The Double-Edged Role of Noncanonical Oncogenes and Tumor Suppressor Genes in Cancer Progression; An Oncojanus Function

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 December 2017) | Viewed by 79387

Special Issue Editors

Dept. of Medical and Surgical Sciences, Unit of Medical Genetics, Pol. S.Orsola-Malpighi, University of Bologna, via Massarenti 9, 40138, Bologna, Italy
University of Bologna, Italy, Dept. of Pharmacy and Biotechnology- FABIT, via Selmi 3, 40126, Bologna, Italy

Special Issue Information

Dear Colleagues,

Current research in oncology is uncovering diverse properties of genes involved in cancer development and progression. An increasing number of genes and proteins appear to play prominent roles in one or more of the hallmarks of cancer depicted by Hanahan and Weinberg. To further complicate the already intricate pathway deregulation occurring in cancer cells, many genes in tumorigenesis have opposite effects on cancer progression according to the context and even to the type of mutations that they acquire, not to mention the gene dosage. This field of genetic oncology is relatively novel and requires a revisiting of the canonical concepts of oncogene and tumor suppressor gene. The roles of autophagy genes; AMPK; isocitrate dehydrogenase; metabolic enzymes such as respiratory complex I; and even the well-known pleiotropic p53 ought to be gauged carefully in the balance between cancer promotion and inhibition. The Special Issue will collect contributions from experts in genes and proteins whose role in cancer progression has been ascertained, but remains controversial in terms of whether they play a pro- or an anti-tumorigenic role, likely depending on the genetic background, microenvironmental pressures, and stages of tumorigenesis. This is particularly true for genes that are involved in the reprogramming of cancer metabolism, although oncojanus features have been described for other genes as well. In this Special Issue, each contribution will deal specifically with one gene or with a family of closely related genes/proteins (for autophagy, for instance), and illustrate their dualistic role in cancer.

Prof. Giuseppe Gasparre
Prof. Anna Maria Porcelli
Guest Editors

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Keywords

  • cancer progression

  • cancer metabolism

  • mitochondrial DNAoncogenes

  • tumor suppressor genes

  • oncojanus genes

Published Papers (11 papers)

