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A mutant KRAS‐induced factor REG4 promotes cancer stem cell properties via Wnt/β‐catenin signaling
Author(s) -
Hwang JeongHa,
Yoon Junyong,
Cho YongHee,
Cha PuHyeon,
Park JongChan,
Choi KangYell
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32728
Subject(s) - kras , wnt signaling pathway , cancer research , adenomatous polyposis coli , cancer stem cell , colorectal cancer , catenin , mutation , cancer , biology , signal transduction , microbiology and biotechnology , genetics , gene
Mutant KRAS provides a driving force for enhancement of cancer stem cells (CSCs) characteristics contributing transformation of colorectal cancer (CRC) cells harboring adenomatous polyposis coli ( APC ) mutations. Here, we identified the factors mediating the promotion of CSCs properties induced by KRAS mutation through microarray analyses of genes specifically induced in CRC spheroids harboring both KRAS and APC mutations. Among them, REG4 was identified as a key factor since CRISPR/Cas9‐mediated knockout of REG4 most significantly affected the stem cell characteristics in which CSCs markers were effectively suppressed. We show that REG4 mediates promotion of CSCs properties via Wnt/β‐catenin signaling in various in vitro studies including tumor organoid systems. Furthermore, expression patterns of CSCs markers and REG4 correlated in intestinal tumors from Apc min/+ /Kras G12D LA2 mice and in CRC patient tissues harboring both KRAS and APC mutations. The role of REG4 in the tumor‐initiating capacity accompanied by enhancement of CSCs characteristics was also revealed by NSG mice xenograft system. Collectively, our study highlights the importance of REG4 in promoting CSCs properties induced by KRAS mutation, and provides a new therapeutic strategy for CRC harboring both APC and KRAS mutations.