Frequently mutated oncogenes in various type of cancers
The main modifications that characterize cancer are represented by alterations in oncogenes, tumor-suppressor genes, and non-coding RNA genes. Most of these alterations are somatic and the process is a multistep one. Tumors often arise from an initial transformed cell, and after subsequent genetic alterations different cytogenetically clones lead to tumor heterogeneity.
- genomic instability
- epigenetic modification
The main modifications that characterize cancer are represented by alterations in oncogenes, tumor-suppressor genes, and non-coding RNA genes. Most of these alterations are somatic and the process is a multistep one, although germ-line mutations can predispose a person to heritable or familial cancer.
Tumors often arise from an initial transformed cell, and after subsequent genetic alterations different cytogenetically clones lead to tumor heterogeneity. Tumor heterogeneity determines different clinical phenotypes, leading to an individual response to treatment for tumors with the same diagnostic type.
Oncogenes encode proteins that control cell processes such as proliferation and apoptosis. Among these proteins are transcription factors, chromatin remodelers, growth factors, growth factor receptors, signal transducers, and apoptosis regulators. Activation of oncogenes by structural alterations (chromosomal rearrangement, gene fusion, mutation, and gene amplification) or epigenetic modification (gene promoter hypomethylation) confers an increased or a deregulated expression. Therefore, cells with such alterations possess a growth advantage or an increased survival rate. Translocations and mutations occur early on in tumor progression, whereas amplification usually occurs during late tumor stages.
A proto-oncogene is a normal gene that presents a potential to become an oncogene after a genetic alteration (mutation), leading to an increased expression. Usually, proto-oncogenes code for proteins that control cell growth and differentiation through signal transduction and execution of mitogenic signals. Upon activation, a proto-oncogene (or its product onco-protein) becomes a tumor-inducing agent. Most known examples of proto-oncogenes include
Oncogene products can comprise a variety of molecules such as transcription factors, chromatin remodelers, growth factors, growth factor receptors, signal transducers, and apoptosis regulators, each playing an important role in neoplastic transformation. For example, studies have shown that in prostate carcinomas the fusion between the
Mutations in an oncogene may lead to a change in the structure of encoded protein, enhancing its transforming activity. Oncogenes are activated by point mutations (substitutions) and may either enhance or degrade the function of a protein. Table 1 shows the occurrences of mutations in each oncogene among some tissues .
|T cell lymphoma||
|Acute lymphoblastic leukemia||
|Acute myeloid leukemia||
|Biliary tract cancer||
In cancer, mutations occur in many oncogenes, most notable being
BRAF is a protein member of the
There were identified mutations in hotspot codons (12, 13, and 61) of different
C-KIT gene encodes a receptor tyrosine kinase (KIT). All the mutations were founded in exon 11, 13, and 17. The most common is V559A mutation that results in an amino acid substitution at position 559 in KIT, from a valine (V) to an alanine (A) . While BRAF and NRAS mutations are common and significant in cutaneous melanomas, C-KIT mutations were detected in acral melanomas, mucosal melanomas, conjunctival melanomas, and cutaneous melanomas 
2.2. Colorectal cancer
The development of colorectal cancer (CRC) is a multistep process that occurs due to the accumulation of several genetic alterations, which are associated with oncogenes and tumor suppressor genes, as well as genes involved in DNA damage recognition and repair.
Most of the
In colorectal cancer,
2.3. Thyroid cancer
Activating point mutations of
There is a high correlation between the position of the point mutation and the phenotype of the disease. Three subtypes based on clinical presentation are defined: MEN 2A, MEN 2B, and FMTC.
2.4. Hepatocellular Carcinomas (HCC)
In HCC, only one mutation (
2.5. Pancreatic cancer
The highest incidence of
2.6. Cervical cancer
Cervical cancer harbors high rates of potentially targetable oncogenic mutations.
3. Gene amplification and chromosomal translocations
The interest regarding the role of genomic context in promoting amplification was intensely investigated, but is still under debate. An important interest remains to establish the tendency of some genomic region to be subject to amplification. Past researches showed that different regions of the genome were more subjected to be amplified than others, but the molecular substrate was unknown . At present, several mechanisms and models have been proposed to explain gene amplification in oncogenesis.
