Use of qPCR to Evaluate Efficiency of the Bulky DNA Damage Removal in Extracts of Mammalian Cells with Different Maximum Lifespan.

Proteins of nucleotide excision repair system (NER) are responsible for detecting and removing a wide range of bulky DNA damages, thereby contributing significantly to the genome stability maintenance within mammalian cells. Evaluation of NER functional status in the cells is important for identifying pathological changes in the body and assessing effectiveness of chemotherapy. The following method, described herein, has been developed for better assessment of bulky DNA damages removal in vitro, based on qPCR. Using the developed method, NER activity was compared for the extracts of the cells from two mammals with different lifespans: a long-lived naked mole-rat (Heterocephalus glaber) and a short-lived mouse (Mus musculus). Proteins of the H. glaber cell extract have been shown to be 1.5 times more effective at removing bulky damage from the model DNA substrate than the proteins of the M. musculus cell extract. These results are consistent with the experimental data previously obtained. The presented method could be applied not only in fundamental studies of DNA repair in mammalian cells, but also in clinical practice.

Comparative time-series multi-omics analyses suggest H1.2 involvement in anoxic adaptation and cancer resistance.

The naked mole rat (NMR), Heterocephalus glaber, is known as the longest-lived rodent and is extraordinarily resistant to hypoxia and cancer. Here, both NMR embryonic fibroblasts (NEFs) and their mouse counterparts (MEFs) were subjected to anoxic conditions (0% O2, 5% CO2). A combination of comparative transcriptomics and proteomics was then employed to identify differentially expressed genes (DEGs). Notably, we observed distinct levels of histone H1.2 (encoded by HIST1H1C) accumulation between NEFs and MEFs. Subsequent mechanistic analyses showed that higher H1.2 expression in NEFs was associated with the lower expression of its inhibitor, PARP1. Additionally, we discovered that H1.2 can directly interact with HIF-1α PAS domains, thereby promoting the expression of HIF-1α through facilitating the dimerization with HIF-1ß. The overexpression of H1.2 was also found to trigger autophagy and to suppress the migration of cancer cells, as well as the formation of xenograft tumors, via the NRF2/P62 signaling pathway. Moreover, an engineered H1.2 knock-in mouse model exhibited significantly extended survival in hypoxic conditions (4% O2) and showed a reduced rate of tumor formation. Collectively, our results indicate a potential mechanistic link between H1.2 and the dual phenomena of anoxic adaptation and cancer resistance.

Naked mole-rat TMEM2 lacks physiological hyaluronan-degrading activity.

Mouse transmembrane protein 2 (mTMEM2) has been identified as a hyaluronidase, which has extracellularly G8 and GG domains and PbH1 repeats; however, our previously study showed that human TMEM2 (hTMEM2) is not a catalytic hyaluronidase due to the absence of the critical amino acid residues (His248/Ala303) in the GG domain. Naked mole-rats (NMRs) accumulate abundant high-molecular weight hyaluronan (HA) in their tissues, suggesting decreased HA degradation. Therefore, we aimed to evaluate the HA-degrading activity of NMR TMEM2 (nmrTMEM2) and compare it with those of mTMEM2 and hTMEM2. The amino acid residues of nmrTMEM2 (Asn247/Val302) are similar to Asn248/Phe303 of hTMEM2, and nmrTMEM2-expressing HEK293T cells showed negligible activity. We confirmed the significance of these amino acid residues using an inactive chimeric TMEM2 with the human GG domain, which acquired catalytic activity when Asn248/Phe303 was substituted with His248/Ala303. Semi-quantitative comparison of the activities of the membrane-fractions derived from m/h/nmrTMEM2-expressing HEK293T cells revealed that at least 20- and 14-fold higher amounts of nmr/hTMEM2 were required to degrade HA to the same extent as by mTMEM2. Thus, unlike mTMEM2, nmrTMEM2 is not a physiological hyaluronidase. The inability of nmrTMEM2 to degrade HA might partially account for the high-molecular-weight HA accumulation in NMR tissues.

Patterns of Genetic Diversity and Gene Flow Associated With an Aridity Gradient in Populations of Common Mole-rats, Cryptomys hottentotus hottentotus.

