present study, the mRNA expression levels of SET, PP2A and β-catenin were examined in 31 pairs of human colorectal adenocarcinoma tissues and corresponding adjacent normal colorectal tissues by quantitative real-time polymerase chain reaction (qPCR). A small interfering RNA targeting SET was transfected into the human colon carcinoma cell lines, LS174T and SW480. The mRNA levels of SET, PP2A, β-catenin, c-Myc, E-cadherin and p53 were determined by qPCR analysis and the protein levels of SET, c-Myc, PP2A and β-catenin were examined by western blot analysis. mRNA expression levels of SET and β-catenin were found to be elevated in 22 (70.9%) samples, while PP2A expression levels were upregulated in eight (25.8%) samples. In addition, the knockdown of SET mRNA expression caused the upregulation of PP2A and c-Myc in the two cell lines, whereas β-catenin, E-cadherin and p53 mRNA expression was downregulated. Consistent with these results, the protein expression of β-catenin and c-Myc was found to be downregulated, whereas PP2A was upregulated at the protein level. Based on these results, we proposed that SET is essential in the carcinogenesis of human colorectal adenocarcinoma. In addition, it is suggested that SET promotes carcinogenesis through regulation of the Wnt signaling pathway.

The therapeutic effects of SET/I2PP2A inhibitors on canine melanoma

“…Consistent with this observation, SET inhibitors more effectively killed CMeC-2 melanoma cells. Although increased SET expression and its correlation with adverse prognosis were observed in various human tumors [ 6 , 8 ], our unexpected results suggest that a higher level of SET expression does not always mean a higher contribution for tumorigenic potential. The molecular mechanism of this complexity remains unknown, but genetic mutations or differences in post-translational modifications on SET may contribute to this mechanism.…”

“…PP2A inhibits the tumorigenic potential, such as disordered cell proliferation and cancer cell stemness, by suppressing tumor-promoting signals, such as ERK1/2, Akt/PKB and c-Myc [ 16 , 20 ]. SET/I2PP2A is a potent physiological inhibitor of PP2A, and the expression of SET is increased in various human cancers including breast cancer, pancreatic cancer, colorectal cancer and chronic myeloid leukemia [ 8 , 9 , 14 , 18 ]. In human melanoma, SET knockdown (KD) suppressed tumor growth [ 8 ].…”

“…SET/I2PP2A is a potent physiological inhibitor of PP2A, and the expression of SET is increased in various human cancers including breast cancer, pancreatic cancer, colorectal cancer and chronic myeloid leukemia [ 8 , 9 , 14 , 18 ]. In human melanoma, SET knockdown (KD) suppressed tumor growth [ 8 ]. We previously reported that canine cells express several isoforms of the SET protein and showed that canine SETα protein has approximately 94% homology with human SETα [ 3 ].…”

Diagnostic Value of SFRP1 as a Favorable Predictive and Prognostic Biomarker in Patients with Prostate Cancer

“…The Wnt/β-catenin signaling pathway is abnormally activated in a wide range of human malignancies [48–54]. This aberrant activation contributes to tumorigenesis by up-regulating the expression of various downstream target genes, such as MDR-1, Livin, cyclin D1 and c-Myc [15,55].…”

Eviction of linker histone H1 by NAP-family histone chaperones enhances activated transcription

“…Later, recurrent translocations involving SET and CAN (also called Nup214), a nucleoporin, were found to be associated with several distinct malignancies, including myeloid leukemias, colorectal, oral, and ovarian cancers [ 25 – 27 ]. The SET-CAN fusion protein dysregulates several potentially oncogenic nuclear processes, including aberrant retention of proteins targeted for export, stimulation of the wnt signaling pathway, and transcriptional activation of HOXA target genes [ 28 – 30 ]. Furthermore, misregulation of SET disrupts the catalytic activity of PP2A, which is linked to aberrant patterns of gene expression via effects on histone post-translational modifications [ 31 ], further linking SET to transcriptional regulation.…”