3.1. Gene amplification
Besides point mutations resulting in amino acid substitutions, a proto-oncogene may be activated by chromosomal alterations. Among the most important cromosomal abnormalities is gene amplification, which is an increase of the copy number for a specific chromosomal region. The consequence of chromosome fragment amplification is associated with overexpression of the amplified gene(s) and is a characteristic of cancer . Amplified genes (hundreds of copies of normally diploid genes) may be organized as extrachromosomal elements (double minute chromosomes) as repeated units at a single locus or scattered throughout the genome.
At this moment, the relationships between the two forms of gene amplification found in tumors, the intrachromosomal homogeneously staining regions (HSRs) and the extrachromosomal DNA molecules, double minutes (dmins), are not well understood .
Several models for initiation of amplification have been described involving defects in DNA replication or telomere dysfunction and chromosomal fragile sites. Regarding the DNA replication initial proposals, based on extra rounds of replication due to replication origins misfiring appear to be incorrect modification of models invoking replication of extrachromosomal DNA . Another theory involves the double-strand DNA breaks (frequent in replicating cells) generated by the collapse of replication forks that are unable to progress due to DNA structure lesions, therefore providing an opportunity to initiate the amplification process .
Telomeres are repetitive nucleotide sequences, with the role to prevent the loss of DNA sequences, resulted as a consequence of the incomplete DNA replication at the chromosome ends. Telomere shortening can block cell division; this mechanism appears to prevent genomic instability and development of cancer in aged cells by limiting the number of cell divisions . Telomerase is responsible for telomere replication and is inactive in most somatic cells. With every cell division, the DNA telomere sequence is shortened by 40–50 bp. Telomere shortening in humans can induce replicative senescence, which blocks cell division. When telomeres are short to a critical length (replicative limit), cellular senescence is induced and normal cells cease to proliferate. This mechanism appears to prevent genomic instability and development of cancer in aged cells by limiting the number of cell divisions. In cancer, tumor cells escape replicative limit and acquire the capability to maintain telomere length through cell divisions by telomerase reactivation, or by using a recombination-based mechanism and alternate lengthening of telomeres (ALT) [53, 54]. An experimental murine model (lacking the RNA component of telomerase-TercK/K mice) for telomere dysfunction demonstrated the promotion of gene amplification. Tumor genomes arising in mutant mice contain chromosomal rearrangements, amplifications, and deletions commonly associated with human tumors [55, 56]. Despite the established correlation between telomerase reactivation and telomeres lengthening in cancer, recent literature review and analysis  suggest this is unlikely, because shorter telomeres and telomerase inactivation is more often associated with increased cancer rates, and the mortality from cancer occurs late in life.
In humans, shorter telomeres were associated with poorer health and aging and were also observed in preneoplastic stages, supporting a role for this mechanism in generating genomic aberrations in oncogenesis [57–60]. The model for gene amplification due to telomere abnormalities and the break at fragile sites (discussed below) was first described in maize and results from the breakage/fusion/bridge (B/F/B) cycles . B/F/B cycles are initiated when broken ends of chromosomes fuse, resulting in a dicentric chromosome. During anaphase, the two centromeres are pulled in opposite directions and the dicentric chromosome generates a chromosome with an inverted duplication of terminal sequences to break. The B/F/B cycle continues in the next cell cycle because this chromosome also has broken ends. The B/F/B cycles were observed like primary mechanism for gene amplification in hamster cells .
In human cancer, evidence of B/F/B cycles was provided by the high frequency of anaphase bridges in early passage tumor cells and tumors [63, 64]. On the other hand, it was proven that human tumor cells in culture presenting gene amplification contain DM chromosomes, and the clones with low-copy amplification contained structures related to B/F/B cycles [65, 66]. There are evidences that B/F/B cycles may generate amplicons. These results were obtained by cytogenetic analyses of HSRs in tumor cell lines and in model systems with amplifications following drug treatments [67, 68]. The model explains that loss of the DNA sequences distal to the gene under selection or their translocation to another chromosome is also possible.
