TRAP1 regulates stemness through Wnt/β-catenin pathway in human colorectal carcinoma.
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/β-catenin pathway. Mechanistically, TRAP1 maintenance of stemness is mediated by the regulation of Wnt/β-catenin signaling, through the modulation of the expression of frizzled receptor ligands and the control of β-catenin ubiquitination/phosphorylation. Remarkably, TRAP1 is associated with higher expression of β-catenin and several Wnt/β-catenin target genes in human CRCs, thus supporting the relevance of TRAP1 regulation of β-catenin in human pathology. This study is the first demonstration that TRAP1 regulates stemness and Wnt/β-catenin pathway in CRC and provides novel landmarks in cancer biology and therapeutics.
Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
Giacomo
G
Lettini
Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
Lorenza
L
Sisinni
Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
Valentina
V
Condelli
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
Danilo Swann
DS
Matassa
Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
Vittorio
V
Simeon
Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
Francesca
F
Maddalena
CEINGE, Biotecnologie Avanzate, University of Naples Federico II, Naples, Italy.
Marica
M
Gemei
Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
Elvira
E
Lopes
Pathology Unit, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
Giulia
G
Vita
CEINGE, Biotecnologie Avanzate, University of Naples Federico II, Naples, Italy.
Luigi
L
Del Vecchio
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
Franca
F
Esposito
Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.|Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
Matteo
M
Landriscina
D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000378:metabolism; D002999:Clone Cells; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D054875:Ubiquitination; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
D020410:Activated-Leukocyte Cell Adhesion Molecule; D018841:HSP90 Heat-Shock Proteins; C092306:TRAP1 protein, human; D051176:beta Catenin
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