Xiaobo Zhang Editor

Virus
Infection and
Tumorigenesis
Hints from Marine Hosts’ Stress
Responses


Virus Infection and Tumorigenesis


Xiaobo Zhang
Editor

Virus Infection and
Tumorigenesis
Hints from Marine Hosts’ Stress Responses


Editor
Xiaobo Zhang
College of Life Sciences
Zhejiang University
Hangzhou, Zhejiang, China

ISBN 978-981-13-6197-5    ISBN 978-981-13-6198-2 (eBook)
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Contents

1Overview of Virus Infection and Tumorigenesis ������������������������������������    1
Geng Yang and Xiaobo Zhang
2Marine Viruses ������������������������������������������������������������������������������������������   25
Tianliang He, Min Jin, and Xiaobo Zhang
3Marine Invertebrate Stress Responses to Virus Infection����������������������   63
Yaodong He, Yi Gong, and Xiaobo Zhang
4The Roles of MicroRNAs in Antiviral Immunity
of Marine Invertebrates����������������������������������������������������������������������������  105
Yalei Cui, Le Shu, and Xiaobo Zhang
5Marine Microbe Stress Responses to Bacteriophage Infection ������������  141
Min Jin, Tianliang He, and Xiaobo Zhang
6Roles of Microbial Metabolites in Bacteriophage-Microbe

Interactions������������������������������������������������������������������������������������������������  175
Chenxi Xu, Min Jin, and Xiaobo Zhang
7Tumorigenesis and Metabolism Disorder������������������������������������������������  209
Fan Yang, Le Shu, and Xiaobo Zhang
8Effects of MicroRNAs from Marine Invertebrate Stress
Responses to Virus Infection on Tumorigenesis��������������������������������������  251
Yi Gong, Yalei Cui, and Xiaobo Zhang
9Antitumor Activities of Secondary Metabolites from Marine
Microbe Stress Responses to Virus Infection������������������������������������������  285
Tianliang He, Chenxi Xu, and Xiaobo Zhang

v


Chapter 1

Overview of Virus Infection
and Tumorigenesis
Geng Yang and Xiaobo Zhang

Abstract  In order to keep metabolic homeostasis and normal physiological environments, cells must maintain metabolic balance. Cancer is a disease, in which
metabolic disturbance is one of the most obvious signatures leading to the survival
and growth of cancer cells. On the aspect of virus infection to hosts, the metabolic
machinery of living cells is manipulated by viruses for completing their life cycles
including fulfilling their replication and overcoming the host defense mechanisms.
These alterations associated with virus infection can change normal metabolism or/
and reconstruct metabolic homeostasis of host cells. In terms of metabolic disorder,
there exists a relationship between virus infection and tumorigenesis. In essential,
antiviral molecules can maintain metabolic homeostasis of cells. Therefore antiviral
molecules may possess antitumor capacity. Antiviral molecules produced during

marine hosts’ stress responses to virus infection may be important resources for
screening antitumor drugs.
Keywords  Marine organism · Stress response · Metabolic homeostasis · Virus
infection · Tumorigenesis
It is well known that metabolic balance is required for cells to keep homeostasis and
normal physiological conditions. Over the last decades, there have been accumulating evidences linking tumorigenesis to metabolic disorder. Upon transformation of
normal cells into abnormal states, the metabolic disorder is severely disturbed. For
example, Warburg effect is enhanced, antioxidant molecules are produced to counteract the detrimental effects of reactive oxygen species (ROS), and cell microenvironment is changed into hypoxia, low pH, and high glucose concentration.
Ultimately, cells become cancerous due to the mutation of the metabolic genes.
Viral abundance in the environment is enormous. During the virus-host interactions,
G. Yang
Institute of Bioengineering, Zhejiang Academy of Medical Sciences, Hangzhou, China
X. Zhang (*)
College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
e-mail:
© Springer Nature Singapore Pte Ltd. 2019
X. Zhang (ed.), Virus Infection and Tumorigenesis,
/>
1


2

G. Yang and X. Zhang

virus infection results in metabolic disturbance of host cells. These modifications
associated with virus infection can change normal metabolism and reconstruct metabolic homeostasis of host cells, thus facilitating virus proliferation and infection.
Therefore, in the aspect of metabolic disturbance, cancer cells and virus-infected
host cells are similar on some levels.


1.1  The Significance of Virus in the Ocean
More than 70% of the Earth’s surface is covered by the oceans. The oceans control
the climate, provide significant amount of protein that is consumed globally, and
produce approximately half of the Earth’s oxygen. It is well known that 90% of the
living biomass in the sea are microorganisms which can drive the nutrient and
energy cycles in the world’s oceans (Fuhrman 1999). However, it is not so well
known that approximately 20% of the biomass of ocean is killed by virus per day
and viruses are one of the largest reservoirs of unexplored genetic diversity on the
Earth (Fuhrman 1999). The virosphere exits in every environment on the Earth,
from the atmosphere to the deep sea. Nowhere is more important for viruses than in
the world’s oceans due to the observation that millions of virus-like particles are
present in every milliliter of ocean water (Suttle 2005). It has become evident that
viruses are major players in the mortality of marine microorganisms and affect
nutrient and energy cycles consequently (Mojica and Brussaard 2014).
Although the discovery of marine viruses is still emerging, it has been increasingly clear that we need to incorporate viruses and virus-mediated processes into
our understanding of biogeochemistry and take advantage of virus-host interaction
for the benefits of human health. Progress in our understanding of marine viruses
and their effects on hosts is becoming rapid. However, there are still a lot of challenges existing. In some aspects, the knowledge about the marine viruses that infect
invertebrates and vertebrates greatly exceeds our knowledge of those that infect
microorganisms due to the reasons that the biology, pathology, and diversity of
many viruses that infect commercially important species (especially cultivated species) drive our great attention and we gain a lot of knowledge from studying them.
But in other cases, we know little about the reservoirs and sources of these viruses,
or the impact of virus infection on organisms that are not commercially significant
(Buck et al. 2006). It is clear that viral pathogens infect a broad range of evolutionarily divergent groups of marine organisms. However, most of our knowledge has
been driven by the economic consequences of viral disease. For example, in the
marine aquaculture industry, enormous losses in production can be attributed to
viral diseases. It is quite astonishing that so many different pathogens can infect
some already well-investigated organisms, such as shrimp (Rajendran et al. 2012).
Some of these discoveries have been extraordinary, in the case of white spot syndrome virus (WSSV), which infects shrimp (Li and Xiang 2013).
Generally, comparing with the understanding of pathology of viral diseases, we

know little about their modes of transmission or where these viruses occur outside


