Abstract
A widespread decrease of mature microRNAs is often observed in human malignancies giving them potential to act as tumor suppressors. Thus, microRNAs may be potential targets for cancer therapy. The global miRNA deregulation is often the result of defects in the miRNA biogenesis pathway, such as genomic mutation or aberrant expression/localization of enzymes and cofactors responsible of miRNA maturation. Alterations in the miRNA biogenesis machinery impact on the establishment and development of cancer programs. Accumulation of pri-microRNAs and corresponding depletion of mature microRNAs occurs in human cancers compared to normal tissues, strongly indicating an impairment of crucial steps in microRNA biogenesis. In agreement, inhibition of microRNA biogenesis, by depletion of Dicer1 and Drosha, tends to enhance tumorigenesis in vivo. The p53 tumor suppressor gene, TP53, is mutated in half of human tumors resulting in an oncogene with Gain-Of-Function activities. In this review we discuss recent studies that have underlined a role of mutant p53 (mutp53) on the global regulation of miRNA biogenesis in cancer. In particular we describe how a new transcriptionally independent function of mutant p53 in miRNA maturation, through a mechanism by which this oncogene is able to interfere with the Drosha processing machinery, generally inhibits miRNA processing in cancer and consequently impacts on carcinogenesis.
Highlights
MicroRNAs are small non coding singlestranded RNAs of about 20–25 nucleotides in length that regulate gene expression by binding to complementary target mRNAs and promoting their decay or inhibiting their translation [1–3]. 1881 human mirRNA loci, annotated on miRBase21, and an even greater number of predicted miRNA targets have been identified in the human genome
P68 (DDX5) and p72/p82 (DDX17) are prototypic members of the DEAD box protein family of RNA helicases. Both p68 and p72 are responsible for the processing of a subset of pri-miRNAs [38, 59] and acting as a bridge between Drosha and other proteins can impact on cancer development by regulating known oncogenes and tumor suppressors
In the 2015, Jiang FZ et al found that the overexpression of different mutp53 proteins (C135Y, R175H, R248Q, R273H) in p53-null endometrial carcinoma cell lines (HEC-50) disrupts p68-Drosha complex assembly and inhibits the recruitment of Drosha on pri-miRNA26a1 [56], confirming in part the results obtained by Suzuki on colon cancer cells [52]
Summary
MicroRNAs (miRNAs) are small non coding singlestranded RNAs of about 20–25 nucleotides in length that regulate gene expression by binding to complementary target mRNAs and promoting their decay or inhibiting their translation [1–3]. 1881 human mirRNA loci, annotated on miRBase21, and an even greater number of predicted miRNA targets have been identified in the human genome. Both p68 and p72 are responsible for the processing of a subset of pri-miRNAs [38, 59] and acting as a bridge between Drosha and other proteins can impact on cancer development by regulating known oncogenes and tumor suppressors.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Journal of Experimental & Clinical Cancer Research
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