Genetic adaptation is the change of a population toward a phenotype that best fits the present ecological conditions of the environment it inhabits. As environmental conditions change, allele frequencies shift, resulting in different populations of the same species possessing genetic variation and divergent phenotypes. Cooperatively breeding common mole-rats (Cryptomys hottentotus hottentotus) inhabit environments along an aridity gradient in South Africa, which provides an opportunity for local genetic adaptations to occur. Using one mitochondrial gene (cytochrome b) and 3,540 SNP loci across the whole genome, we determined the phylogenetic relationship, population structure and genetic diversity of five populations of C. h. hottentotus located along an aridity gradient. Mitochondrial data identified population-specific clades that were less distinct in the two mesic populations, potentially indicating historical or recent gene flow, or the retention of ancestral haplotypes. Arid and semi-arid populations formed a distinct cluster from the non-arid populations. Genetic diversity and gene flow were higher in arid-dwelling individuals, suggesting greater connectivity and interactions between colonies in arid regions in comparison to mesic ones. Using an Aridity Index, we determined that isolation by environment, rather than isolation by geographical distance, best explains the genetic distance between the populations. Further analyses using target loci may determine if there are differing underlying genetic adaptations among populations of C. h. hottentotus. These analyses could help unravel population differences in response to environmental factors within a subspecies of bathyergid mole-rat and determine the adaptive capacity of this small nonmigratory subterranean rodent species in response to aridification in the face of climate change.

Features of the CD1 gene family in rodents and the uniqueness of the immune system of naked mole-rat.

Cluster of Differentiation 1 (CD1) proteins are widely expressed throughout jawed vertebrates and present lipid antigens to specific CD1-restricted T lymphocytes. CD1 molecules play an important role in immune defense with the presence or absence of particular CD1 proteins frequently associated with the functional characteristics of the immune system. Here, we show the evolution of CD1 proteins in the Rodentia family and the diversity among its members. Based on the analysis of CD1 protein-coding regions in rodent genomes and the reconstruction of protein structures, we found that Heterocephalus glaber represents a unique member of the suborder Hystricomorpha with significant changes in protein sequences and structures of the CD1 family. Multiple lines of evidence point to the absence of CD1d and CD1e and probably a dysfunctional CD1b protein in Heterocephalus glaber. In addition, the impact of CD1d loss on the CD1d/Natural killer T (NKT) cell axis in the naked mole-rat and its potential implications for immune system function are discussed in detail.

Genetic diversity of the largest African mole-rat genus, Bathyergus. One, two or four species?

Recent advances in sequencing technology and phylogenetic methods allow us to solve puzzling taxonomic questions using detailed analyses of genetic diversity of populations and gene flow between them. The genus of solitary-living dune mole-rat, Bathyergus, is quite unique among six genera of African mole-rats. The animals are by far the largest and the only scratch digging mole-rat genus possessing a skull less adapted to digging, grooved upper incisors, and more surface locomotor activity. Most authors recognize two species of dune mole-rats, B. suillus and B. janetta, but according to others, the genus is monotypic. In addition, recent molecular studies have revealed cryptic genetic diversity and suggested the existence of up to four species. In our study, we used mitochondrial and genome-wide nuclear data collected throughout the distribution of the genus to investigate the number of species. In agreement with previous studies, we found Bathyergus to be differentiated into several distinct lineages, but we also found evidence for a degree of gene flow between some of them. Furthermore, we confirmed that B. janetta is nested within B. suillus, making the latter paraphyletic and we documented an instance of local mitochondrial introgression between these two nominal species. Phylogeographic structure of the genus was found to be very shallow. Although traditionally dated to the Miocene, we found the first split within the genus to be much younger estimated to 0.82 Ma before present. Genealogical distinctiveness of some lineages was very low, and the coancestry matrix showed extensive sharing of closely related haplotypes throughout the genus. Accordingly, Infomap clustering on the matrix showed all populations to form a single cluster. Overall, our study tends to support the existence of only one species of Bathyergus namely, B. suillus. Environmental niche modelling confirmed its dependence on sandy soils and the preference for soils with relatively high carbon content. Bayesian skyline plots indicate recent population decline in the janetta lineage, probably related to global environmental change.

Hypoxia-induced downregulation of RNA m6A protein machinery in the naked mole-rat heart.

