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TRAP1 regulates stemness through Wnt/?-catenin pathway in human colorectal carcinoma.

ABSTRACT: Colorectal carcinoma (CRC) is a common cause of cancer-related death worldwide. Indeed, treatment failures are triggered by cancer stem cells (CSCs) that give rise to tumor repopulation upon initial remission. Thus, the role of the heat shock protein TRAP1 in stemness was investigated in CRC cell lines and human specimens, based on its involvement in colorectal carcinogenesis, through regulation of apoptosis, protein homeostasis and bioenergetics. Strikingly, co-expression between TRAP1 and stem cell markers was observed in stem cells located at the bottom of intestinal crypts and in CSCs sorted from CRC cell lines. Noteworthy, TRAP1 knockdown reduced the expression of stem cell markers and impaired colony formation, being the CSC phenotype and the anchorage-independent growth conserved in TRAP1-rich cancer cells. Consistently, the gene expression profiling of HCT116 cells showed that TRAP1 silencing results in the loss of the stem-like signature with acquisition of a more-differentiated phenotype and the downregulation of genes encoding for activating ligands and target proteins of Wnt/?-catenin pathway. Mechanistically, TRAP1 maintenance of stemness is mediated by the regulation of Wnt/?-catenin signaling, through the modulation of the expression of frizzled receptor ligands and the control of ?-catenin ubiquitination/phosphorylation. Remarkably, TRAP1 is associated with higher expression of ?-catenin and several Wnt/?-catenin target genes in human CRCs, thus supporting the relevance of TRAP1 regulation of ?-catenin in human pathology. This study is the first demonstration that TRAP1 regulates stemness and Wnt/?-catenin pathway in CRC and provides novel landmarks in cancer biology and therapeutics.

SUBMITTER: Lettini G

PROVIDER: S-EPMC5071570 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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TRAP1 regulates stemness through Wnt/β-catenin pathway in human colorectal carcinoma.

Lettini Giacomo G Sisinni Lorenza L Condelli Valentina V Matassa Danilo Swann DS Simeon Vittorio V Maddalena Francesca F Gemei Marica M Lopes Elvira E Vita Giulia G Del Vecchio Luigi L Esposito Franca F Landriscina Matteo M

Cell death and differentiation 20160923 11

Colorectal carcinoma (CRC) is a common cause of cancer-related death worldwide. Indeed, treatment failures are triggered by cancer stem cells (CSCs) that give rise to tumor repopulation upon initial remission. Thus, the role of the heat shock protein TRAP1 in stemness was investigated in CRC cell lines and human specimens, based on its involvement in colorectal carcinogenesis, through regulation of apoptosis, protein homeostasis and bioenergetics. Strikingly, co-expression between TRAP1 and stem ...[more]

PMID: 27662365

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Project description:BackgroundTransmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. However, the role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive.MethodsWe investigated the expression of TM4SF1 in the Oncomine, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of CRC tissues. The effect of TM4SF1 on the epithelial-to-mesenchymal transition (EMT) and cancer stemness of CRC cells was investigated by Transwell, wound healing and sphere formation assays. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which TM4SF1 modulates EMT and cancer stemness in CRC.ResultsTM4SF1 expression was markedly higher in CRC tissues than in non-tumour tissues and was positively correlated with poor prognosis. Downregulation of TM4SF1 inhibited the migration, invasion and tumour sphere formation of SW480 and LoVo cells. Conversely, TM4SF1 overexpression significantly enhanced the migration, invasion and tumoursphere formation potential of CRC cells, Additionally, TM4SF1 silencing inhibited the EMT mediated by transforming growth factor-β1 (TGF-β1). Mechanistically, gene set enrichment analysis (GSEA) predicted that the Wnt signalling pathway was one of the most impaired pathways in TM4SF1-deficient CRC cells compared to controls. The results were further validated by WB, which revealed that TM4SF1 modulated SOX2 expression in a Wnt/β-catenin activation-dependent manner. Furthermore, we found that knockdown of TM4SF1 suppressed the expression of c-Myc, leading to decreased c-Myc binding to the SOX2 gene promoter. Finally, depletion of TM4SF1 inhibited metastasis and tumour growth in a xenograft mouse model.ConclusionOur study substantiates a novel mechanism by which TM4SF1 maintains cancer cell stemness and EMT via the Wnt/β-catenin/c-Myc/SOX2 axis during the recurrence and metastasis of CRC.

Dataset Information

TRAP1 regulates stemness through Wnt/?-catenin pathway in human colorectal carcinoma.

Publications

TRAP1 regulates stemness through Wnt/β-catenin pathway in human colorectal carcinoma.

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