HSR may arise from the integration or fusion of double minute with a chromosome . Currently, the data available suggests that fusion and reintegration constitute a pathway for the evolution of extrachromosomal elements, but the site of HSR insertion has never been characterized at a nucleotide resolution .
3.2. Fragile sites
Fragile sites are part of normal chromosome structures existing in each individual and represent chromosome regions that are late in replicating and prone to breakage under conditions of replication stress. Fragile sites occur after partial inhibition of DNA synthesis and are constituted in regions presenting site-specific gaps and breaks on metaphase chromosomes. Common fragile sites are normally stable in somatic cells, but it was observed that following treatment of cultured cells with replication inhibitors, fragile sites display gaps, breaks, rearrangements [69, 70]. Fragile sites extend over large regions of high DNA flexibility and are associated with genes.
The molecular nature and mechanisms involved in fragile site instability was unknown till recently. In many cancer cells, fragile sites and associated genes suffer frequent deletions and/or rearrangement, demonstrating their role in genome instability during the oncogenesis process. As a group, fragile sites are heterogeneous and seem to extend over broad regions 0.3–9-Mb long. The regions comprising fragile site are particularly associated with a high frequency of recombinogenic events, including co-localization with chromosome aberrations sites related to various cancers .
Accordingly to several studies, there are around 127 known fragile sites in the human genome, defined as "common" or "rare" based on their frequency [71, 72]. Common fragile sites (CFSs) are a normal part of the human genome and are typically replicative stable . CFSs are not the result of nucleotide repeat expansion mutations. The majority of breakages at CFSs are further distinguished depending on their sensitivity to the drugs used to induce their expression (e.g., low doses of the antibiotic aphidocilin (APH)) .
The breakage effect of APH may be reduced by using a co-treatment with low concentrations of the topoisomerase I inhibitor and camptothecin (CPT) . CFS regions are highly conserved in vertebrate species, including mouse and primates [76–78]. CFSs initiate proper replication but slow to complete it, introducing breaks from unreplicated regions of DNA . The mechanism proposed for CFS instability resides in this late replication. Late replication may occur due to formation of non-B DNA structures such as hairpins and toroids that block the replication fork in AT rich regions .
Rare fragile sites (RFSs) are classified into two sub-groups based on the compounds that induce breakage, folate-sensitive groups and nonfolate-sensitive groups, which are sensitive at bromodeoxyuridine (BrdU) or distamycin A, an antibiotic that binds to AT-pairs of the DNA sequence. The folate-sensitive group is characterized by an expansion of CGG repeats, while the nonfolate-sensitive group contains many AT-rich minisatellite repeats [81–83]. The genome instability mechanism of CGG and AT-rich repeats characteristic for RFSs can form DNA structure (hairpins and other non-B DNA) replication forks, leading to breakage [84, 85]. On the other hand, it was demonstrated that DNA polymerase stops at CTG and CGG triplet repeat sequences, which can result in continuous DNA synthesis via slippage .
Fragile site regions are stable in normal cells and become unstable in tumor cells. The breakage of the fragile sites may be caused by mutations leading to a blockage of replication, or by a cell cycle perturbation and gene involved in the DNA repair process deregulation . Several reports developed the concepts that underlie the mechanisms leading to fragile site expression and chromosomal rearrangements at fragile sites in tumors. The analysis of DNA damage response in various tumor types, including bladder, breast, colorectal, and lung tumors, found that early stages of cancer development are associated with an active DNA damage response, including phosphorylated ATR (ataxia telangiectasia and Rad3-related protein), ATM (ataxia telangiectasia mutated), CHK1 (checkpoint kinases), CHK2 kinases, phosphorylated histone H2AX, and p53 [87-88].
These events are linked to a high frequency of LOH (loss of heterozygoty) at known fragile site regions. The explained mechanisms sustained that in precancerous lesions, the blockage or collapsed replication leads to ATR activation and with subsequent DNA double strand breaks. Tumor cells that escape apoptosis or cell cycle arrest will exhibit allelic imbalances, especially at target fragile sites because of replication sensitivity. Further, the model sustains the necessity of p53 mutation and/or other genes involved in checkpoints control, leading therefore to cancer progression. Lesions at common fragile sites are indicators of replication stress during early stages of tumorigenesis .