Naked mole-rats, Heterocephalus glaber, are champion hypoxia-tolerant rodents that live under low oxygen conditions in their subterranean burrows. Detrimental effects of low oxygen can be mitigated through metabolic rate depression (MRD), metabolic reorganization, and global downregulation of nonessential cellular processes. Recent research has progressively implicated epigenetic modifications - rapid, reversible changes to gene expression that do not alter the DNA sequence itself - as major players in implementing and maintaining MRD. N6-adenosine (m6A) methylation is the most prevalent mammalian RNA modification and is responsible for pre-mRNA processing and mRNA export from the nucleus. Hence, m6A -mediated conformational changes alter the cellular fate of transcripts. The present study investigated the role of m6A RNA methylation responses to 24 h of hypoxia exposure in H. glaber cardiac tissue. Total protein levels of m6A writers/readers/erasers, m6A demethylase activity, and total m6A quantification were measured under normoxic vs. hypoxic conditions in H. glaber heart. While there was no change in either demethylase activity or total m6A content, many proteins of the m6A pathway were downregulated during hypoxia. Overall, m6A may not be a signature hypoxia-responsive characteristic in H. glaber heart, but downregulation of the protein machinery involved in m6A cycling points to an alternate biological involvement. Further research will explore other forms of RNA modifications and other epigenetic mechanisms to determine the controls on hypoxia endurance in this subterranean mammal.

[Evolution of cancer resistance in the animal kingdom]. / Évolution de la résistance au cancer dans le monde animal.

Cancer is an inevitable collateral problem inherent in the evolution of multicellular organisms, which appeared at the end of the Precambrian. Faced to this constraint, a range of diverse anticancer defenses has evolved across the animal kingdom. Today, investigating how animal organisms, especially those of large size and long lifespan, manage cancer-related issues has both fundamental and applied outcomes, as it could inspire strategies for preventing or treating human cancers. In this article, we begin by presenting the conceptual framework for understanding evolutionary theories regarding the development of anti-cancer defenses. We then present a number of examples that have been extensively studied in recent years, including naked mole rats, elephants, whales, placozoa, xenarthras (such as sloths, armadillos and anteaters) and bats. The contributions of comparative genomics to understanding evolutionary convergences are also discussed. Finally, we emphasize that natural selection has also favored anti-cancer adaptations aimed at avoiding mutagenic environments, for example by maximizing immediate reproductive efforts in the event of cancer. Exploring these adaptive solutions holds promise for identifying novel approaches to improve human health.

Title: Évolution de la résistance au cancer dans le monde animal. Abstract: Le cancer est un dommage collatéral inévitable inhérent à l'évolution des organismes multicellulaires, apparus à la fin du Précambrien. L'exploration de la manière dont les animaux, en particulier ceux de grande taille et de longue durée de vie, font face au cancer, comporte des enjeux à la fois fondamentaux et appliqués. Dans cet article, nous commençons par présenter le cadre conceptuel nécessaire pour comprendre les théories qui traitent de l'évolution des défenses anti-cancéreuses. Nous présentons ensuite un certain nombre d'exemples, notamment les rats-taupes nus, les éléphants, les baleines, les xénarthres (paresseux, tatous et fourmiliers), les chauves-souris et les placozoaires1. Les contributions de la génomique comparative à la compréhension des convergences évolutives sont également abordées. Enfin, nous indiquons que la sélection naturelle a également favorisé des adaptations visant à éviter les zones mutagènes, par exemple, ou à maximiser l'effort de reproduction immédiat en cas de cancer. L'exploration de ces solutions, intéressante conceptuellement, pourrait aussi permettre d'envisager de nouvelles approches thérapeutiques pour la santé humaine.

Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles.

The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, metabolomics and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57/BL6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57/BL6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span.

Evolutionary history and systematics of European blind mole rats (Rodentia: Spalacidae: Nannospalax): Multilocus phylogeny and species delimitation in a puzzling group.