1  Overview of Virus Infection and Tumorigenesis

3

of the host. Results have shown that a large amount of molecular diversity takes
place in many of these families. Some viruses can infect a wide range of hosts, thus
taking the advantage of circulating between marine waters and freshwaters and
making the transmission of viruses to new are as a threat. For example, by phylogenetic analyses of isolates of infectious hypodermal and hematopoietic necrosis virus
(IHHNV), a rhabdovirus that infects shrimp and is widespread in the northeast
Pacific ocean, we can get the conclusion that the virus has not only been transmitted
among fish stocks in North America, but has also been transmitted to marine and
freshwater fish stocks in Europe and Asia (Kurath et al. 2003). Another example is
that viral hemorrhagic septicemia virus (vHsv) is also a rhabdovirus that is primarily discovered in farms in Europe but has also been isolated from more than 40 species of marine fishes (Meyers et al. 1999). Phylogenetic analysis indicates that the
European freshwater viruses have a common marine ancestor and diverged from
their North American marine (Meyers et al. 1999). vHsv has been detected in fish
from lakes in Atlantic Canada, Michigan, United States, where it has been associated with several mass mortality events that have affected different fish species
(Cutrin et al. 2007; Gagne et al. 2007).

1.2  Roles of Bacteriophages in the Extreme Environment
Bacteriophages are commonly referred to as phages and are defined as viruses that
infect bacteria. Bacteriophages are considered as the most abundant and diverse
biological entities in aquatic systems with an estimated population density of 107
per ml of seawater (Brum and Sullivan 2015). They are not only abundant but also
important players in the energy and nutrient cycles through the lysis of host microbial cells (Hurwitz and Sullivan 2013). The interactions between bacteriophages
and bacteria have been investigated by scientists as tools to understand basic molecular biology, horizontal gene transfer, genetic recombination events, and how bacterial evolution has been driven by phage. Oceans cover over 70% of the Earth’s
surface, produce more than half of the oxygen in the atmosphere, and absorb the
most carbon dioxide from it (Antunes et al. 2015). Marine microbes, which constitute more than 90% of the living biomass in the sea, are the major drivers of these

energy cycles. Considering that viruses kill roughly 20% of this biomass each day
(Suttle 2007), it is clear that marine bacteriophages play a critical role in the biosphere. Currently, bacteriophages infecting thermophiles have attracted more and
more investigations to gain insights on how they have adapted to extreme environment (Liu and Zhang 2008; Song et al. 2011; Ye and Zhang 2008). However, only a
few thermophilic bacteriophages have been isolated from deep-sea hydrothermal
vents. In 2006, a bacteriophage GVE2 was obtained from Geobacillus sp. E263,
which was isolated from a deep-sea hydrothermal field in the east Pacific. The
genome of GVE2 has been sequenced, which contains 62 open reading frames (Liu
and Zhang 2008). GVE2 is a thermophilic and lytic bacteriophage that infects
Geobacillus sp. E263 as the lysin and C1 proteins are essential for the lytic process


4

G. Yang and X. Zhang

of GVE2 (Song et al. 2011; Ye and Zhang 2008). Based on proteomic analysis and
random arbitrarily primed PCR (RAP-PCR) of Geobacillus sp. E263 from virus-­
free and GVE2-infected samples, 20 differentially expressed genes and proteins
were revealed, in which aspartate aminotransferase is essential in virus infection
(Wei and Zhang 2010). Further analysis shows that the MreB cytoskeleton of
Geobacillus sp. plays important roles in the bacteriophage infection at high temperature (Jin et al. 2015). In order to reveal the roles of metabolites in the interactions between bacteria and bacteriophages, the metabolomic profilings of
GVE2-infected and virus-free Geobacillus sp. E263 are characterized (Jin et  al.
2015). It is found that the metabolites tryptophol, adenine, and hydroxybenzyl alcohol are significantly elevated in Geobacillus sp. E263  in response to the GVE2
infection (Jin et  al. 2015). A novel quinoid compound 2-amino-6-hydroxy-[1,4]benzoquinone and L-norleucine, which have antitumor activities, are isolated from
the GVE2-challenged Geobacillus sp. E263, indicating that the metabolites from
the phage-challenged deep-sea microbes may be a kind of promising sources for
antitumor drug discovery (He et al. 2018; Xu et al. 2017).
There is no doubt that viruses and virus-mediated processes are of great importance in the ocean. We still lack the knowledge of quantitative estimates of the rates
of infection and virus-mediated interaction with hosts. As a result, our understanding of the effects of viruses on emergent properties such as marine invertebrate
stress responses to virus infection or marine microbe stress responses to bacteriophage infection is far from complete. Similarly, we are far from being able to translate the genetic complexity of marine viruses into an understanding of biological

potential.

