Oncogenic Potential of SARS-CoV-2: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by María Pilar Rodríguez Ledo.

The relationship between viral infections and the risk of developing cancer is well known. Multiple mechanisms participate in and determine this process. The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in the deaths of millions of people worldwide.

  • cancer
  • COVID-19
  • immunosuppression
  • SARS-CoV-2

1. Introduction

The link between viral infections and the risk of developing cancer is well known. It is estimated that 15.4% of all cancer cases can be attributed to carcinogenic infections, for which viruses are the main risk factor [1]. In 1964, Epstein et al. [2] identified the first human oncogenic virus. Since then, multiple viruses have been studied for their potential role in aiding the development of cancer [3]. To date, at least seven human cancer oncogenic viruses have been shown to have strong connections to various forms of cancer in humans, including the Epstein–Barr virus, human papillomavirus and the hepatitis B and C viruses [4]. The mechanisms involved are varied and range from chronic inflammation to immunosuppression and DNA modification. Indeed, viruses can transform cells via a variety of mechanisms, such as providing external oncogenes, over-activating human oncogenes and/or inhibiting tumour suppressors [5].
Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ongoing outbreak of the novel coronavirus disease 2019 (also known as COVID-19) that started in Wuhan (China) have rapidly become the most important global health problems, infecting more than 600 million people and causing more than 6.5 million deaths worldwide [6]. Although COVID-19 was clearly associated with severe respiratory disease at the beginning of the pandemic [7], it was soon realised that COVID-19 is a systemic infection implicated in multiple extra-pulmonary complications (i.e., myocardial injury and neurological disease) [8,9][8][9]. In addition to the current clinical situation, there are also increasing concerns about the long-term consequences of these infections. One such concern is the increased risk of new chronic diseases (e.g., diabetes) [10,11][10][11]. Indeed, a significant number of COVID-19 patients (37–57%) [12,13][12][13] have reported a wide range of persistent symptoms (i.e., fatigue or muscle weakness, general pain, weight loss, etc.) in the 6 months after infection, known as long COVID (LC) [14]. Merad et al. [15] suggested that the leading hypotheses include the persistence of viral antigens and RNA [16] in tissues that drive chronic inflammation, autoimmunity [17,18][17][18] that is triggered by acute viral infection, dysbiosis in the microbiome or virome and the possibility of chronic tissue damage in different organs and tissues [19,20][19][20].
The structural proteins in SARS-CoV-2 include the spike glycoprotein (which is known for its pathogenicity, i.e., it facilitates virus entry into healthy cells), the nucleocapsid (which is implicated in genome replication), a membrane protein (which is implicated in virus assembly) and the envelope protein. SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2), which is a cell surface receptor that is highly expressed in the ileum, vascular endothelia, kidneys, lungs, kidneys, testes and immune cells [21,22,23][21][22][23].