Species delimitation is a powerful approach to assist taxonomic decisions in challenging taxa where species boundaries are hard to establish. European taxa of the blind mole rats (genus Nannospalax) display small morphological differences and complex chromosomal evolution at a shallow evolutionary divergence level. Previous analyses led to the recognition of 25 'forms' in their distribution area. We provide a comprehensive framework to improve knowledge on the evolutionary history and revise the taxonomy of European blind mole rats based on samples from all but three of the 25 forms. We sequenced two nuclear-encoded genetic regions and the whole mitochondrial cytochrome b gene for phylogenetic tree reconstructions using concatenation and coalescence-based species-tree estimations. The phylogenetic analyses confirmed that Aegean N. insularis belongs to N. superspecies xanthodon, and that it represents the second known species of this superspecies in Europe. Mainland taxa reached Europe from Asia Minor in two colonisation events corresponding to two superspecies-level taxa: N. superspecies monticola (taxon established herewith) reached Europe c. 2.1 million years ago (Mya) and was followed by N. superspecies leucodon (re-defined herewith) c. 1.5 Mya. Species delimitation allowed the clarification of the taxonomic contents of the above superspecies. N. superspecies monticola contains three species geographically confined to the western periphery of the distribution of blind mole rats, whereas N. superspecies leucodon is more speciose with six species and several additional subspecies. The observed geographic pattern hints at a robust peripatric speciation process and rapid chromosomal evolution. The present treatment is thus regarded as the minimum taxonomic content of each lineage, which can be further refined based on other sources of information such as karyological traits, crossbreeding experiments, etc. The species delimitation models also allowed the recognition of a hitherto unnamed blind mole rat taxon from Albania, described here as a new subspecies.

Evolution of high-molecular-mass hyaluronic acid is associated with subterranean lifestyle.

Hyaluronic acid is a major component of extracellular matrix which plays an important role in development, cellular response to injury and inflammation, cell migration, and cancer. The naked mole-rat (Heterocephalus glaber) contains abundant high-molecular-mass hyaluronic acid in its tissues, which contributes to this species' cancer resistance and possibly to its longevity. Here we report that abundant high-molecular-mass hyaluronic acid is found in a wide range of subterranean mammalian species, but not in phylogenetically related aboveground species. These subterranean mammalian species accumulate abundant high-molecular-mass hyaluronic acid by regulating the expression of genes involved in hyaluronic acid degradation and synthesis and contain unique mutations in these genes. The abundant high-molecular-mass hyaluronic acid may benefit the adaptation to subterranean environment by increasing skin elasticity and protecting from oxidative stress due to hypoxic conditions. Our work suggests that high-molecular-mass hyaluronic acid has evolved with subterranean lifestyle.

Integration of fluorescence in situ hybridization and chromosome-length genome assemblies revealed synteny map for guinea pig, naked mole-rat, and human.

Descriptions of karyotypes of many animal species are currently available. In addition, there has been a significant increase in the number of sequenced genomes and an ever-improving quality of genome assembly. To close the gap between genomic and cytogenetic data we applied fluorescent in situ hybridization (FISH) and Hi-C technology to make the first full chromosome-level genome comparison of the guinea pig (Cavia porcellus), naked mole-rat (Heterocephalus glaber), and human. Comparative chromosome maps obtained by FISH with chromosome-specific probes link genomic scaffolds to individual chromosomes and orient them relative to centromeres and heterochromatic blocks. Hi-C assembly made it possible to close all gaps on the comparative maps and to reveal additional rearrangements that distinguish the karyotypes of the three species. As a result, we integrated the bioinformatic and cytogenetic data and adjusted the previous comparative maps and genome assemblies of the guinea pig, naked mole-rat, and human. Syntenic associations in the two hystricomorphs indicate features of their putative ancestral karyotype. We postulate that the two approaches applied in this study complement one another and provide complete information about the organization of these genomes at the chromosome level.

Duplications of Human Longevity-Associated Genes Across Placental Mammals.

