Τίτλος:
Mutant p53 gain of function underlies high expression levels of colorectal cancer stem cells markers
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Emerging notion in carcinogenesis ascribes tumor initiation and aggressiveness to cancer stem cells (CSCs). Specifically, colorectal cancer (CRC) development was shown to be compatible with CSCs hypothesis. Mutations in p53 are highly frequent in CRC, and are known to facilitate tumor development and aggressiveness. Yet, the link between mutant p53 and colorectal CSCs is not well-established. In the present study, we set to examine whether oncogenic mutant p53 proteins may augment colorectal CSCs phenotype. By genetic manipulation of mutant p53 in several cellular systems, we demonstrated that mutant p53 enhances colorectal tumorigenesis. Moreover, mutant p53-expressing cell lines harbor larger sub-populations of cells highly expressing the known colorectal CSCs markers: CD44, Lgr5, and ALDH. This elevated expression is mediated by mutant p53 binding to CD44, Lgr5, and ALDH1A1 promoter sequences. Furthermore, ALDH1 was found to be involved in mutant p53-dependent chemotherapy resistance. Finally, analysis of ALDH1 and CD44 in human CRC biopsies indicated a positive correlation between their expression and the presence of oncogenic p53 missense mutations. These findings suggest novel insights pertaining the mechanism by which mutant p53 enhances CRC development, which involves the expansion of CSCs sub-populations within CRC tumors, and underscore the importance of targeting these sub-populations for CRC therapy. © 2018 The Author(s).
Συγγραφείς:
Solomon, H.
Dinowitz, N.
Pateras, I.S.
Cooks, T.
Shetzer, Y.
Molchadsky, A.
Charni, M.
Rabani, S.
Koifman, G.
Tarcic, O.
Porat, Z.
Kogan-Sakin, I.
Goldfinger, N.
Oren, M.
Harris, C.C.
Gorgoulis, V.G.
Rotter, V.
Εκδότης:
Nature Publishing Group
Λέξεις-κλειδιά:
aldehyde dehydrogenase; aldehyde dehydrogenase isoenzyme 1; cisplatin; Hermes antigen; protein p53; mutant protein; protein p53; TP53 protein, human; tumor marker, animal experiment; animal model; animal tissue; Article; cancer stem cell; carcinogenesis; colorectal cancer; colorectal cancer cell line; colorectal carcinoma; controlled study; drug resistance; gain of function mutation; gene sequence; genetic manipulation; human; human tissue; missense mutation; mouse; mutant; nonhuman; priority journal; promoter region; protein expression; animal; cancer stem cell; colorectal tumor; female; gene expression regulation; genetics; metabolism; nude mouse; physiology; transgenic mouse; tumor cell culture, Animals; Biomarkers, Tumor; Colorectal Neoplasms; Female; Gain of Function Mutation; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Mice, Transgenic; Mutant Proteins; Mutation, Missense; Neoplastic Stem Cells; Tumor Cells, Cultured; Tumor Suppressor Protein p53
DOI:
10.1038/s41388-017-0060-8