Fragile sites regions are targets for the initiation of the amplification process due to breakage. Several studies showed that boundaries of some amplicons generated through the amplification process mapped to common chromosomal fragile sites in hamster cells [89–90]. Evidences of the role of fragile sites in human cancer regarding gene amplification are scarce. One example of cell line model is for the
Aphidicolin-sensitive fragile sites FRA5D, FRA5F, and FRA5C, which map distal to dihydrofolate reductase gene (
3.3. Amplified genes in cancer
The amplification process is important for deciphering oncogenesis molecular biology, prognosis, and targeted therapies. A good example of gene amplification is dihydrofolate reductase gene (
In breast cancer,
Among the best-known oncogenes that are amplified in cancer cells is
In malignant thyroid tumors,
New data were acquired using array-CGH technique, bringing to knowledge the complex aspect of oncogene amplification in cancer. Using array-CGH analysis on identification of an 8p12 amplicon in anaplastic thyroid carcinoma (ATC) cell lines, six genes were found to be amplified,
In cervical cancer, the array-CGH technique revealed that the 3q26.3 amplification was the most consistent chromosomal aberration in primary tissues of cervical carcinoma, and an increased copy number of
In pancreatic cancer, chromosome 19q13 was found amplified containing
DNA amplification represents an important mechanism during human multistep hepatocarcinogenesis. Several genes were found to be amplified within 1q21 amplicon in hepatocellular carcinoma:
Amplification of the
3.4. Chromosomal translocations
Chromosomal translocations (CTs) are very common in human cancer, and the molecular mechanisms involved are complex and poorly understood. CTs are involved in several types of cancer, particularly in hematopoietic and lymphoid tumors . This type of chromosomal abnormality seems to provide a selective growth advantage for some stem or progenitor cells, which may further initiate the development of some malignant tumors. In case of oncogenes, CTs may change the original locations of proto-oncogenes, generating effects on the gene products through two major ways [122, 123]. One is to generate oncogenic fusion proteins and the other way is that proto-oncogenes are brought into proximity with regulatory elements, causing the overexpression of proto-oncogene.
The first specific chromosomal translocation identified in human cancer was the Philadelphia chromosome [t(9;22)], which underlies chronic myeloid leukemia (CML). The fusion of chromosomes 9 and 22 leads to the joining of two unrelated genes, the
A classic example is the overexpression of proto-oncogene c-MYC in Burkitt lymphoma due to t(8;14) that results in
The t(11;14) translocation juxtaposes
The ability to grow leukemic cells in culture long enough to allow cytogenetic analysis has facilitated the characterization of chromosomal translocations in leukemia. However, specific chromosomal translocations have also been observed in solid tumors. Aside from interchromosomal translocations, intrachromosomal translocations are also associated with cancer. Around 60–70% of PTCs have a characteristic inv(10)(q11.2q21). The breakpoint is represented by
It has been shown that in prostate carcinomas, the fusion between
The translocations of ETS are often found in human cancer, such as Ewing sarcoma [136–137], leukemia [138–139], prostate cancer , and breast cancer . These once disparate tumors are now defined by a chromosomal translocation fusing the EWS gene to a number of transcription factors of the ETS gene family (the most common chimeric protein is EWS-FLI1) . This chimeric product presumably acts directly on target promoters to direct the expression of genes that induce cellular proliferation. Identification of EWS translocations allowed the molecular grouping of a class of tumors whose proliferation is driven by similar genetic alterations and that respond to similar chemotherapeutic regimens.
4. Oncogene hypomethylation
The first epigenetic modification observed in human cancer was the loss of DNA methylation at the 5’citosine level (m5C residues replaced by unmethylated C residues), reported in 1983 . This discovery was often regarded as an unwelcome complication, and all of the attention was focused on the opposite effect hypermethylation of promoters of genes that are silenced in cancers (e.g., tumor-suppressor genes). Global hypomethylation of DNA in cancer was found associated especially with repeated DNA elements; this modification did not represent a research direction for many years . However, changes in the pattern of DNA methylation have been a consistent modification in cancer cells. Both hypo- and hypermethylation were observed at various loci, but at this moment it is clear that DNA methylation plays an important role in carcinogenesis.