Natural selection has shaped a wide range of lifespans across mammals, with a few long-lived species showing negligible signs of ageing. Approaches used to elucidate the genetic mechanisms underlying mammalian longevity usually involve phylogenetic selection tests on candidate genes, detections of convergent amino acid changes in long-lived lineages, analyses of differential gene expression between age cohorts or species, and measurements of age-related epigenetic changes. However, the link between gene duplication and evolution of mammalian longevity has not been widely investigated. Here, we explored the association between gene duplication and mammalian lifespan by analyzing 287 human longevity-associated genes across 37 placental mammals. We estimated that the expansion rate of these genes is eight times higher than their contraction rate across these 37 species. Using phylogenetic approaches, we identified 43 genes whose duplication levels are significantly correlated with longevity quotients (False Discovery Rate (FDR) < 0.05). In particular, the strong correlation observed for four genes (CREBBP, PIK3R1, HELLS, FOXM1) appears to be driven mainly by their high duplication levels in two ageing extremists, the naked mole rat (Heterocephalus glaber) and the greater mouse-eared bat (Myotis myotis). Further sequence and expression analyses suggest that the gene PIK3R1 may have undergone a convergent duplication event, whereby the similar region of its coding sequence was independently duplicated multiple times in both of these long-lived species. Collectively, this study identified several candidate genes whose duplications may underlie the extreme longevity in mammals, and highlighted the potential role of gene duplication in the evolution of mammalian long lifespans.

Phylogenetic modeling of enhancer shifts in African mole-rats reveals regulatory changes associated with tissue-specific traits.

Changes in gene regulation are thought to underlie most phenotypic differences between species. For subterranean rodents such as the naked mole-rat, proposed phenotypic adaptations include hypoxia tolerance, metabolic changes, and cancer resistance. However, it is largely unknown what regulatory changes may associate with these phenotypic traits, and whether these are unique to the naked mole-rat, the mole-rat clade, or are also present in other mammals. Here, we investigate regulatory evolution in the heart and liver from two African mole-rat species and two rodent outgroups using genome-wide epigenomic profiling. First, we adapted and applied a phylogenetic modeling approach to quantitatively compare epigenomic signals at orthologous regulatory elements and identified thousands of promoter and enhancer regions with differential epigenomic activity in mole-rats. These elements associate with known mole-rat adaptations in metabolic and functional pathways and suggest candidate genetic loci that may underlie mole-rat innovations. Second, we evaluated ancestral and species-specific regulatory changes in the study phylogeny and report several candidate pathways experiencing stepwise remodeling during the evolution of mole-rats, such as the insulin and hypoxia response pathways. Third, we report nonorthologous regulatory elements overlap with lineage-specific repetitive elements and appear to modify metabolic pathways by rewiring of HNF4 and RAR/RXR transcription factor binding sites in mole-rats. These comparative analyses reveal how mole-rat regulatory evolution informs previously reported phenotypic adaptations. Moreover, the phylogenetic modeling framework we propose here improves upon the state of the art by addressing known limitations of inter-species comparisons of epigenomic profiles and has broad implications in the field of comparative functional genomics.

Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice.

Abundant high-molecular-mass hyaluronic acid (HMM-HA) contributes to cancer resistance and possibly to the longevity of the longest-lived rodent-the naked mole-rat1,2. To study whether the benefits of HMM-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHas2). nmrHas2 mice showed an increase in hyaluronan levels in several tissues, and a lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHas2 mice shifted towards that of longer-lived species. The most notable change observed in nmrHas2 mice was attenuated inflammation across multiple tissues. HMM-HA reduced inflammation through several pathways, including a direct immunoregulatory effect on immune cells, protection from oxidative stress and improved gut barrier function during ageing. These beneficial effects were conferred by HMM-HA and were not specific to the nmrHas2 gene. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exported to other species, and open new paths for using HMM-HA to improve lifespan and healthspan.

Chromosome-level Asian elephant genome assembly and comparative genomics of long-lived mammals reveal the common substitutions for cancer resistance.

The naked mole rat (Heterocephalus glaber), bats (e.g., genus Myotis), and elephants (family Elephantidae) are known as long-lived mammals and are assumed to be excellent cancer antagonists. However, whether there are common genetic changes underpinning cancer resistance in these long-lived species is yet to be fully established. Here, we newly generated a high-quality chromosome-level Asian elephant (Elephas maximus) genome and identified that the expanded gene families in elephants are involved in Ras-associated and base excision repair pathways. Moreover, we performed comparative genomic analyses of 12 mammals and examined genes with signatures of positive selection in elephants, naked mole rat, and greater horseshoe bat. Residues at positively selected sites of CDR2L and ALDH6A1 in these long-lived mammals enhanced the inhibition of tumor cell migration compared to those in short-lived relatives. Overall, our study provides a new genome resource and a preliminary survey of common genetic changes in long-lived mammals.