2. Senescence and Viral Infections

Biological ageing is associated with higher risks of developing several types of cancer [24]. One of the most important mechanisms in the ageing process is referred to as cellular senescence, which is also implicated in many age-related comorbidities [25], including cancer. Cellular senescence (CS) is a program activated by normal cells in response to different types of stress, such as DNA damage, telomeres shortening, oxidative stress and oncogene stimuli. When cells enter in senescence, they leave the cell cycle, lose their capability to proliferate in response to mitogenic stimuli and undergo multiple phenotypic changes, including the increased activity of lysosomal acidic beta-galactosidase, among others. Therefore, cellular senescence could be considered as a tumour suppressive mechanism by itself. However, CS is considered to be a double-edged sword [26]. One of the most important features of senescent cells is the secretion of proinflammatory factors, which is known as the senescence-associated secretory phenotype (SASP). This phenotype involves the secretion of cytokines, chemokines, proteases, growth factors and extracellular media elements, as well as degrading enzymes. The accumulation of senescent cells has been suggested to be one of the causes of chronic inflammation that may eventually induce tumorigenesis [27,28,29,30][27][28][29][30]. Following a viral infection, a large number of cellular stress response pathways are activated that, in most cases, help to control virus replication. In this sense, numerous different articles have described the links between viral infections and CS [31,32,33][31][32][33]. Indeed, several viruses have developed mechanisms that interfere with cellular senescence, which could be interpreted as viral strategies to evade the cellular antiviral system [33]. Baz-Martinez et al. [31] explored the antiviral power of CS using the vesicular stomatitis virus as a model and evaluated different stimuli involved in cellular senescence in both murine and human primary and tumour cells. They observed that cellular senescence demonstrated antiviral activity that reduced virus replication and infectivity and viral protein synthesis and apoptosis, irrespective of the trigger [31]. There is a reciprocal relationship between COVID-19 and CS, since coronavirus infections promote CS. Camell et al. [34] reported that SARS-CoV-2 surface antigen spike-1 was able to amplify the SASP of cultured human senescent cells and that a related mouse β-coronavirus (HMV) increased proinflammatory SASP factors and senescent cell burden in infected mice. Tripathi et al. [35] also observed that SARS-CoV-2 induced cellular senescence in human non-senescent cells and exacerbated SASP through the toll-like receptor (TLR)-3. In a similar way, Evangelou et al. [36] examined autopsied lung tissue samples from COVID-19 patients and age-matched non-COVID-19 controls and found that infected cells exhibited cellular senescence and a proinflammatory phenotype. They suggested that cellular senescence was mediated by DNA damage and the activation of the DNA damage response pathway [36]. Recently, Balnis et al. [37] published the first reported evidence that DNA methylation changes in circulating leukocytes endured for at least 1 year after recovery from acute COVID-19 infection. Along the same line, Moneglli et al. [38] analysed a group of 144 age- and sex-matched COVID-19-free persons with some risk factors and post-COVID-19 patients. In the post-COVID-19 patients, an acceleration of their biological blood clock was observed, particularly among those under 60 years of age [38]. Significant telomere shortening, which is another marker of ageing, was also observed. Cao et al. [39] found that COVID-19 could accelerate epigenetic ageing in infected patients, although this process could be reversed in some patients. Although no patients with LC were included in that study, the authors speculated that epigenetic ageing and telomere length could contribute to LC symptoms. Victor et al. [40] observed that SARS-CoV-2 infection resulted in transcriptional upregulation of the DNA damage response to ataxia telangiectasia and Rad3-related proteins, as well as a reduction in telomere length [40]. These conditions have been associated with genome instability but so far, the clinical implications are unknown. However, Franzen et al. [41] analysed blood samples from 50 patients who were hospitalised with severe SARS-CoV-2 infections and did not observe any evidence of accelerated epigenetic ageing or significantly shortened telomere lengths.

3. Chronic Inflammation and Viral Infections

Chronic inflammation has been identified as an important step in tumorigenesis [42] and two particular events appear to be required to activate that step [43]. Firstly, tumour-associated viruses must develop mechanisms that help them to evade host immune systems. Secondly, persistent infections must be capable of inducing mild but persistent inflammation. Indeed, the transformation of cells by viruses is important in the development of tumorigenesis. Chronic inflammation may also increase the generation of mutations and may consequently increase the risk of tumour development [44]. There is evidence to support the idea that inflammatory pathways remain altered for long periods of time after COVID-19 infection. Doykov et al. [45] observed that 40–60 days after COVID-19 infection, a significant inflammatory response was observed that was associated with an anti-inflammatory response (which is characterised by a Th17 inflammatory profile), a reduced anti-inflammatory response (which is characterised by lower levels of IL-10 and IL-4) and mitochondrial stress, even in asymptomatic patients. Convalescent patients with mild or asymptomatic infections have also shown neutrophil dysfunction, which could increase a patient’s susceptibility to cancer [46]. This is caused by an increase in the count of low-density neutrophils (LDNs), whose immunosuppressive activity is well known. The increase in LDNs correlates with a poor T-cell response and greater disease severity. It has been hypothesised that lymphopenia could lead to the inability to control the infection or viral dissemination [46]. So, an increase in myeloid-derived suppressor cells could diminish the inflammatory response and inhibit effector T-cell response and IFN-γ production. In the same way, Queiroz et al. [47] observed significantly higher levels of IL-17 and IL-2 in subjects with LC. However, the cytokine levels of IFN-γ, TNF and IL-6 did not show any significant differences. No change in IL-6 is important because in cases where there is the hyperactivation of this interleukin, the IL-6/JAK/STAT3 pathway is also hyperactivated, which occurs in many types of cancer [48]. Another possibility could be the “reactivation” of SARS-CoV-2 or other viruses. It is believed that residual virus cells could remain in certain organs or tissues, which could result in long-lasting immunomodulatory effects. This could explain the low-grade inflammation that has been described in some convalescent patients [49,50][49][50]. This chronic inflammation coupled with oxidative stress could lead to tissue and DNA damage. TLR activation is induced in response to RNA viruses, thereby stimulating the synthesis of proinflammatory cytokines and interferons [51] that contribute to limiting viral infection or viral replication. However, coronaviruses can antagonise interferons, thus evading host immune systems [52]. Finally, the SARS-CoV-2 spike protein contains a furin-like cleavage site that is absent in the other SARS-like CoVs, so its inhibition may represent a potential antiviral strategy [53]. This spike protein promotes the activation of the NLRP3 inflammasome and NF-κB inflammatory pathways [54,55,56][54][55][56]. Elevated inflammasome pathways, which are present in older people, have been associated with age-related comorbidities [57,58][57][58]. Indeed, increased inflammasome activity as a consequence of a viral infection may contribute to the age-related impairment of immune responses.