1.3  Virus Infection and Host Metabolism
During virus infection, viruses take advantage of the metabolic machinery of living
cells to complete their life cycles by interfering with the normal procedures of metabolic functions of host cells to maximize their replication and to overcome the host
cell defense mechanisms (Galvan-Alvarez et al. 2012). It has been reported that, at
the early stage of virus infection, host cell metabolic homeostasis is manipulated,
such as the pentose phosphate pathway, glycolysis, and fatty acid metabolism, to
accomplish the energy requirement of viruses (Chen et  al. 2011; Diamond et  al.
2010; Munger et al. 2006). Damage to the host cell’s metabolism will lead to cell
death upon virion maturation. In shrimp, a Warburg-like effect is induced in hemocytes of WSSV-infected shrimp at the early stage of virus infection, which helps the
virus to meet its high demand for cellular energy during virus replication (Su et al.
2014). As reported, virus infection also disturbs the protein metabolism of host cells
as well as cell metabolism in favor of its replication (Liu et al. 2015b).
The activation of innate immune responses is critical in defending host cells from
viruses (Dang and Kim 2018). Upon sensing invading viruses, host cells trigger various signaling events that ultimately lead to severe immune responses. The ­secretion of


1  Overview of Virus Infection and Tumorigenesis

5

interferons (IFNs) and the expressions of antiviral factors, including inflammatory
cytokines and IFN-stimulated genes (ISGs), are launched, which is the first step of
innate immune responses preventing viral spread and promoting subsequent adaptive
immune responses (Gall et al. 2018). Innate immune responses are usually activated
within infected cells through the recognition of viral elements, including viral proteins
and viral nucleic acids. These sensors can locate either in cytoplasm [e.g., retinoic
inducible gene-I (RIG-I)-like receptors and nucleotide-binding oligomerization
(NOD)-like receptors] or in endosome [e.g., Toll-like receptors (TLRs)] (Piya and

Kim 2018). Nonetheless, virtually all viruses have evolved mechanisms to evade and/
or inhibit these responses within infected cells to facilitate virus infection. Except for
the activation of innate immunity, the host cells interact with the virus in several layers
of viral states, including extracellular native virus, intracellular viral components, and
the viral replicate intermediate (Kim et al. 2018).
Host immune response is first activated by sensing the viral infection through
various pattern recognition receptors (PRRs) (Uppal et al. 2018). In order to sense
different kinds of viruses, specialized cells and cellular factors have been evolved
by detection of specific viral elements in different viral forms. The immune response
differs greatly based on type of virus and route of infection. For RNA virus, it has
been demonstrated that the TLR7/myeloid differentiation primary response 88
(MYD88) pathway but not the RIG-I/IPS-1 pathway is triggered upon infection
with inactivated influenza virus vaccine containing viral ssRNA, although both of
them are parallel innate immune pathways (Koyama et al. 2007). For DNA viruses,
TLR9 can recognize the unmethylated DNA and share the downstream signaling
pathway with the adapter protein MYD88 (Schmitz et al. 2007).
In multicellular organisms, cells are functioning as a single fundamental unit
against the virus infection. As soon as a host cell is attacked by the virus, the host
cell will start a bunch of events to both alert itself and the neighboring cells countering the invader and trigger the effector cells and proinflammatory immune
responses. This happens via the production of many molecules, such as cytokines
which help the neighbor cells to produce some inhibitory effects on virus infection and replication (Watanabe 2004). Because the speed of pathogen replication
is a rate-limited step in the viral pathogenesis, the establishment of such an intercellular immune system including intercellular interaction is beneficial to host
antiviral defense, which contributes to clearing the pathogen and limiting its
spread into infected tissues without waiting for the launch of the classical immune
response (Zhi et al. 2018).
Not only the invaded viruses are conducting modifications and development in
host cells, but also the microenvironment of host cells experience some modifications after a successful virus infection, resulting in the favor of the next infection or
to counter it. For instance, specific memory T cells reside in the infection site, which
are termed as resident memory T cells. These T cells are resident within the infected
cells and can dramatically launch immune responses if the recurrent infection takes

place (Cheuk et al. 2017; Misiak et al. 2017; Sckisel et al. 2014). The other example


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G. Yang and X. Zhang

is, after severe lung infection, the damaged lung tissue leads to a repair process that
changes the lung matrix composition, such as more collagen and fibronectin deposition, providing additional binding sites for viruses.
In the evolution of host-virus interaction, to help in the continuity of the infection
cycle, the virus has evolved counter defenses. Some viruses have employed strategies to fight against the natural killer (NK) cells or to destroy the MHC I (major
histocompatibility complex) antigen presentation, thus inactivating the NK cells.
For example, poliovirus encodes protein 3A, which can interact with the endoplasmic reticulum (ER) membrane to inhibit protein transport from the ER to the Golgi
apparatus, thus preventing the transport of the MHC-bearing polio-specific peptide
to the cell membrane (Deitz et al. 2000). Foot-and-mouth disease (FMD) inhibits
protein transport using its viral 2 BC protein (Moffat et al. 2007). The Tat protein of
HIV (human immunodeficiency virus) interferes with class I MHC messenger RNA
(mRNA) transcription (Petersen et al. 2003). Relocalization of the class I MHC to
the trans-Golgi network by the retrovirus Nef protein results in the downregulation
of the surface expression of MHC-I (Swann et al. 2001). Primarily, normal cells can
be protected from the NK-mediated cell lysis by the presentation of HLA (human
lymphocyte antigen)-C and HLA-E molecules on the membrane of cells. It is
believed that some retroviruses such as HIV-1 can specifically disrupt the expression of HLA-A and HLA-B but not HLA-C and HLA-E on the membrane. As a
result, the infected cells are protected from being killed by NK cells (Goulder and
Walker 2012).
Because virus finishes its life cycle in host cells, virus infection changes host’s
metabolism, leading to the metabolic disorder of host cells and the occurrence of
diseases especially tumorigenesis.

1.3.1  Virus Infection and Host Glucose Metabolism

Glucose homeostasis is regulated by maintaining the output and the storage of glucose (Klover and Mooney 2004). Glucose metabolism in cells can be divided mainly
into two categories anabolism and catabolism, which include gluconeogenesis, glycolysis, aerobic oxidation, and the pentose phosphate pathway. It has already been
demonstrated that virus infection can affect either gluconeogenesis or glucose aerobic oxidation. For example, hepatitis B virus X protein (HBx) functions as an
important positive regulator of gluconeogenesis (Shin et  al. 2011). In the HBx-­
overexpressing mice, the elevated HBx expression significantly upregulates the
gene expression of hepatic key gluconeogenic enzymes and the production of
hepatic glucose, resulting in hyperglycemia and impaired glucose tolerance.
Overexpression of HBx causes the nuclear translocation and activation of NF-E2-­
related factor 2, leading to upregulation of glucose-6-phosphate dehydrogenase,
which is the first and rate-limiting enzyme of the PPP (pentose phosphate pathway)
converting glucose-6-phosphate into 6-phosphogluconolactone (Liu et al. 2015a).
Enhancement of the PPP by HBx-mediated elevation of G6PD (glucose-6-­phosphate


