Open AccessCRKL oncogene is downregulated by p53 through miR‐200s
Author(s) -
Tamura Miyuki,
Sasaki Yasushi,
Kobashi Kenta,
Takeda Kousuke,
Nakagaki Takafumi,
Idogawa Masashi,
Tokino Takashi
Publication year - 2015
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12713
Subject(s) - downregulation and upregulation , oncogene , microrna , cancer research , cancer , biology , chemistry , gene , cell cycle , genetics
Tumor suppressive miRNAs that target oncogenes are frequently downregulated in cancers, and this downregulation leads to oncogene pathway activation. Thus, tumor suppressive miRNAs and their target oncogenes have been proposed as useful targets in cancer treatment. miR‐200 family downregulation has been reported in cancer progression and metastasis. T he miR‐200 family consists of two gene clusters, miR‐200b/200a/429 and miR‐200c/141, which are located on human chromosomes 1 and 12, respectively. Here, we identified that p53 response elements are located around both clusters of the miR‐200 family and confirmed that miR‐200s are transcriptional targets of the p53 family. In silico analyses of mi RNA targets established the CRKL oncogene as a potential target for miR‐200b/200c/429. Moreover, miR‐200b/200c/429 inhibited CRKL mRNA and protein expression by directly targeting its 3′‐ UTR region. Importantly, endogenous CRKL expression was decreased in cancer cells through the introduction of p53 family and endogenous p53 activation. Moreover, the downregulation of CRKL by si RNA inhibited cancer cell growth. The Oncomine database demonstrates that CRKL is overexpressed in a subset of cancer types. Furthermore, CRKL is significantly overexpressed in primary breast cancer tissues harboring mutant TP 53 . Our results demonstrate that the p53 target miR‐200b/200c/429 miRNAs are negative regulators of the CRKL oncogene.