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Review

18 pages, 2253 KiB  
Review
The Oncojanus Paradigm of Respiratory Complex I
by Giulia Leone, Houda Abla, Giuseppe Gasparre, Anna Maria Porcelli and Luisa Iommarini
Genes 2018, 9(5), 243; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9050243 - 07 May 2018
Cited by 18 | Viewed by 4794
Abstract
Mitochondrial respiratory function is now recognized as a pivotal player in all the aspects of cancer biology, from tumorigenesis to aggressiveness and chemotherapy resistance. Among the enzymes that compose the respiratory chain, by contributing to energy production, redox equilibrium and oxidative stress, complex [...] Read more.
Mitochondrial respiratory function is now recognized as a pivotal player in all the aspects of cancer biology, from tumorigenesis to aggressiveness and chemotherapy resistance. Among the enzymes that compose the respiratory chain, by contributing to energy production, redox equilibrium and oxidative stress, complex I assumes a central role. Complex I defects may arise from mutations in mitochondrial or nuclear DNA, in both structural genes or assembly factors, from alteration of the expression levels of its subunits, or from drug exposure. Since cancer cells have a high-energy demand and require macromolecules for proliferation, it is not surprising that severe complex I defects, caused either by mutations or treatment with specific inhibitors, prevent tumor progression, while contributing to resistance to certain chemotherapeutic agents. On the other hand, enhanced oxidative stress due to mild complex I dysfunction drives an opposite phenotype, as it stimulates cancer cell proliferation and invasiveness. We here review the current knowledge on the contribution of respiratory complex I to cancer biology, highlighting the double-edged role of this metabolic enzyme in tumor progression, metastasis formation, and response to chemotherapy. Full article
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12 pages, 3197 KiB  
Review
TRAP1 Regulation of Cancer Metabolism: Dual Role as Oncogene or Tumor Suppressor
by Danilo Swann Matassa, Ilenia Agliarulo, Rosario Avolio, Matteo Landriscina and Franca Esposito
Genes 2018, 9(4), 195; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9040195 - 05 Apr 2018
Cited by 62 | Viewed by 6604
Abstract
Metabolic reprogramming is an important issue in tumor biology. An unexpected inter- and intra-tumor metabolic heterogeneity has been strictly correlated to tumor outcome. Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a molecular chaperone involved in the regulation of energetic metabolism in cancer [...] Read more.
Metabolic reprogramming is an important issue in tumor biology. An unexpected inter- and intra-tumor metabolic heterogeneity has been strictly correlated to tumor outcome. Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a molecular chaperone involved in the regulation of energetic metabolism in cancer cells. This protein is highly expressed in several cancers, such as glioblastoma, colon, breast, prostate and lung cancers and is often associated with drug resistance. However, TRAP1 is also downregulated in specific tumors, such as ovarian, bladder and renal cancers, where its lower expression is correlated with the worst prognoses and chemoresistance. TRAP1 is the only mitochondrial member of the Heat Shock Protein 90 (HSP90) family that directly interacts with respiratory complexes, contributing to their stability and activity but it is still unclear if such interactions lead to reduced or increased respiratory capacity. The role of TRAP1 is to enhance or suppress oxidative phosphorylation; the effects of such regulation on tumor development and progression are controversial. These observations encourage the study of the mechanisms responsible for the dualist role of TRAP1 as an oncogene or oncosuppressor in specific tumor types. In this review, TRAP1 puzzling functions were recapitulated with a special focus on the correlation between metabolic reprogramming and tumor outcome. We wanted to investigate whether metabolism-targeting drugs can efficiently interfere with tumor progression and whether they might be combined with chemotherapeutics or molecular-targeted agents to counteract drug resistance and reduce therapeutic failure. Full article
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17 pages, 4203 KiB  
Review
CD99: A Cell Surface Protein with an Oncojanus Role in Tumors
by Maria Cristina Manara, Michela Pasello and Katia Scotlandi
Genes 2018, 9(3), 159; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9030159 - 13 Mar 2018