1  Overview of Virus Infection and Tumorigenesis

7

1-dehydrogenase) provides host cells with more ribose for nucleotide biosynthesis
to support their proliferation, which may contribute to virus-associated hepatocarcinogenesis. On the other hand, by combining proteomics, metabolomics, and
molecular biological assays in HepG2 cell models, researchers have provided a
holistic view of the interplay between host metabolism and virus infection (Accardi
et  al. 2015). They point out that the enzymes regulating the glycolysis pathway,
such as alpha-enolase, fructose-bisphosphate aldolase, phosphoglycerate kinase 1,
triosephosphate isomerase, and glucose-6-phosphate isomerase, and enzymes
involving in the tricarboxylic acid (TCA) cycle, including succinate dehydrogenase,
citrate synthase, and malate dehydrogenase, are all dramatically upregulated in
HepG2 cells after virus infection, subsequently resulting in elevated levels of corresponding intermediates, such as fumarate, succinate, and 2-oxoglutarate in the
TCA cycle and lactate in glycolysis (Marsden et al. 2015; Panthu et al. 2017). These
data suggest that glycolysis and the TCA cycle are modified in host cells to facilitate

virus life cycle.

1.3.2  Virus Infection and Host Lipid Metabolism
The liver, the main organ for the production of ketone, the synthesis and circulation
of lipids (such as fatty acids, fats, phospholipids, and cholesterol), and the oxidation
of fatty acids, is critical in lipid metabolism (Fessler 2008; Nguyen et al. 2008). A
significant amount of basic researches has indicated that virus infection to the liver
has an effect on fatty acid metabolism. For example, studies have shown that HBV
(hepatitis B virus) can promote the synthesis of fatty acids (Yang et al. 2008). Based
on HPLC/MS (high-performance liquid chromatography/mass spectrometry) analysis and 2-DE (two-dimensional electrophoresis), Acyl-CoA binding protein identified in fatty acid metabolism and synthesis is markedly increased in hepatitis B
virus transgenic mice (Yang et al. 2008).

1.3.3  Virus Infection and Host Nucleic Acid Metabolism
As well known, the main role of nucleotide is to serve as the substrate for the biosynthesis of nucleic acids. Previous investigations have found that DNA damage
can induce abnormalities of nucleic acid metabolism (Dan et al. 2016). It has also
been demonstrated that virus infection can influence nucleic acid metabolism of
host cells via virus-induced DNA damage, which may result in the onset of carcinogenesis (Na et al. 2016). Thus, identifying the altered nucleic acid metabolites under
virus induction may help us to understand the occurrence of tumors. One study
using a systematic approach combining metabonomics and mRNA microarray analysis indicates that virus infection firstly induces DNA damage and then disrupts
nucleic acid metabolism of host cells, resulting in the inhibition of expressions of


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G. Yang and X. Zhang

DNA damage repair gene expression, such as NHEJ1 TP53, BRCA1, DDB1, RPA1,
and TCEA1, and of the intermediates of nucleic acid metabolism, including guanosine, inosine, and uridine, which in turn blocks DNA repair and possibly contributes
to the development of cancers (Dan et al. 2016).


1.3.4  Virus Infection and Host Vitamin Metabolism
Vitamin A, including retinene, retinol, and retinoic acid, is critical in visual function
as well as cell growth and differentiation (Maniwa et al. 2015). It has been demonstrated that retinoic acid can enhance the transcription of viral genes and virus replication through the activation of RXRa (Huan and Siddiqui 1992). Very interestingly,
another study shows that virus infection can promote retinol metabolism-related
proteins RBP, CRBP1, and ALDH1 as shown by 2-DE and MS/MS analysis
(Paemanee et al. 2016). It is rational that more retinols will be transported into cells,
which is further converted into retinoic acid during virus infection. Virus infection
may upregulate retinoic acid by increasing retinol metabolism and therefore facilitating self-replication through the activation of RXRa, resulting in an increased risk
of tissue damage, which is considered a positive feedback (Gouthamchandra et al.
2014; Jones et al. 2016).

1.4  Cancer and Metabolism
Cancer is an example of a disease process in which metabolic changes are one of the
reasons to promote cell survival and growth. Altered metabolism has been known to
characterize tumors (Tanasova et  al. 2018). By studying rare, monogenic disorders
caused by mutations in genes encoding metabolic enzymes or regulators, it has been
revealed that cancer cells share a common metabolic phenotype of impaired respiration
and increased desire for energy. Hundreds of these cancers, which are termed “inborn
errors of metabolism,” are mainly discovered in childhood. Some “inborn errors of
metabolism” characterize the chronic systemic loss of a particular metabolic pathway
that can lead to malignancy. In recent years, it has been observed that the metabolic
changes accompanying malignancy have been broadened far beyond energy metabolism to an oncogenic metabolic network that enhances proliferation and survival of cancer cells (Rinaldi et  al. 2018). It is now widely accepted that to supply the lipids,
nucleotides, and amino acids required to support proliferation, cancer cells change and
reprogram their metabolism to favor anabolism over catabolism (Hanahan and Weinberg
2011). Thus, metabolic disorder is recently classified as an emerging hallmark of cancer.
However, cancer involves numerous biological hallmarks acquired together, such as
resistance to cell death, sustaining proliferative signaling, and each one of these may
involve specific aspects of metabolic disorder and reprogramming. Understanding
which metabolic changes exert primary effects on cancer initiation is therefore helpful
to find a cure for cancer therapy (Hainaut and Plymoth 2013).



