Potential role of Escherichia coli DNA mismatch repair proteins in colon cancer

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Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx

Potential role of Escherichia coli DNA mismatch repair proteins in colon cancer Shahanavaj Khan a,b,∗ a Department of Bioscience, Shri Ram Group of College (SRGC), Muzaffarnagar, UP, India Nanomedicine & Biotechnology Research Unit, Department of Pharmaceutics, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia

b

Accepted 5 May 2015

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Pathogenesis of EPEC in colorectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1. DNA repair genes and colorectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3. Idiosyncratic association of E. coli with colorectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4. Possible role of E. coli in host cell cycle modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. Cytotoxic necrotizing factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. Cycle inhibiting factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.3. Cytolethal distending toxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.4. Polyketide synthase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5. Possible role of the MutS, MutL and MutY gene of E. coli in CRC etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 6. Entry of intracellular E. coli effector molecules in host nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 7. In-silico prediction of E. coli MMR proteins host sub cellular localization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 8. Possible effects of MMR proteins or its epigenetic regulators in CRC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 9. Opportunity of horizontal gene transfer in progression of CRC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 10. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 11. Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Summary The epithelium of gastrointestinal tract organizes many innate defense systems against to microbial intruders such as integrity of epithelial, rapid eviction of infected cells, quick turnover of epithelial cell, intrinsic immune responses and autophagy. However, Enteropathogenic Escherichia coli (EPEC) are equipped with well developed infectious tricks that evade the host defense systems and utilize the gastrointestinal epithelium as a multiplicative foothold. During multiplication on and within the epithelium, EPEC secrete various toxins that can weaken, usurp, and use many host cellular systems. However, the possible mechanisms of pathogenesis are still poorly elusive. Recent study reveals

∗ Corresponding author at: Nanomedicine & Biotechnology Research Unit, Department of Pharmaceutics, College of Pharmacy, PO Box 2457, King Saud University, Riyadh 11451, Saudi Arabia. Tel.: +966 547186047. E-mail address: [email protected]

http://dx.doi.org/10.1016/j.critrevonc.2015.05.002 1040-8428/© 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Khan S. Potential role of Escherichia coli DNA mismatch repair proteins in colon cancer. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.05.002

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the existence of EPEC in colorectal cancer patients and their potential role in depletion of DNA mismatch repair (MMR) proteins of host cell in colonic cell lines. The EPEC colonised intracellularly in colon mucosa of colorectal carcinoma whereas extracellular strain detected in mucosa of normal colon cells. Interestingly, alteration in MutS, MutL complexes and MUTYH of mammalian cells may be involved in development of CRC. These data propose that MMR of E. coli may be potential therapeutic targets and early detection biomarkers for CRC. This article reviews the potential role of E. coli MutS, MutL and MutY protein in CRC etiology. © 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: E. coli; DNA repair genes; In-silico; Protein targeting; etiology; CRC

1. Introduction

2. Pathogenesis of EPEC in colorectal cancer

Colorectal cancer (CRC) is the third most prevalent cancer and fourth most common reason of malignancy death in the world. About 693,933 deaths and 1360,602 new cases were recorded worldwide due to high prevalence of CRC according to the GLOBOCAN estimates in 2012 [1]. Aetiology of CRC is multifaceted and very complicated. The association of infectious agents in the etiology of cancer has focused the interest of scientists in resent year. The microbial communities of intestine known as “microbiota” have crucial role in health and disease of human and other living beings. The microbiota normally controls the host in a beneficial style through altering the immune and gastrointestinal functions, applying defence against pathogenic microbes [2]. The gut microbiota is probably connected in the growth of colorectal carcinoma through different mechanisms. This is due to the effective role of inflammation in creating conditions that can intensely change local immune responses and, subsequently, tissue homeostasis. At present, a connection of bacterial, viral and other infectious agents with cancer is found in about 15–20% of the entire malignancies [3,4]. Primarily commensal inhabitant Escherichia coli is a member of the mammalian intestinal microbiota, colonizing the gut after birth and persisting throughout the life of the host. E. coli isolates can be classified in five major phylogenetic groups including A, B1, B2, D and E. The B2 group of E. coli are retrieved less frequently although can remain exist in the colon in compression to other groups and show about 30–50% of isolates separated from the feces of healthy persons residing in high-income states [5]. Pathogenic strains belong to B2 and D phylogroups are involved in intestinal and extra-intestinal diseases, whereas most fecal strain A1 and B1 phylogroup are non-pathogenic. Subgroup B2 and D generally carries virulence factors that are lacking in subgroup A and B1 strains. The colonic mucosa of CRC patients showed cyclomodulin-producing E. coli, mostly belonging to B2 phylogroup [6]. The potential role of the human gut microbiota including E. coli for colon cancer has not received serious attention. Furthermore efforts are needed to completely understand the possible role of pathogenic E. coli in progression and development of CRC.

