The p53/microRNA connection in gastrointestinal cancer

Abstract

The protein encoded by the TP53 gene is one of the most important suppressors of tumor formation, which is also frequently inactivated in gastrointestinal cancer. MicroRNAs (miRNAs) are small noncoding RNAs that inhibit translation and/or promote degradation of their target messenger RNAs. In recent years, several miRNAs have been identified as mediators and regulators of p53’s tumor suppressing functions. p53 induces expression and/or maturation of several miRNAs, which leads to the repression of critical effector proteins. Furthermore, certain miRNAs regulate the expression and activity of p53 through direct repression of p53 or its regulators. Experimental findings indicate that miRNAs are important components of the p53 network. In addition, the frequent genetic and epigenetic alterations of p53-regulated miRNAs in tumors indicate that they play an important role in cancer initiation and/or progression. Therefore, p53-regulated miRNAs may represent attractive diagnostic and/or prognostic biomarkers. Moreover, restoration of p53-induced miRNAs results in suppression of tumor growth and metastasis in mouse models of cancer. Thus, miRNA-based therapeutics may represent a feasible strategy for future cancer treatment. Here we summarize the current published state-of-the-art on the role of the p53-miRNA connection in gastrointestinal cancer.

Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer

“…These small noncoding RNAs exert their action by binding to the 3′-untranslated region (3′-UTR) of their target mRNA resulting in degradation of mRNA from more than 60 % of human genes [67–69]. Depending on the cellular function of miRNAs targets, these molecules could be either an oncogene or a tumor suppressor gene [70].…”

The regulation of the p53/MDM2 feedback loop by microRNAs

“…Furthermore, overexpression of miR-504 promotes the tumorigenicity of colorectal cancer cells in xenograft tumor models in vivo in a largely p53-dependent manner [17] . In addition to miR-125b and miR-504, many other miRNAs that directly target p53 were reported to promote cancer cell proliferation through repressing the p53 mediated-apoptosis, cell cycle arrest and/or senescence [12, 18-20] . Many of these miRNAs have been reported to be overexpressed in different types of cancer, which can directly repress the p53 protein levels to impair the tumor suppressive function of p53 [12, 18, 19] .…”

“…In addition to the above-mentioned miRNAs that directly repress p53, a group of miRNAs has been identified to activate p53 by directly repressing MDM2, such as miR-192, miR-194, miR-215, miR-605, miR-25, miR-32, miR-17-3p, miR-143, miR-145, miR-661, miR-660, etc [12, 18, 21] . Almost all of these miRNAs have been demonstrated to be able to inhibit cancer cell proliferation through promoting the p53-mediated apoptosis, cell cycle arrest and/or senescence [12, 18, 21] .…”

“…Almost all of these miRNAs have been demonstrated to be able to inhibit cancer cell proliferation through promoting the p53-mediated apoptosis, cell cycle arrest and/or senescence [12, 18, 21] . Some of them were also reported to repress the migration and invasion of cancer cells and reverse epithelial-mesenchymal-transition (EMT) to inhibit cancer metastasis [22, 23] .…”

“…Interestingly, some of these miRNAs, such as miR192, miR-194, miR-215, miR-605, miR-143 and miR-145, were also identified to be the transcriptional targets of p53. These miRNAs form positive feedback loops with p53 and help to activate p53 especially under the condition of stress [12, 18, 21] .…”