1  Overview of Virus Infection and Tumorigenesis

9

On the other hand, the initiating event in the pathway to malignancy seems to be
related directly or indirectly to the accumulation of one or more toxic metabolites.
For example, hepatocellular carcinoma (HCC) is usually related to the inactivation
of some enzymes in the liver, which leads to chronic, toxic metabolite accumulation
and ultimately tissue damage and fibrosis (Yin et al. 2004). This pathway to HCC is
observed in tyrosinemia type I, hemochromatosis, porphyria, Wilson disease, and
mitochondrial DNA (mtDNA) depletion (Cassiman et al. 2007; Savas et al. 2006;
Xu et al. 2005). Metabolite accumulation involves cancer in organs besides the liver.
Tissue toxicity is often aggravated by additional insults such as virus infection,
smoking, alcohol, and other processes that result in enhanced free radical production (Harrison and Bacon 2005). This mechanism of disease suggests that preventing toxin accumulation will reduce cancer occurrence, even without the need to
upregulate the activity of the metabolic dysfunctional pathways. This therapeutic
method is well applied in tyrosinemia type I, where nitisinone 2(2nitro4trifluoromethylbenzoyl) 1,3cyclohexanedione (NTBC), the inhibitor for tyrosine degradation, prevents toxin accumulation, reducing cancer risk and improving organ
function (Bartlett et al. 2014). Oncometabolites, in contrast to metabolic toxins, can
be viewed as molecules that promote malignancy without first inflicting chronic tissue dysfunction (Yang et al. 2013). The concept of oncometabolites was first established from the investigation of metabolites accumulating in tumors possessing
different mutations in metabolic enzymes. In general, these metabolites exhibit the
ability in a way by interfering with protein function, which mimics the effects of
mutations in tumor suppressors or oncogenes. These metabolites are greatly
involved in biological pathway of malignancy (Yang et al. 2013).
Generally, metabolic disorder is associated with the regulation of gene expression. In the majority of cancers examined, the genes for glycolysis are overexpressed
(Lopez-Rios et  al. 2007). It is reported that the glucose avidity of carcinomas is
presented as the result of the installment of glycolysis for cellular proliferation and
the impairment of mitochondrial activity in the cancer cells (Ortega et al. 2009). The
stabilization of hypoxia-inducible factor 1 alpha (HIF1α) in cancer cells and the
transcriptional activity of c-myc can increase the expression levels of most of the

genes encoding glycolytic enzymes, including GLUT1 and lactate dehydrogenase­A (LDHA), which in turn increase tumor aggressiveness and lead to poor survival,
which is all the evidence for the metabolic reprogram of the cancer cells (Ortega
et al. 2009).

1.5  A
 ntiviral Stress Responses of Marine Organisms
and Antitumor of Human Being
Researchers have long attempted to elucidate the roles of viruses in causing cancers.
It is estimated that cancer viruses cause 15 to 20 percent of all cancers in humans
worldwide (Mirzaei and Faghihloo 2018; Mirzaei et  al. 2018). Viruses typically
initiate cancer development by suppressing the host’s immune system, causing
inflammation over a long period of time, or by altering host metabolism (Lawson


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G. Yang and X. Zhang

et al. 2018). Perception into the development and spread of cancer-induced viruses
has made us to concentrate on preventing potential cancer development by either
inhibiting virus infection or by targeting and destroying the virus before it causes
cancer. Viral antigens, which cause the cells to grow abnormally, are produced by
host cells that are infected by viruses (Bommareddy et  al. 2018). Emerging evidence indicates that impaired cellular energy metabolism is the representative characteristic of nearly all cancers in spite of cellular or tissue origin, especially aerobic
glycolysis (Saavedra-Garcia et  al. 2018). In this book, however, we focus on the
relationship between the stress responses of marine organisms against virus infection and human tumorigenesis.
It is well known that virus can only finish its life cycle in host cells. The metabolism of host cells must be altered when the host is infected by viruses, leading to
metabolic disorder of host. To fight against the virus invasion and proliferation, host
cells would produce some molecules to maintain the metabolic homeostasis of host
or to establish a new metabolic homeostasis of virus-infected cells when the viruses
cannot be killed. These molecules have antiviral activities. In  the essence, these

antiviral molecules maintain the metabolic homeostasis of host during host stress
responses to virus infection. It is also well known that tumorigenesis results from
metabolic disorder of normal cells. Thus, in terms of metabolic disorder, the antiviral molecules derived from virus-challenged host may possess antitumor activities,
which may restore the metabolic disorder of tumor cells to normal metabolic
homeostasis. In recent years, the relationship between antiviral stress responses of
marine organisms and antitumor of human being has been explored in WSSV-­
infected shrimp and GVE2-challenged bacteria.

1.5.1  T
 he Roles of miRNAs Derived from Shrimp Stress
Responses to Virus Infection in Human Tumorigenesis
Viruses are good at gene regulation. Their parasitic life style employs host machinery to carry out basic biological processes, from transcription to protein synthesis
(Niepmann et al. 2018). Thus, viruses can dramatically downsize their genomes to
the minimum number of genes essential for successful infection. For example, typical mammalian herpesviruses possess from 70 to 200 genes in 120,000 to 250,000
base pairs of viral genomic DNA (Sadeghipour and Mathias 2017). Compared with
those of the host, the viral genomes are significantly compacted. Of the 3.2 billion
base pairs in the human genome, only about 2% sequences encode proteins. On the
contrary, 80–90% of a herpesviral genome is capable of coding proteins (Panasiuk
et al. 2018). Although the genomes of the viruses are much smaller than those of
their hosts, viruses can still be capable of producing both proteins and noncoding
RNAs (ncRNAs) to regulate critical components in the networks of host genes to
ensure successful infection. Therefore, a deeper understanding about the virus-host
interactions can uncover important mechanisms of gene regulation. In the past