Cited by 49 | Viewed by 9310
Abstract
The cell surface molecule CD99 has gained interest because of its involvement in regulating cell differentiation and adhesion/migration of immune and tumor cells. However, the molecule plays an intriguing and dual role in different cell types. In particular, it acts as a requirement [...] Read more.
The cell surface molecule CD99 has gained interest because of its involvement in regulating cell differentiation and adhesion/migration of immune and tumor cells. However, the molecule plays an intriguing and dual role in different cell types. In particular, it acts as a requirement for cell malignancy or as an oncosuppressor in tumors. In addition, the gene encodes for two different isoforms, which also act in opposition inside the same cell. This review highlights key studies focusing on the dual role of CD99 and its isoforms and discusses major critical issues, challenges, and strategies for overcoming those challenges. The review specifically underscores the properties that make the molecule an attractive therapeutic target and identifies new relationships and areas of study that may be exploited. The elucidation of the spatial and temporal control of the expression of CD99 in normal and tumor cells is required to obtain a full appreciation of this molecule and its signaling. Full article
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20 pages, 1149 KiB  
Review
Dynamin-Related Protein 1 at the Crossroads of Cancer
by Ana Rita Lima, Liliana Santos, Marcelo Correia, Paula Soares, Manuel Sobrinho-Simões, Miguel Melo and Valdemar Máximo
Genes 2018, 9(2), 115; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9020115 - 21 Feb 2018
Cited by 65 | Viewed by 8246
Abstract
Mitochondrial dynamics are known to have an important role in so-called age-related diseases, including cancer. Mitochondria is an organelle involved in many key cellular functions and responds to physiologic or stress stimuli by adapting its structure and function. Perhaps the most important structural [...] Read more.
Mitochondrial dynamics are known to have an important role in so-called age-related diseases, including cancer. Mitochondria is an organelle involved in many key cellular functions and responds to physiologic or stress stimuli by adapting its structure and function. Perhaps the most important structural changes involve mitochondrial dynamics (fission and fusion), which occur in normal cells as well as in cells under dysregulation, such as cancer cells. Dynamin-related protein 1 (DRP1), a member of the dynamin family of guanosine triphosphatases (GTPases), is the key component of mitochondrial fission machinery. Dynamin-related protein 1 is associated with different cell processes such as apoptosis, mitochondrial biogenesis, mitophagy, metabolism, and cell proliferation, differentiation, and transformation. The role of DRP1 in tumorigenesis may seem to be paradoxical, since mitochondrial fission is a key mediator of two very different processes, cellular apoptosis and cell mitosis. Dynamin-related protein 1 has been associated with the development of distinct human cancers, including changes in mitochondrial energetics and cellular metabolism, cell proliferation, and stem cell maintenance, invasion, and promotion of metastases. However, the underlying mechanism for this association is still being explored. Herein, we review the published knowledge on the role of DRP1 in cancer, exploring its interaction with different biological processes in the tumorigenesis context. Full article
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14 pages, 769 KiB  
Review
Glutamine Synthetase: Localization Dictates Outcome
by Alessandra Castegna and Alessio Menga
Genes 2018, 9(2), 108; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9020108 - 19 Feb 2018
Cited by 37 | Viewed by 7834
Abstract
Glutamine synthetase (GS) is the adenosine triphosphate (ATP)-dependent enzyme that catalyses the synthesis of glutamine by condensing ammonium to glutamate. In the circulatory system, glutamine carries ammonia from muscle and brain to the kidney and liver. In brain reduction of GS activity has [...] Read more.