New deep sequencing methylome analyses have shown much more cancer-linked hypomethylation of unique gene sequences and hypermethylation of repeated sequences than previously found [145–148]. Targeting DNA repetitive sequence, DNA hypomethylation may induce genomic instability and mutation events in cancer genomes [149–152] by altering the intranuclear positioning of chromatin enhancing recombination [153–155] and activating retroviral elements . Promoter hypomethylation of some genes may be associated with the development of cancer by regulating the activity of genes .
4.1. Genomic hypomethylation profiles in cancer
DNA methylation principally occurs at 5’ cytosine from dinucleotide CpG sites [158, 159]. CpG dinucleotides are found in C+G-rich regions in the genome termed CpG islands, localized frequently at promoter or gene regulatory level. However, the vast majority of CpG dinucleotides are localized within the intergenic and intronic regions of the DNA, particularly within repeat sequences and transposable elements. Unmethylated CpG islands at gene level are associated with gene transcription. In normal somatic cells, between 70% and 90% of CpG dinucleotides are methylated, which constitute approximately 0.75–1% of the total number of bases in the genome, while most CpG islands are unmethylated . A part of genes promoter region are methylated as part of normal developmental processes or tissue specific (e.g., germ-line specific genes-MAGE genes) . In X chromosomes in female dosage compensation (imprinted genes of X chromosomes in females), where only one of two copies is active, methylation of regulatory regions is involved in the repression of the expression of the silent loci .
Recently, high-resolution genome-wide analyses of DNA methylation changed the idea that considers oncogenesis being characterized predominantly of hypomethylated DNA repeats and hypermethylated gene regions [163–164]. The hallmark for cancer is represented by global losses of DNA methylation with local hypermethylation and hypomethylation of specific genes [165–167].
Evaluation of the majority of cancers showed that a major contributor to global DNA hypomethylation is hypomethylation of tandem and interspersed DNA repeats [165, 168]. Several studies using CpG methylation-sensitive restriction endonucleases or sodium bisulfite reported that hypomethylation was often found at gene sequence level (including metastasis-associated genes) [157, 165].
4.2. Hypomethylation of DNA repeats sequence in cancer
Repeat sequences are represented by transposable elements found interspersed throughout the genome, or simple repeat sequences, such as DNA satellites, found in pericentromeric or subtelomeric region of chromosomes. These are normally methylated within the healthy genome .
In cancer, hypomethylation of DNA repeats is a result of the demethylation process rather than the preexisting hypomethylation in a cancer stem cell . The frequency of cancer-associated hypomethylation of DNA repeats is dependent with disease progression (tumor grade, stage) [171, 172]. Hypomethylation is also seen in tumor adjacent tissues and in benign tumors (breast fibroadenomas and ovarian cystadenomas), but at a lower level than cancer [145, 165, 173, 174].
Hypomethylation may affect transcription and hypomethylation of interspersed DNA repeats within promoter modifies the chromatin boundaries resulting in transcription activation of nearby genes [175, 176]. Along with the effects upon transcription, hypomethylation can affect alternative splicing and hypomethylation of a minor portion of interspersed DNA repeats may occasionally cause induction of retroviral element transcription . Several studies reported numerous evidences for the causal relationships between DNA hypomethylation and increased transcription as well as hypomethylation and cancer [177–179].
Regions of cancer-associated changes in DNA methylation are found in short interspersed or clustered regions, as well as in long blocks [180–182]. Dante et al. described hypomethylation of LINE-1 (a highly repeated interspersed repeat) in mononuclear cells from patients with chronic lymphocytic leukemia . Along with hypomethylation of LINE-1, Alu repeats were also subsequently observed hypomethylated in many other types of cancers [183–186]. In breast adenocarcinomas, ovarian epithelial cancers, and Wilms tumors, a hypomethylation of centromeric and juxtacentromeric satellite DNA was noted [173, 174, 187]. Moreover, another classes of tandem repeats (macrosatellite DNAs) and segmental duplications were found hypomethylated in various cancers [188–190]. The loss of DNA methylation in cancer varies according to the tumor type and subclasses of DNA repeat [191–193].