1  Overview of Virus Infection and Tumorigenesis

11

decades, viral RNAs are considered as either templates for the translation of viral

protein, which exert functions, or as viral pathogen-associated molecular patterns
(PAMPs) to be detected by host pattern-recognition receptors (PRRs) in innate antiviral immunity. However, accumulating studies provide intriguing evidence that
virus can not only produce RNAs for translation but also synthesis virus microRNAs (miRNAs) for directly inhibiting host mRNA.
miRNAs, a class of small noncoding RNA molecules of about 22 nt in length,
can regulate the expressions of target genes at the posttranscriptional level (Bartel
2009). Primary miRNAs are transcribed by RNA polymerase II, which are then
processed by Drosha within the nucleus to produce pre-miRNAs of about 65 nucleotides in length (Shukla et al. 2011). The pre-miRNA is then transported into the
cytoplasm and further cleaved by the RNAse III-like endonuclease Dicer to produce
their mature form miRNAs. The guide strand of the miRNA duplex is then loaded
into the RNA-induced silencing complex (RISC), which contains a member of the
double-stranded RNA-binding protein Argonaute family (Ago), and the other strand
is degraded. Subsequently the loading RNA recognizes and binds to conserved
complementary target sites of the target mRNAs (often in the 3′ untranslated region)
through authentical base-pairing between the seed region of approximately 6- to
8-oligonucleotides (Reddy 2015), resulting in the deadenylation and degradation or
by leading to translational inhibition of mRNAs (Hsieh et al. 2014). Thus far, >2500
human miRNAs (hsa-mir) and 1900 mouse miRNAs (mmu-mir) have been identified and described at the miRBase website (Ludwig et al. 2017).
During virus infection, the expression profile of host miRNAs is influenced as
the result of viral modulation of cellular miRNA expression (Skalsky and Cullen
2010). Invading viruses can also encode miRNAs to participate in the virus-host
interactions. For example, Epstein-Barr virus (EBV), a member of the gamma subfamily of Herpesviridae, was the firstly reported to encode viral miRNAs (Pfeffer
et  al. 2004). So far, 44 mature miRNAs encoded by EBV have been reported
(Amoroso et al. 2011; Cai et al. 2006; Zhu et al. 2009). Besides EBV, many other
herpesviruses have also been found to encode large numbers of viral miRNAs, such
as Kaposi sarcoma-associated herpesvirus (KSHV) (Cai et al. 2005; Pfeffer et al.
2005). However, most mammalian viruses, including simian virus 40 (SV40) and
adenovirus, encode a single viral miRNA (Grundhoff and Sullivan 2011). Viral
miRNAs have great effects on virus infection by regulating virus or host gene
expression to avoid the host defenses and/or to maintain latent and persistent infection (Choy et al. 2008; Liang et al. 2011). In the mammalian virus SV40, the viral
miRNA miR-S1 does not directly enhance the replication of SV40, but it can protect

virus-infected cells from elimination by the host immune system (Sullivan et  al.
2005). The SV40 miRNA targets the host mRNA encoding the SV40 antigens,
which are viral transcription factors that induce the expression of late viral genes
(Sullivan et al. 2005). Many viral miRNAs target mRNAs of virus early genes or
DNA polymerase genes (Cullen 2009). Modulated by a plurality of host cell environments, viral miRNAs can regulate expression of viral genes and promote cell
environments conducive to the virus life cycle.


12

G. Yang and X. Zhang

Stress mainly refers to living cells being suddenly challenged by conditions of a
strong and harmful stimulus, such as infection, surgery, or hypoxia (Jindal and
Young 1992). Among them, it has been clearly demonstrated that virus infection
induces a variety of stress responses. For examples, vaccinia virus infection to
human monocyte-macrophages induces a severe stress response, leading to significant inhibition of mRNA expression levels and activation of interactions between
heat shock proteins and viral components (Sedger and Ruby 1994). Newcastle disease virus infection can stimulate the stress response and accumulate the mRNAs
and proteins in cells as well (Cuadrado-Castano et al. 2015). As soon as cells are
exposed to conditions of environmental stress, the cells would deviate from the
original status, resulting in dysregulation of macromolecules (proteins, mRNAs,
and lipids) and even causing metabolic disorder (Clarke et al. 2012). If the stress
responses are not coped properly, cells may result in tumorigenesis ultimately. To
survive from virus infection and maintain metabolic balances, the cells have evolved
multiple mechanisms to deal with stress responses, such as clearance of damaged
molecules by autophagy and regulation of certain gene expression programs (Yu
and Long 2015). It is well known that microRNAs (miRNAs) play indispensible
roles in gene expression regulation (Bushati and Cohen 2007). Their involvements
in the stress responses of virus infection to hosts have been demonstrated. It is well
known that miRNAs are loaded onto Ago protein to target the sites of the corresponding mRNAs, predominantly in the 3’ UTRs (untranslated regions), leading to

the destabilization of the mRNAs or translation inhibition to regulate many cellular
pathways (Bartel 2009; Shukla et al. 2011). As cells can adapt miRNA pathways to
regulate gene expression to deal with stress responses, more and more investigations have been performed to examine the roles of miRNAs in stress responses during virus-host interaction. Several lines of evidence indicate that virus infection can
alter the expression levels of host miRNAs (Leung and Sharp 2010). It has also been
reported that the miRNAs of marine invertebrate Marsupenaeus japonicus shrimp
present different expression patterns in response to virus infection (Cui et al. 2015).
The profile of miRNAs is changed in HIV type 1 (HIV-1)-positive individuals
(Houzet et al. 2008). Emerging data have shown that miRNAs play key roles in the
regulation of metabolism upon stress responses (Bandiera et al. 2016). When human
hepatocytes are challenged with hepatitis C virus, miR-146a-5p can control fatty
acid metabolism and energetic metabolism that contribute to the pathogenesis of
liver disease (Bandiera et al. 2016). Therefore, the miRNAs, which play important
roles in the stress responses, can regulate the metabolism of organisms. As well
known, metabolic disturbance would contribute to tumorigenesis. Previous investigations have also shown that the altered cellular metabolism in cancer cells can
result in malignant transformation and the initiation, growth, and maintenance of
tumors (Le et al. 2018; Seyfried et al. 2014). In this context, miRNAs may bridge
the stress response and tumor progression. The miRNAs possessing antiviral activity may have antitumor capacity.
Apoptosis, one form of programmed cell death, is considered an important cellular defense mechanism that inhibits viral replication and eliminates infected cells
in multicellular organisms (Qin et al. 2017). If apoptosis takes places before com-


