Emerging roles of microRNAs as molecular switches in the integrated circuit of the cancer cell

Abstract

Transformation of normal cells into malignant tumors requires the acquisition of six hallmark traits, e.g., self-sufficiency in growth signals, insensitivity to antigrowth signals and self-renewal, evasion of apoptosis, limitless replication potential, angiogenesis, invasion, and metastasis, which are common to all cancers (Hanahan and Weinberg 2000). These new cellular traits evolve from defects in major regulatory microcircuits that are fundamental for normal homeostasis. The discovery of microRNAs (miRNAs) as a new class of small non-protein-coding RNAs that control gene expression post-transcriptionally by binding to various mRNA targets suggests that these tiny RNA molecules likely act as molecular switches in the extensive regulatory web that involves thousands of transcripts. Most importantly, accumulating evidence suggests that numerous microRNAs are aberrantly expressed in human cancers. In this review, we discuss the emergent roles of microRNAs as switches that function to turn on/off known cellular microcircuits. We outline recent compelling evidence that deregulated microRNAmediated control of cellular microcircuits cooperates with other well-established regulatory mechanisms to confer the hallmark traits of the cancer cell. Furthermore, these exciting insights into aberrant microRNA control in cancer-associated circuits may be exploited for cancer therapies that will target deregulated miRNA switches.

Phospho-ΔNp63α/microRNA network modulates epigenetic regulatory enzymes in squamous cell carcinomas

“…6,[12][13][14][15][16][17][74][75][76][77][78] Transcriptional regulation of gene expression, ultimately leading to activation or repression of target genes, involves many layers of control including activating mechanisms, such as demethylation of promoter DNA sequences, acetylation, or demethylation of histones, subsequently affecting chromatin remodeling and repression mechanisms, such as methylation of promoter DNA sequences and methylation or deacetylation of histones forming nucleosome structures around promoter sequences, and microRNA. 2,25,56,58,65,67,[79][80][81][82][83][84] Our current studies shed a light on the potential role for p-ΔNp63α/microRNA network in these epigenetic regulatory molecular layers, essentially leading to modulation of tumor cell response to chemotherapeutic drugs through cell cycle arrest and apoptosis.…”

“…and modulation of transcription factors (e.g., TP53 and TP63) has also started to emerge, creating a controlled feedback mechanism. 19,28,[76][77][78]85 The miR-29 family was shown to directly target DNMT3A and DNMT3B and indirectly target DNMT1 through regulation of the transactivator SP1 or RBL2, [86][87][88] while miR-148 and miR-140 were shown to target DNMT1 and DNMT3B. [89][90][91] miR-101 was shown to regulate the expression of EZH2, catalytic subunit of the polycomb repressive complex 2, which mediates epigenetic gene silencing by trimethylating histone H3 lysine 27.…”

A novel oncogenic role for the miRNA-506-514 cluster in initiating melanocyte transformation and promoting melanoma growth

“…Significant data have accumulated showing that dysregulated miRNAs act as oncogenes (onco-miRs) or tumor suppressors (TS-miRs) through their effects on various pathways critical to the cancer phenotype (Landais et al, 2007;Sotiropoulou et al, 2009;Segura et al, 2010). Multiple studies have characterized these dysregulated miRNAs in diverse cancer types, including melanoma (Lu et al, 2005;Felicetti et al, 2008;Mirnezami et al, 2009;Sotiropoulou et al, 2009).…”

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“…The microRNAs act posttranscriptionally in these organisms to reduce the levels of multiple target transcripts and their encoded proteins. 8,9 They also regulate major cellular functions, including cell proliferation, apoptosis, differentiation, timing of developmental transitions, and organ development. 10 Among a subset of microRNAs which were differentially expressed in the islets (islet/acinar ratio > 150), microRNA-7 was the most abundant in rat and human islets.…”