4. The Oncogenic Potential of SARS-CoV-2

Another mechanism that could implicate SARS-CoV-2 in the risk of developing cancer could be the oncogenic potential. SARS-CoV-2 has developed similar strategies to other viruses (e.g., the Epstein–Barr virus) to control p53, which represents a threat to the virus [81,82][59][60]. Because the onco-suppressive protein p53 plays an important role in the apoptotic signalling pathway, it has been hypothesized that the long-term inhibition of p53 by SARS-CoV-2 could produce carcinogenic effects [83][61]. Gomez-Carballa et al. [83][61] examined three gene expression datasets and demonstrated that p53 was downregulated during acute SARS-CoV-2 infection and LC. The multidomain non-structural protein 3 (Nsp3) SARS-CoV-2 protein promotes the degradation of p53 through the activation of RING and E3 ubiquitin ligase, which are implicated in apoptosis. In addition, coronaviruses encode endoribonuclease non-structural protein 15 (Nsp15), which interacts with another important tumour suppressor, the retinoblastoma protein (pRb) [84][62], through the ubiquitin–proteasome pathway [85][63]. Nsp15 expression leads to a reduction in pRb expression, which induces cell transformation, chromosomal instability and changes in cell cycle-associated gene expression [86,87][64][65]. This is highly relevant because p53 and pRb are recognised as important tumour suppressor genes [84,88][62][66]. Given the ability of SARS-CoV-2 to inhibit both p53 and pRb, SARS-CoV-2 could have oncogenic potential. In fact, SARS-CoV-2 non-structural protein 1 can interact with DNA polymerase alpha (Pol-a), being a source of instability because Pol-a is not only involved in the initiation of replication, but also in the coordination of cell cycle progression and the DNA damage response. A high molecular mimicry has also been reported between the spike glycoprotein and various tumour suppressor proteins (e.g., BC11B, BRCA1 and 2, PLAT2 and 3, etc.) [79][67]. These repeated epitopes have also been found in multiple infectious pathogens, opening up the possibility of immunologic imprinting. This phenomenon could lead to autoimmune cross-reactivity and, potentially, cancer development. Ebrahimi et al. [89][68] evaluated the possible correlations between SARS-CoV viruses and cancer in an in silico study model. Different analyses showed that four genes (PTEN (proliferation and cellular death), CREB1 (transcription activator), CASP3 (cell apoptosis) and SMAD3 (transcription factor and cell proliferation) were key in cancer development. According to the TCGA database results, these four genes were upregulated in pancreatic adenocarcinoma [89][68]. In a similar way, Zhao et al. [90][69] performed a genome-wide cross-trait analysis to investigate the shared genetic architectures and putative genetic associations between COVID-19 and the three main female-specific cancers (breast cancer, epithelial ovarian cancer and endometrial cancer). Although the authors did not find any evidence of genetic correlations between COVID-19 and the female-specific cancers, the cross-trait meta-analysis found that these conditions shared multiple mechanistic pathways (connecting the hematologic system, immune system and cell proliferation), especially in breast cancer and ovarian cancer [90][69]. Finally, Shen et al. [91][70], driven by the higher incidence of COVID-19 among cancer patients, used bioinformatics techniques to analyse the differentially expressed genes (DEGs) that are common to three of the most prevalent cancers (breast, liver and colon) and COVID-19. The authors identified 38 DEGs through a cross-comparison evaluation that was conducted on Jvenn. They also performed GO and KEGG enrichment analyses, starting from those 38 DEGs. They found that the DEGs were enriched in “elastic fibre assembly”, “collagen-containing extracellular matrices” and “oestrogen 2-hydoroxylase activity”. After that, 10 hub genes were identified and their possible relationships with the onset and progression of cancer were evaluated. The authors reported that some transcription factors (i.e., STAT3, NFKB1, FOXC1, HINFP and JUN) also showed correlations with respiratory illnesses and the progression of malignancies. Another bioinformatic analysis reported the upregulation of some tumour-related genes in SARS-CoV-2 patients, particularly among genes that are involved in cell cycle regulation or cellular senescence processes [92][71].

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