Comparative analysis of bats and rodents' genomes suggests a relation between non-LTR retrotransposons, cancer incidence, and ageing.

The presence in nature of species showing drastic differences in lifespan and cancer incidence has recently increased the interest of the scientific community. In particular, the adaptations and the genomic features underlying the evolution of cancer-resistant and long-lived organisms have recently focused on transposable elements (TEs). In this study, we compared the content and dynamics of TE activity in the genomes of four rodent and six bat species exhibiting different lifespans and cancer susceptibility. Mouse, rat, and guinea pig genomes (short-lived and cancer-prone organisms) were compared with that of naked mole rat (Heterocephalus glaber) which is a cancer-resistant organism and the rodent with the longest lifespan. The long-lived bats of the genera Myotis, Rhinolophus, Pteropus and Rousettus were instead compared with Molossus molossus, which is one of the organisms with the shortest lifespan among the order Chiroptera. Despite previous hypotheses stating a substantial tolerance of TEs in bats, we found that long-lived bats and the naked mole rat share a marked decrease of non-LTR retrotransposons (LINEs and SINEs) accumulation in recent evolutionary times.

Damage-Free Shortening of Telomeres Is a Potential Strategy Supporting Blind Mole-Rat Longevity.

Telomere shortening or loss of shelterin components activates DNA damage response (DDR) pathways, leading to a replicative senescence that is usually coupled with a senescence-associated secretory phenotype (SASP). Recent studies suggested that telomere aberration that activates DDR may occur, irrespective of telomere length or loss of shelterin complex. The blind mole-rat (Spalax) is a subterranean rodent with exceptional longevity, and its cells demonstrate an uncoupling of senescence and SASP inflammatory components. Herein, we evaluated Spalax relative telomere length, telomerase activity, and shelterin expression, along with telomere-associated DNA damage foci (TAFs) levels with cell passage. We show that telomeres shorten in Spalax fibroblasts similar to the process in rats, and that the telomerase activity is lower. Moreover, we found lower DNA damage foci at the telomeres and a decline in the mRNA expression of two shelterin proteins, known as ATM/ATR repressors. Although additional studies are required for understanding the underling mechanism, our present results imply that Spalax genome protection strategies include effective telomere maintenance, preventing early cellular senescence induced by persistent DDR, thereby contributing to its longevity and healthy aging.

Small RNA sequencing in hypoxic naked mole-rat hearts suggests microRNA regulation of RNA- and translation-related processes.

The naked mole-rat (Heterocephalus glaber) regularly endures intermittent periods of hypoxia in its burrows, surviving in part due to metabolic rate depression (MRD)-a strategy of conserving cellular resources by downregulating nonessential gene expression and reorganizing cellular processes. miRNA are short, noncoding RNAs already implicated for their roles in numerous models of extreme environmental stress; given their rapid, reversible nature, they are ideal for implementing MRD. We performed small RNA sequencing on cardiac tissue from normoxic versus 24 h hypoxic naked mole-rats, and used bioinformatics to predict 18 miRNAs which may be differentially regulated during hypoxia. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway mapping further suggest these miRNAs play roles in largely translation-related functions, including RNA processing and catabolism.

Carcinogenesis resistance in the longest-lived rodent, the naked mole-rat.

Certain mammalian species are resistant to cancer, and a better understanding of how this cancer resistance arises could provide valuable insights for basic cancer research. Recent technological innovations in molecular biology have allowed the study of cancer-resistant mammals, despite the fact that they are not the classical model animals, which are easily studied using genetic approaches. Naked mole-rats (NMRs; Heterocephalus glaber) are the longest-lived rodent, with a maximum lifespan of more than 37 years, and almost never show spontaneous carcinogenesis. NMRs are currently attracting much attention from aging and cancer researchers, and published studies on NMR have continued to increase over the past decade. Cancer development occurs via multiple steps and involves many biological processes. Recent research on the NMR as a model for cancer resistance suggests that they possess various unique carcinogenesis-resistance mechanisms, including efficient DNA repair pathways, cell-autonomous resistance to transformation, and dampened inflammatory response. Here, we summarize the molecular mechanisms of carcinogenesis resistance in NMR, which have been uncovered over the past two decades, and discuss future perspectives.