Gathering the result of the presented studies, we may conclude that in many types of cancer, hypomethylation of DNA repeats represents a highly informative prognostic marker and/or predictor of survival [194–197].
4.3. Hypomethylation of DNA gene enhancer sequence in cancer
Gene expression levels may be further modulated by DNA methylation levels at upstream enhancer sites , which can affect the binding of transcription factors at (CpG) islands . In normal cells, DNA demethylation at enhancer’s level is correlated with upregulation of expression of the associated gene. It was shown that the binding of FoxA1/FOXA1 transcriptional factors to enhancers is inhibited by DNA methylation at the respective binding site . In this case, modification of DNA methylation status (demethylation) at the enhancer level may lead to an open chromatin state allowing the access of transcription factors at the active enhancer [201–202]. Following DNA demethylation, FoxD3 transcription factor binds at the enhancer level, allowing the recruitment of FoxA1 and conversion of the enhancer to a state that is set for activity. Local DNA demethylation leads also to changes in histone H3K27 or H3K9 methylation . FOXA1 is an important factor for oncogenesis being involved in various types of cancer . Thus, DNA hypomethylation from transcription regulatory regions may cause changes in expression .
4.4. Genomic hypomethylation in promoters and within gene bodies
Hypomethylation of transcription regulatory regions is less frequent than hypermethylation of CpG island promoters in cancer. Some of the gene regions (including transcription control sequences) were associated with loss of DNA methylation. Currently, there are data that sustain that promoter hypomethylation of some genes may be associated with the development of cancer, regulating the activity of genes . For example, promoter hypomethylation of specific immunity-related genes (e.g., cytokine IL-10) may activate the specific gene expression to inhibit the immune response in breast cancer , and the promoter hypomethylation of SPAN-Xb, an immunogenic antigen, can induce de novo B-cell response in myeloma cells . However, the biological significance of promoter hypomethylation in cancer is still poorly understood . Hypomethylation of gene promoters must cooperate with other key activators such as transcriptional factors to control gene expression [207, 208].
Promoters may overlap tissue-specific (T-DMR) or cancer-specific (C-DMR) differentially methylated DNA regions . Most of the non-imprinted, autosomal T-DMR promoters are not the main type of vertebrate DNA promoters, and the genes presenting T-DMR promoters become activated after experimentally induced demethylation 5-deoxyazacytidine .
Intragenic epigenetic marks have been also involved in normal gene expression regulation and inverse relationships between imprinted gene expression and DNA methylation level was observed . T-DMR regions were found not only inside many genes, but also in downstream promoters, flanking certain subsets of genes [211, 212]. Moreover, besides first exon, T-DMRs are also present at exonic and intronic sequences, insulators, intragenic ncRNA genes, and 3 ‘terminal regions [213, 214].
The role of these regions is to connect DNA and chromatin, inducing tissue-specific chromatin epigenetic marks inside genes [215, 216]. This relationship between DNA and chromatin modification at gene level may help determine alternative promoter usage, modulate the rate of transcription initiation or elongation, and direct the choice of alternative splice sites [217, 218]. For moderately expressed genes, DNA methylation level in the middle of the gene is correlated with higher transcription rates, being related to nucleosome positioning . In genes with CpG-poor promoters, methylated sequences located downstream binds Polycomb repressor complexes , which are being associated with repression of promoters .
On the other hand, certain histone modifications may direct the choice of splice junction through direct interactions with proteins that mark exon–intron junctions, altering rates of transcription and nucleosome positioning [221, 222]. As we mentioned before, DNA methylation may also be involved in regulating alternative splicing, intron–exon junctions being enriched in sharp transitions in DNA methylation levels  (e.g., malignant prostate cancer cells have enrichment of DNA hypermethylation at exon–intron junctions ). Therefore, these findings highlight the involvement of DNA methylation levels in determining alternative splicing in tumor cells, suggesting that cancer-associated DNA hypomethylation in intronic and exonic sequences can modulate the amount and type of gene products and thereby contribute to tumor formation or progression.
