CRKL oncogene is downregulated by p53 through miR‐200s

Abstract

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. The 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 miRNA 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 siRNA 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 TP53 . Our results demonstrate that the p53 target miR-200b/200c/429 miRNAs are negative regulators of the CRKL oncogene.

Crk-like adapter protein is overexpressed in cervical carcinoma, facilitates proliferation, invasion and chemoresistance, and regulates Src and Akt signaling

“…Statistical analysis indicated that CrkL overexpression was correlated with advanced TNM grade and lymph node metastasis, suggesting its association with cervical cancer invasion. The present study revealed that CrkL is overexpressed in human cervical carcinoma and is associated with an advanced stage of disease, which is in accordance with previous data that confirmed CrkL as an oncogene (24–26). …”

“…The expression and biological functions of CrkL have been implicated in numerous types of human malignancy, including breast, lung, pancreatic and colorectal carcinomas (17,18,21,24). However, the involvement of CrkL in human cervical carcinoma has not been reported.…”

miR-193b–Regulated Signaling Networks Serve as Tumor Suppressors in Liposarcoma and Promote Adipogenesis in Adipose-Derived Stem Cells

“…CRKL is upregulated in numerous cancer types (29). However, there is limited knowledge of miRNA regulation of CRKL (29), and only four miRNAs (miR-126 and miR-200b/200c/429) were previously identified as direct regulators of CRKL (36,37). In liposarcoma cells, inhibition of CRKL and FAK significantly represses activation of FAK-SRC signaling, resulting in cell-cycle arrest and apoptosis.…”

The long noncoding RNA PCAT-1 links the microRNA miR-215 to oncogene CRKL-mediated signaling in hepatocellular carcinoma

“…CRKL encodes a protein kinase containing SH2 and SH3 domains, which has been shown to activate the RAS and JUN kinase signaling pathways. The kinase is vital in malignant transformation of multiple cancers, including HCC (25,26,28,42,43). Liu et al applied in situ proximity ligation assay and determined that the novel interaction, CRKL-FLT1, has a high centrality ranking, and the expression of this interaction is strongly correlated with the migratory ability of HCC.…”