Glutamine synthetase (GS) is the adenosine triphosphate (ATP)-dependent enzyme that catalyses the synthesis of glutamine by condensing ammonium to glutamate. In the circulatory system, glutamine carries ammonia from muscle and brain to the kidney and liver. In brain reduction of GS activity has been suggested as a mechanism mediating neurotoxicity in neurodegenerative disorders. In cancer, the delicate balance between glutamine synthesis and catabolism is a critical event. In vitro evidence, confirmed in vivo in some cases, suggests that reduced GS activity in cancer cells associates with a more invasive and aggressive phenotype. However, GS is known to be highly expressed in cells of the tumor microenvironment, such as fibroblasts, adipocytes and immune cells, and their ability to synthesize glutamine is responsible for the acquisition of protumoral phenotypes. This has opened a new window into the complex scenario of the tumor microenvironment, in which the balance of glutamine consumption versus glutamine synthesis influences cellular function. Since GS expression responds to glutamine starvation, a lower glutamine synthesizing power due to the absence of GS in cancer cells might apply a metabolic pressure on stromal cells. This event might push stroma towards a GS-high/protumoral phenotype. When referred to stromal cells, GS expression might acquire a ‘bad’ significance to the point that GS inhibition might be considered a conceivable strategy against cancer metastasis. Full article
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18 pages, 695 KiB  
Review
RhoB: Team Oncogene or Team Tumor Suppressor?
by Julia A. Ju and Daniele M. Gilkes
Genes 2018, 9(2), 67; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9020067 - 30 Jan 2018
Cited by 44 | Viewed by 6556
Abstract
Although Rho GTPases RhoA, RhoB, and RhoC share more than 85% amino acid sequence identity, they play very distinct roles in tumor progression. RhoA and RhoC have been suggested in many studies to contribute positively to tumor development, but the role of RhoB [...] Read more.
Although Rho GTPases RhoA, RhoB, and RhoC share more than 85% amino acid sequence identity, they play very distinct roles in tumor progression. RhoA and RhoC have been suggested in many studies to contribute positively to tumor development, but the role of RhoB in cancer remains elusive. RhoB contains a unique C-terminal region that undergoes specific post-translational modifications affecting its localization and function. In contrast to RhoA and RhoC, RhoB not only localizes at the plasma membrane, but also on endosomes, multivesicular bodies and has even been identified in the nucleus. These unique features are what contribute to the diversity and potentially opposing functions of RhoB in the tumor microenvironment. Here, we discuss the dualistic role that RhoB plays as both an oncogene and tumor suppressor in the context of cancer development and progression. Full article
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19 pages, 703 KiB  
Review
PGC1α: Friend or Foe in Cancer?
by Francesca Mastropasqua, Giulia Girolimetti and Maria Shoshan
Genes 2018, 9(1), 48; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9010048 - 22 Jan 2018
Cited by 62 | Viewed by 6911
Abstract
The PGC1 family (Peroxisome proliferator-activated receptor γ (PPARγ) coactivators) of transcriptional coactivators are considered master regulators of mitochondrial biogenesis and function. The PGC1α isoform is expressed especially in metabolically active tissues, such as the liver, kidneys and brain, and responds to energy-demanding situations. [...] Read more.
The PGC1 family (Peroxisome proliferator-activated receptor γ (PPARγ) coactivators) of transcriptional coactivators are considered master regulators of mitochondrial biogenesis and function. The PGC1α isoform is expressed especially in metabolically active tissues, such as the liver, kidneys and brain, and responds to energy-demanding situations. Given the altered and highly adaptable metabolism of tumor cells, it is of interest to investigate PGC1α in cancer. Both high and low levels of PGC1α expression have been reported to be associated with cancer and worse prognosis, and PGC1α has been attributed with oncogenic as well as tumor suppressive features. Early in carcinogenesis PGC1α may be downregulated due to a protective anticancer role, and low levels likely reflect a glycolytic phenotype. We suggest mechanisms of PGC1α downregulation and how these might be connected to the increased cancer risk that obesity is now known to entail. Later in tumor progression PGC1α is often upregulated and is reported to contribute to increased lipid and fatty acid metabolism and/or a tumor cell phenotype with an overall metabolic plasticity that likely supports drug resistance as well as metastasis. We conclude that in cancer PGC1α is neither friend nor foe, but rather the obedient servant reacting to metabolic and environmental cues to benefit the tumor cell. Full article
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Graphical abstract