1  Overview of Virus Infection and Tumorigenesis

13

pletion of viral replication, progeny virion production will be greatly blockaded,
preventing virus spread in the host. On the other hand, various strategies have been
evolved by many viruses to suppress apoptosis of host cells during virus infection,
thus prolonging the viability of host cells until sufficient progenies of the virus have
been generated (Koyama et al. 2003). However, in order to facilitate the assembly

or release of progeny virus without triggering inflammatory responses, viruses
sometimes intentionally induce apoptosis (Hay and Kannourakis 2002). In our previous study, it was found that 199 miRNAs were involved in the regulation of apoptosis of shrimp, among which 8 miRNAs were evolutionarily conserved in animals,
by shrimp miRNA microarray (Yang et al. 2014). The results indicate that miR-100
silencing results in the increase of apoptotic activity of shrimp hemocytes and further lead to the decreases of virus genome copies in shrimp and virus-infected
shrimp mortality compared with the controls, suggesting that miR-100 can serve as
an anti-apoptosis miRNA (Yang et al. 2014). A further analysis of primary tumor
samples from gastric cancer patients shows a significant correlation between miR-­
100 upregulation and primary human gastric tumorigenesis and progression (Yang
et al. 2017b). The results of in vivo and in vitro experiments indicate that miR-100
antagonism specifically triggers apoptosis of poorly differentiated gastric cancer
cells but not non-cancerous gastric cells. These data present that miR-100 is essential for regulating the progression of gastric tumors. It is found that during the regulation of p53-dependent apoptosis of tumor cells, miR-100 antagonism inhibits the
degradation of ubiquitin-mediated p53 protein by activating RNF144B, which is an
E3 ubiquitination ligase. As a result, the miR-100-RNF144B-pirh2-p53 pathway is
triggered. These findings highlight a novel mechanism of ubiquitin-mediated p53
protein degradation in apoptosis and demonstrate that anti-miR-100 possessing
antiviral activity has antitumor capacity (Yang et al. 2017b).
It is well known that miRNAs possess multiple targets, implying that an individual miRNA can regulate the expressions of different genes from different species. In the virus-host interactions, virus infection results in metabolic disturbance
of host cells to enhance Warburg effect, fatty acid synthesis, and glutaminolysis. In
order to restore the virus-caused metabolic disorder of host cells, some miRNAs can
be upregulated or downregulated to regulate the expressions of miRNAs’ target
genes (Cui et  al. 2017). These antiviral miRNAs may have antitumor capacity,
because tumorigenesis results from metabolic disorder of cells. In our study, it is
found that shrimp miR-34, which is upregulated during white spot syndrome virus
(WSSV) infection, has antiviral activity in shrimp (Cui et  al. 2017). The results
show that the expression of shrimp miR-34 in breast cancer cells and in mice in vivo
can suppress the growth and metastasis of breast cancer by targeting human CCND1,
CDK6, CCNE2, E2F3, FOSL1, and MET genes in a cross-phylum manner, respectively (Cui et al. 2017). The data of this study indicate that miRNAs with antiviral
activities can be promising sources for antitumor drug discovery. With the discovery
of leukemia stem cells, there has been a growing understanding that malignant
tumors consist of two distinct cell subpopulations, the few cells that continue to

generate descendant cells semi-permanently (cancer stem cells) and the other cells
that eventually stop growing as a consequence of differentiation and aging (cancer


14

G. Yang and X. Zhang

non-stem cells). In another investigation from our group (Yang et al. 2017a), we
report that a novel approach to ablate melanoma stem-like cells by targeting the
transcription factor YB-1, which is significantly and selectively upregulated in these
cells in melanoma. Silencing YB-1 expression is sufficient to significantly inhibit
the stemness of melanoma stem-like cells. In exploring YB-1 targeting, we discover
that the shrimp microRNA miR-S8 can suppress human YB-1 expression in melanoma stem-like cells. Mechanistic investigations reveal that miR-S8 recognizes the
3’ UTR of YB-1 mRNA and mediates its degradation. In tumor cells and xenograft
experiments, miR-S8 suppresses the tumorigenic capacity of melanoma stem-like
cells by targeting human YB-1. Overall, our results illuminate a novel aspect of
miRNA-mediated cross-species gene expression and its use in regulating cancer
stem-like cells. These findings indicate that the antiviral miRNAs derived from
shrimp stress responses to virus infection can possess the antitumor capacity of
human being in a cross-species manner (Yang et al. 2017a).

1.5.2  E
 ffects of Metabolites from Bacterial Stress Response
to Bacteriophage Infection on Tumorigenesis
Oceans, which cover more than 70% of the Earth’s surface, represent an enormous
resource for the discovery of potential therapeutic agents for diseases (Mayer et al.
2017; Russo et al. 2015). Marine organisms are important sources of bioactive molecules that have been identified from oceans to treat various diseases, including
cancers (Wang et al. 2017). Unusual marine environments contribute to chemical
diversity, which is a great resource of novel active substances for the development

of bioactive products (Anjum et  al. 2017). Among them, natural products from
microorganisms have been a major resource for the discovery of new antitumor
drugs (Hansen and Andersen 2016). In the past decades, it is easier and more convenient to isolate natural products from terrestrial microbes. However, due to the
intensive exploration, the discovery and development of new drugs from terrestrial
microbes have been greatly hindered currently. Therefore, the exploration for new
bioactive microbial natural products has extended into marine environment (Cherigo
et al. 2015). Since the 1970s, many structurally diverse natural products with significant bioactivities have been discovered from marine microbes (Robles-Fernandez
et al. 2013). Besides antibiotics, antitumor drugs are also screened from the marine
microbial metabolites. Right now, more and more antitumor drugs under clinical
trials are obtained from marine microbes (De and Chatterji 2017; Valcarcel et al.
2017).
It is well known that one of the characters of normal cell physiology is the metabolic hemostasis. However, because of mutations of the metabolic genes, the metabolic homeostasis of cancer cells has been gradually changed, ultimately resulting
in malignant tumors (Cairns et al. 2011). Over the last few decades, there are accumulating evidences about tumorigenesis associating with metabolic disorder (Wang