Gene encoding the protease urokinase (
DNA hypomethylation is closely associated with morphological dedifferentiation in thyroid cancers. Four oncogenes (
Hypomethylation and increased expression in cancer has been shown for
Hypomethylation and overexpression of some imprinted genes, including the
The putative oncogene,
Aberrant hypomethylation and overexpression of
Evidence is accumulating for the biological significance and clinical relevance of DNA hypomethylation in cancer and for cancer-linked demethylation, and those seem to be highly dynamic processes.
5. MicroRNA genes
At present, a special consideration is given to small non-coding RNA molecules (microRNA) to their functions and involvement in human diseases. There are an extensive number of studies that link microRNA alterations to cancer pathogenesis. MicroRNA genes encode for a single RNA strand of about 21 to 23 nucleotides, which regulate gene expression by specifically targeting certain mRNAs in order to prevent them from coding for a specific protein. Some microRNA genes are mapped in chromosomal regions that undergo rearrangements, deletions, and amplifications in cancer. A growing amount of data demonstrates that microRNA genes display a different pattern of expression in various malignancies; they are found up-regulated or down-regulated and therefore can function either as oncogenes activating the malignant transformation (by down-regulating tumor-suppressor genes), or as tumor-suppressor genes blocking the malignant transformation (by down-regulating oncogenes). In numerous types of cancers, many different microRNA have been shown to act as oncogenes, their expression profiling presenting specific signatures associated with malignant transformation. Cancer-associated microRNA molecules are also called oncomir (oncomiR).
The first microRNA that has been proven to act as oncogene in human cancer was
Along with the
Another important oncomir is represented by
A promising oncomir is also
Altogether, these studies illustrate a major role for microRNA genes in cancer pathogenesis (Table 2); many of them have oncogenic activity and could represent valuable biomarkers very useful for cancer screening or assessment of the therapeutic effects of anti-cancer treatments.
||Glioblastoma||Increase cell growth
Promote cell cycle
|Increase cell growth
|Promote cell growth
Promote cell migration
Promote tumor growth
|Promote cell invasion
|Cervix||Increase cell Proliferation
Increase cell migration
|Promote cell proliferation||
|Prostate||Promote epithelial-mesenchymal transition||
|Induce tumor angiogenesis
Activate AKT/ERK signaling
|Increase docetaxel resistance||
|Promote cell proliferation
Promote tumor growth
Promote cell motility
Promote cell invasion
|Blood||Promote cell migration
Promote cell growth
||Prostate||Promote cell cycle G1/S transition
Increase colony formation
|Breast||Increase cell migration
Increase cell invasion
|Increase tamoxifen resistance||
|Glioblastoma||Increase cell invasion||
|Promote cell proliferation
Promote cell invasion
|Thyroid||Promote cell transition to cell cycle S phase||
|Lung||Induce TRAIL resistance
Increase cell migration
||Blood||Increase cell proliferation
|Promote PI3K-AKT signaling||
|Increase cell proliferation||
|Reduce cell cycle arrest||
|Breast||Promote cell survival
|Promote cell proliferation
Promote tumor development
||Blood||Increase cell growth
Increase cell cycle G1/S transition
|Increase cell proliferation
Increase imatinib -induced cell death
|Retinoblastoma||Promote cell proliferation||
|Lung||Promote cell growth
Reduce reactive oxygen species (ROS) generation
||Breast||Activate TGF-beta signaling
Induce epithelial mesenchymal transition
Induce a tumor initiating cell phenotype
||Liver||Promote epithelial-mesenchymal transition
Increase cell migration
Increase cell invasion
|Promote cell proliferation
Promote tumor growth
|||6. Concluding remarks
Oncogene activation by structural alteration (chromosomal rearrangement, gene fusion, mutation, and gene amplification) or epigenetic modification (gene promoter hypomethylation, microRNA expression pattern) confers an increased or a deregulated expression. Therefore, cells with such alterations possess a growth advantage or an increased survival rate. Given the fact that expression profiling of these alterations determines specific signatures associated with tumor classification, diagnosis, staging, prognosis and response to treatment, it highlights the importance of studying oncogenes activation mechanisms and the great potential that they hold as therapeutic tools in the near future.
This work was supported by Romanian Research Grant PCCA135/2012 and POSDRU/159/1.5 /S/135760
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