23 pages, 3817 KiB  
Review
NF-kappaB: Two Sides of the Same Coin
by Bruno R. B. Pires, Rafael C. M. C. Silva, Gerson M. Ferreira and Eliana Abdelhay
Genes 2018, 9(1), 24; https://0-doi-org.brum.beds.ac.uk/10.3390/genes9010024 - 09 Jan 2018
Cited by 164 | Viewed by 11358
Abstract
Nuclear Factor-kappa B (NF-κB) is a transcription factor family that regulates a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. More recently, constitutive expression of NF-κB has been associated with several types of cancer. [...] Read more.
Nuclear Factor-kappa B (NF-κB) is a transcription factor family that regulates a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. More recently, constitutive expression of NF-κB has been associated with several types of cancer. In addition, microorganisms, such as viruses and bacteria, cooperate in the activation of NF-κB in tumors, confirming the multifactorial role of this transcription factor as a cancer driver. Recent reports have shown that the NF-κB signaling pathway should receive attention for the development of therapies. In addition to the direct effects of NF-κB in cancer cells, it might also impact immune cells that can both promote or prevent tumor development. Currently, with the rise of cancer immunotherapy, the link among immune cells, inflammation, and cancer is a major focus, and NF-κB could be an important regulator for the success of these therapies. This review discusses the contrasting roles of NF-κB as a regulator of pro- and antitumor processes and its potential as a therapeutic target. Full article
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1151 KiB  
Review
Context-Dependent Role of IKKβ in Cancer
by Angustias Page, Manuel Navarro, Cristian Suárez-Cabrera, Ana Bravo and Angel Ramirez
Genes 2017, 8(12), 376; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8120376 - 08 Dec 2017
Cited by 18 | Viewed by 4823
Abstract
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) is a kinase principally known as a positive regulator of the ubiquitous transcription factor family Nuclear Factor-kappa B (NF-κB). In addition, IKKβ also phosphorylates a number of other proteins that regulate many cellular processes, [...] Read more.
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) is a kinase principally known as a positive regulator of the ubiquitous transcription factor family Nuclear Factor-kappa B (NF-κB). In addition, IKKβ also phosphorylates a number of other proteins that regulate many cellular processes, from cell cycle to metabolism and differentiation. As a consequence, IKKβ affects cell physiology in a variety of ways and may promote or hamper tumoral transformation depending on hitherto unknown circumstances. In this article, we give an overview of the NF-κB-dependent and -independent functions of IKKβ. We also summarize the current knowledge about the relationship of IKKβ with cellular transformation and cancer, obtained mainly through the study of animal models with cell type-specific modifications in IKKβ expression or activity. Finally, we describe the most relevant data about IKKβ implication in cancer obtained from the analysis of the human tumoral samples gathered in The Cancer Genome Atlas (TCGA) and the Catalogue of Somatic Mutations in Cancer (COSMIC). Full article
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786 KiB  
Review
Dualistic Role of BARD1 in Cancer
by Flora Cimmino, Daniela Formicola and Mario Capasso
Genes 2017, 8(12), 375; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8120375 - 08 Dec 2017
Cited by 40 | Viewed by 6296
Abstract
BRCA1 Associated RING Domain 1 (BARD1) encodes a protein which interacts with the N-terminal region of BRCA1 in vivo and in vitro. The full length (FL) BARD1 mRNA includes 11 exons and encodes a protein comprising of six domains (N-terminal RING-finger domain, three [...] Read more.
BRCA1 Associated RING Domain 1 (BARD1) encodes a protein which interacts with the N-terminal region of BRCA1 in vivo and in vitro. The full length (FL) BARD1 mRNA includes 11 exons and encodes a protein comprising of six domains (N-terminal RING-finger domain, three Ankyrin repeats and two C-terminal BRCT domains) with different functions. Emerging data suggest that BARD1 can have both tumor-suppressor gene and oncogene functions in tumor initiation and progression. Indeed, whereas FL BARD1 protein acts as tumor-suppressor with and without BRCA1 interactions, aberrant splice variants of BARD1 have been detected in various cancers and have been shown to play an oncogenic role. Further evidence for a dualistic role came with the identification of BARD1 as a neuroblastoma predisposition gene in our genome wide association study which has demonstrated that single nucleotide polymorphisms in BARD1 can correlate with risk or can protect against cancer based on their association with the expression of FL and splice variants of BARD1. This review is an overview of how BARD1 functions in tumorigenesis with opposite effects in various types of cancer. Full article
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1582 KiB  
Review
TRIM8: Making the Right Decision between the Oncogene and Tumour Suppressor Role
by Mariano Francesco Caratozzolo, Flaviana Marzano, Francesca Mastropasqua, Elisabetta Sbisà and Apollonia Tullo
Genes 2017, 8(12), 354; https://0-doi-org.brum.beds.ac.uk/10.3390/genes8120354 - 28 Nov 2017
Cited by 22 | Viewed by 5766
Abstract
The TRIM8/GERP protein is a member of the TRIM family defined by the presence of a common domain structure composed of a tripartite motif including a RING-finger, one or two B-box domains, and a coiled-coil motif. The TRIM8 gene maps on chromosome 10 [...] Read more.
The TRIM8/GERP protein is a member of the TRIM family defined by the presence of a common domain structure composed of a tripartite motif including a RING-finger, one or two B-box domains, and a coiled-coil motif. The TRIM8 gene maps on chromosome 10 within a region frequently found deleted and rearranged in tumours and transcribes a 3.0-kB mRNA. Its expression is mostly ubiquitously in murine and human tissues, and in epithelial and lymphoid cells, it can be induced by IFNγ. The protein spans 551 aa and is highly conserved during evolution. TRIM8 plays divergent roles in many biological processes, including important functions in inflammation and cancer through regulating various signalling pathways. In regulating cell growth, TRIM8 exerts either a tumour suppressor action, playing a prominent role in regulating p53 tumour suppressor activity, or an oncogene function, through the positive regulation of the NF-κB pathway. The molecular mechanisms underlying this dual role in human cancer will be discussed in depth in this review, and it will highlight the challenge and importance of developing novel therapeutic strategies specifically aimed at blocking the pro-oncogenic arm of the TRIM8 signalling pathway without affecting its tumour suppressive effects. Full article
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