Special Issue "The Double-Edged Role of Noncanonical Oncogenes and Tumor Suppressor Genes in Cancer Progression; An Oncojanus Function"
Deadline for manuscript submissions: 31 December 2017
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
Manuscript Submission Information
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tumor suppressor genes
The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.
1. Dualistic role of BARD1 in cancer
Flora Cimmino1,2, Daniela Formicola1,2, Mario Capasso1-3
1Università degli Studi di Napoli Federico II, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, via Sergio Pansini 5, 80131 Naples, Italy
2CEINGE Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy
3IRCCS SDN, Istituto di Ricerca Diagnostica e Nucleare, Via Gianturco 113, 80143 Naples, Italy
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 correlated 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.
2. p53 Modulates MYC-Mediated Cell Competition in Different Cancer Contexts
Simone Di Giacomo1, Manuela Sollazzo1, Giorgia Miloro, Simona Paglia, Dario de Biase, Annalisa Pession, Daniela Grifoni*
1Department of “Farmacia e Biotecnologie”, University of Bologna, Via Selmi 3, 40126 Bologna, Italy.
Cell competition was originally described in Drosophila as a physiological process based on the comparison of relative fitness between neighbouring cells. At the end of the process, suboptimal cells, called losers, are committed to die while stimulating proliferation of the most performant cells, called winners, so maintaining tissue homeostasis. In Drosophila and mammalian development, cells showing high MYC activity behave like winners, growing at the expense of the surrounding cells which succumb by apoptosis, so unveiling a leading role for this oncoprotein in eliciting cell competition. Since MYC protein is upregulated in a large fraction of human cancers, cell competition has been speculated to play a role in human tumourigenesis. Consistently with this hypothesis, we found massive apoptotic death of stromal cells in proximity to MYC-upregulating cancer cells in a relevant number of human tumour samples, and showed that modulation of MYC activity in human cancer cell lines is sufficient to subvert their competitive drive. In Drosophila, MYC-overexpressing cells have been demonstrated to be unable to execute cell competition in a p53 loss-of-function background. With the aim to investigate the role of p53 in MYC-mediated cell competition, we first stained the same cancer samples as above for p53. Interestingly, the tumour regions that did not show significant signs of competitive interactions were also found negative to p53 staining, disclosing a possible function for this protein in promoting cancer-associated cell competition. Further experiments in a Drosophila cancer model helped us define a dose-dependent role of p53 in MYC-overexpressing winner cells, and functional assays in co-cultures of human cancer cells confirmed that p53 function is necessary for the winner cells to execute cell competition. Altogether, our findings reveal a pro-oncogenic role of p53, that appears to cooperate with MYC in driving cell competition in different cancer contexts.
3. Regulation of tumor cell metabolism: is PGC1a a friend or a foe?
Francesca Mastropasqua1*, Giulia Girolimetti1,2* and Maria Shoshan1
1 Dept. of Oncology-Pathology, CancerCenterKarolinska R8:03, Karolinska Institute, 171 76 Stockholm, Sweden
2 Università di Bologna, Scienze Mediche e Chirurgiche, Bologna, Italy
* equal contribution
In many normal tissues, mitochondrial biogenesis and function are regulated via the transcriptional activities of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a). Because alterations in certain mitochondrial functions, notably oxidative phosphorylation (OXPHOS) and the tricarboxylic acid cycle, may either promote or prevent tumorigenesis and tumor progression, the role(s) of PGC1a in cancer are being investigated. Intriguingly, both high and low expression levels of PGC1a have been associated with worse prognosis and aspects of progression. We will in this review summarize recent findings on PGC1a in cancer, both as a prognostic factor and in terms of molecular tumor biology, and will argue that the conflicting findings on PGC1a may be connected to the discussion on whether - or when - cancer cells and tumor progression benefit from increased mitochondrial oxidative phosphorylation (OXPHOS).
4. TRIM8: making the right decision between oncogene and tumour suppressor role
Caratozzolo Mariano Francesco1, Marzano Flaviana1, Mastropasqua Francesca1, Sbisà Elisabetta2 and Tullo Apollonia1
1 Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, IBIOM – CNR – Via G. Amendola 165/A – 70126 Bari, Italy
2 Institute for Biomedical Technologies ITB, CNR-Bari, Via G. Amendola 122/D - 70126 Bari, Italy
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. 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 can be induced by IFNg. 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 TNF-induced NF-kB 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.