Proceedings of the Singapore National Academy of Science

Iron is an essential nutrient required for normal cellular functions, growth, and proliferation. Iron homeostasis is maintained at the cellular and systemic levels by strict regulation of genes involved in the process of iron uptake, storage, export, and surveillance of iron levels. Cellular iron homeostasis is dysregulated in cancer to sustain rapid growth and proliferation. Cellular iron levels are increased in cancer by manipulating the expression of genes involved in iron metabolism. Recent studies show that a class of small non-coding RNA known as microRNA (miRNA) play a major role in the control of iron metabolism. This review summarizes the significance of iron in cancer prognosis and how miRNAs regulate the expression of genes involved in iron metabolism to increase the cellular iron availability in cancer.

Long non-coding RNA (lncRNA) is a new class of endogenous molecules identified in recent years. Studies on the cancer transcriptome have identified a number of lncRNAs with distinct expression patterns in different types of cancer, indicating that this populous group of molecules can modulate cancer progression. In addition, advances in revealing the molecular principles of cancer-associated lncRNAs made them amenable for therapeutic intervention. Although more than 50,000 lncRNAs have been identified, their functions in cellular homeostasis and pathophysiological processes remain largely uncharacterized. In this review, we summarize cancer-related lncRNAs that have been identified in recent years and discuss their mechanistic roles as oncogenes or tumor suppressors. These findings provide insights into clinical application of lncRNAs as biomarkers or therapeutic targets.

Primary myelofibrosis (PMF) is a pluripotent hematopoietic stem cell-derived malignancy, included in the heterogeneous group of myeloproliferative neoplasms (MPNs). PMF diagnosis is based on a composite assessment of clinical and laboratory data. The three major diagnostic criteria are: screening for driver mutations, exclusion of other conditions that can cause myelofibrosis, and bone marrow biopsy displaying megakaryocyte changes and fibrosis. PMF treatment options are only partially disease-modifying and consist mainly of symptom control. Recently, a new targeted therapy was introduced for PMF patients, JAK-STAT inhibitors (i.e. ruxolitinib). However, specific subgroups of patients do not benefit from the JAK-STAT inhibitors: (1) those who are carrying JAK2 mutations, but ruxolitinib does not reduce the spleen size; (2) triple negative patients (no JAK2, CALR, or MPL mutations); and (3) those who discontinue JAK-STAT therapy because of side effects. These subgroups are in need of new therapeutic approaches. Mature microRNAs (miRNAs) range from 16 to 28 nucleotides (nt) in length and regulate specific messenger RNAs at the post-transcriptional level. Numerous in vitro and in vivo studies have reported specific miRNAs, as well as complex miRNA networks, to be dysregulated in PMF. Several of these miRNAs were shown to be implicated in essential events of PMF pathophysiology: increase of bone marrow fibrosis, progression to acute myeloid leukemia, resistance to JAK-STAT inhibitors, and activation of differentiation of hematopoietic stem/progenitor cells into megakaryocytes. Hence, we propose miRNAs as a potential minimally invasive diagnostic tool for PMF and as therapeutic targets that could address the unmet medical needs of these patients.

Skin homeostasis is indispensable for terrestrial life. The skin, sitting at the interface between the dry external environment and the aqueous interior, acts as a barrier to delimit each from the other. Maintaining this barrier function is critical – if it is compromised, pathogen ingress and water loss may have potentially severe consequences. Skin function is supported by an intricate regulatory network incorporating both protein-coding genes as well as non-coding RNA transcripts. This review will focus on microRNAs, a subset of non-coding RNAs which target specific messenger RNAs for post-transcriptional repression. MicroRNAs regulate every aspect of skin biology, from initial cell fate determination during embryogenesis, to steady state keratinocyte maturation and barrier renewal, as well as coordination of the healing process in response to skin damage. An increased appreciation for the role of microRNAs in skin pathologies not only sheds light on the importance of these small RNAs in healthy skin function, but also provides an expanding repertoire of potential therapeutic targets through which these conditions may be addressed.

Mammalian skin appears simple. Its core function is to shield the body from the external environment. Water must be retained to sustain life, whilst harmful pathogens and other environmental insults must be kept out. This simplicity in function belies the array of intricate processes necessary to maintain the skin’s barrier function – multiple series of highly-ordered molecular and cellular events control constant epidermal rejuvenation, as well as rapid repair of any epithelial damage sustained. For internal homeostasis to be maintained, epithelial integrity is essential, and contingent upon precise spatiotemporal control of protein expression in the skin.

Numerous crosstalk interactions between RNA-binding proteins (RBPs) and microRNAs (miRNAs) have been recently reported, unveiling the complexity and importance of gene expression modulation in health and disease. They control physiological processes such as stem cell maintenance, neuronal development or energetic metabolism, but are also responsible for pathological conditions, such as muscle waste and dystrophies, atherosclerosis, obesity and cancer. MiRNAs and RBPs are two of the well-studied post-transcriptional regulators and they may even reciprocally regulate themselves. MiRNAs can act on RBPs expression while RBPs modulate miRNA biogenesis, function and degradation. RBPs and miRNAs modulate mRNA expression at different levels, affecting their stability, splicing and translation efficiency through either competition for overlapping binding or modulation of mRNA structure by binding, but several other forms of interaction have been described. In this review, we will address the current bibliography regarding miRNA:RBP interactions and crosstalk events as well as their implications in health and disease.

Melanoma is the most aggressive and deadly type of skin cancer and presents a major clinical challenge due to its ability to rapidly metastasize and become resistant to immune and targeted therapies. The identification and characterization of new molecular targets and pathways involved in the initiation, progression, and maintenance of melanoma will be critical for the development of superior treatments. Long non-coding RNAs (lncRNAs), a class of non-coding RNAs involved in regulating numerous cellular processes including tumor progression, cancer cell metastasis, and resistance to anti-cancer therapies, may be viable therapeutic targets in melanoma. In this review, we describe lncRNAs that contribute to melanoma development through microRNA (miRNA) sponging, regulation of metabolism, modification of the epigenome, or modulation of pro-tumorigenic signaling pathways. While more work remains to be done to characterize lncRNAs in melanoma, gaining a better understanding of their functions promises to yield a wide range of possibilities to improve melanoma diagnosis, prognosis, and treatment.