1  Overview of Virus Infection and Tumorigenesis

15

et al. 2016). Upon the transformation of normal cells into malignancy, the metabolic
disorder of tumor cells produces antioxidant molecules to counteract the detrimental effects of reactive oxygen species (ROS), enhances the aerobic glycolysis
(Warburg effect), and changes tumor microenvironment into abnormal states of low
pH, low glucose concentration, and hypoxia (Harguindey et  al. 2005; Liu et  al.
2005; Rietman et al. 2013). At present, some antitumor agents targeting metabolic
homeostasis have been identified, such as 2-deoxyglucose, L-asparagine, and dactolisib (Ciavardelli et al. 2014).
In the virus-host interactions, virus infection results in metabolic disturbance of
host cells to enhance Warburg effect, fatty acid synthesis, and glutaminolysis
(Colombo et al. 2001; Jiang et al. 2007; Su et al. 2014). Virus replication and specific cellular substrates for virus particles take great advantage of energy usage from
these modifications of host metabolism. It has been indicated that the metabolism of
host cells can be augmented during virus infection to produce differentially

expressed metabolites. It is found that during the infection of Sulfitobacter sp. by
roseophage, 71% of the detected metabolites are significantly increased, and the
cells infected by phage have also elevated metabolic activity (Ankrah et al. 2014).
These differential metabolites responding to virus infection may have multiple roles
in cells, including inhibiting abnormal metabolism, reconstructing metabolic
homeostasis, and resisting virus proliferation. Therefore, in the aspect of metabolic
disturbance, cancer cells and virus-infected host cells have the similar characteristics. The microbial metabolites in response to virus infection not only take great
effects on the metabolism microbes but also are potential resources for screening
antitumor drugs.
Our results show that the metabolic profiles of the bacteriophage GVE2-infected
and virus-free thermophile Geobacillus sp. E263 from a deep-sea hydrothermal
vent are remarkably different (He et al. 2018). Thirteen metabolites are significantly
elevated, and two metabolites are downregulated in thermophile stress response to
GVE2 infection. Further analysis shows that L-norleucine functions in a way of
eradicating viruses in thermophile and the results of in  vitro and in  vivo assays
reveal that L-norleucine and its derivative significantly suppress the metastasis of
gastric and breast cancer cells. Mechanistically, by interaction with hnRNPA2/B1
protein, L-norleucine inhibits the expressions of Twist1 and Snail, which are two
inhibitors of E-cadherin, and accumulates E-cadherin in cells, thus resulting in the
inhibition of tumor metastasis. Therefore, our findings reveal that the antiviral
homeostasis-maintaining metabolites of microbes, produced during marine hosts’
stress response to virus infection, may be a promising source for antitumor drugs.

1.6  Brief Description of the Book
During host stress response to virus infection, upon the infection of virus, the metabolic machinery of living cells is manipulated by viruses for completing their life
cycles. Because viruses finish their life cycles in host cells, the viruses must


16


G. Yang and X. Zhang
Virus
Virus
infection

Antiviral
molecules

Secondary
metobolites

proteins
Normal cell

Metabolic disorder
Homeostasis
reconstruction

Antiviral
pathways

miRNAs

Antiviral
molecules

Homeostasis and
virus eradication

Metabolic

disregulation

Normal cell

Cancer cell

Cancer cell death

Fig. 1.1  The model for the role of antiviral molecules in maintaining the metabolic homeostasis
of virus-infected host cells and cancer cells

interfere with the normal metabolism of host cells to maximize their replication and
to overcome the host defense mechanisms. On the other hand, the immune responses
of host cells are activated to defend themselves from viruses (Fig. 1.1). Upon sensing invading viruses, the host cells trigger various signaling events that ultimately
lead to severe responses against virus infection. Among these responses, secondary
metabolites, proteins, and miRNAs are generated as antiviral molecules, thus ultimately leading to metabolic homeostasis of host cells or virus eradication (Fig. 1.1).
It is well known that cancer is a disease, in which metabolic change is one of the
most obvious signatures to promote survival and growth of cancer cells. The metabolism of cancer cells is abnormal compared with the corresponding normal cells. In
the aspect of metabolic disturbance, cancer cells and virus-infected host cells are
similar. In the essence, the role of antiviral molecules is to maintain the metabolic
homeostasis of virus-infected host cells. Therefore the antiviral molecules induced
by virus infection may play important roles in antitumor pathways, resulting in
cancer cell death or restoring the disordered metabolism of cancer cells to normal
homeostasis of normal cells (Fig. 1.1).
This book contains nine chapters discussing virus infection and tumorigenesis to
get hints from marine hosts’ stress responses. The first chapter provides a brief
introduction. The second chapter introduces marine viruses, mainly describing the
importance and diversity of marine viruses and the interaction between marine
viruses and their hosts. The third chapter talks about marine invertebrate stress
responses to virus infection, which mainly focuses on responses from several

­species of marine invertebrates after virus infection, such as Arthropoda, Mollusca,
and Echinodermata. The fourth chapter mainly introduces the antiviral role of
microRNA in marine invertebrates. The main contents in this chapter include the
role of microRNA encoded by marine invertebrates in inhibiting viral gene expression and in activating host antiviral signaling pathways. Besides that, this chapter
also talks about the role of microRNA encoded by virus in escaping host antiviral


1  Overview of Virus Infection and Tumorigenesis

17

immunity. The fifth chapter introduces the stress responses of marine microorganisms caused by bacteriophage infection. The main contents in this chapter cover the
antiviral mechanisms of marine microorganisms at various stages of phage infection
including the pathways associated with variation of protein levels and host metabolic levels against the infection. The sixth chapter talks about secondary metabolites in bacteriophage-microbe interactions and their functions in antiviral infection.
The seventh chapter mainly introduces the relationship between tumorigenesis and
metabolism disorder, which focuses on the molecular mechanisms of tumor metabolic disorder, the importance of metabolites in tumorigenesis, and the feasibility of
metabolites being the targets for cancer treatments. The eighth chapter introduces
the effects of microRNAs from marine invertebrate stress responses to virus infection on tumorigenesis. This chapter mainly includes dysregulation of miRNAs from
marine invertebrate in responses to virus infection and the functions of corresponding miRNAs in tumor formation. The ninth chapter covers the antitumor activities
of secondary metabolites from marine microbe stress responses to virus, mainly
including the metabolic disorder caused by the virus infection, the metabolic disorder of the tumor cells, and the antitumor activity of secondary metabolites generated
from viral infection.

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