Pathogenic bacteria EPEC have the capability to causing attaching and effacing lesions on the surface of the host’s intestinal epithelium through distinct colonization adeptness. [7]. E. coli are act as commensal bacteria in human intestine, although several pathogenic isolates have acquired the capability to encourage chronic inflammation and generate many toxins including cyclomodulin, which may be involve in carcinogenesis [8]. The mysterious relationship of colorectal cancer (CRC) with E. coli has attracted the attention of cancer researchers in the role of this particular bacterium in cancer growth and development. E. coli is mainly classified as a commensal bacterium and begins to colonize the human gut with little abundance just after birth [9]. E. coli produce a broad range of proteins into the cells and tissues of host to promote their replication, transcription, survival and dissemination potential. The awareness that these effector proteins can disclose novel pathogenic properties of E. coli has led researchers to identify novel and effective approaches to rapidly characterize and identify these proteins. Recent research confirmed that pathogenic strain of E. coli could also play crucial role in pathogenesis of colorectal cancer [10]. Extremely elevated levels of E. coli, may be related to alterations in colon and intestinal permeability, inflammatory responses associated with inflammatory bowel disease (IBD) [10,11]. There is a broad variety of E. coli genotypes in common serotypes such as pathogenic strains that are responsible for various diseases, infection, and nonpathogenic strains that could be linked with many disease phenotypes. For instance, colonization of mucosa-associated E. coli was identified to induce local inflammation in patients with colon cancer, but not Crohn’s disease whereas another subset of adherentinvasive E. coli was generally observed in individuals with IBD including Crohn’s disease and ulcerative colitis [12–15]. 2.1. DNA repair genes and colorectal cancer The highly conserved region of MutS, MutL and MutY are present in many eukaryotes including yeast, mice and humans in addition to many prokaryotes such as E. coli, Helicobacter pylori, Deinococcus radiodurans, Pseudomonas aeruginosa, Bacillus subtilis, Neisseria gonorrhoeae and Neisseria meningitides [16]. Recently, published papers

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demonstrated that E. coli has the potential to promote invasive carcinoma in mice [17–19]. However corroboration of its etiological capability in humans is still remaining a genuine appraisal, a rational mechanistic explanation for this link has been provided by chronic inflammation. Stimulation of highly reactive chemical species and proinflammatory cytokines during chronic inflammation directs to nitration, oxidation and/or chlorination of nucleotides in RNA, DNA and proteins [20], which may be cause of cancer. The infection of E. coli is involved in inflammatory bowel disease (IBD) due to chronic inflammation of intestine. It has been studied that the cause of IBD involves a regular inflation in mucosa-connected E. coli through a specific manner of adherent and invasive phenotype. Although various species of bacteria are also connected with IBD [21], the current evidence of E. coli mediated carcinogenesis in mice focus our interest towards this micro-organism as a potential etiologic cause in humans CRC. Two types of IBD, such as ulcerative colitis (UC) and Crohn’s disease (CD), are linked with an increased threat in the growth and development of colon cancer [22,23].

3. Idiosyncratic association of E. coli with colorectal cancer It is excellent outcome note that the colorectal carcinoma mucosa, is colonised by intracellular E. coli, although not normal colonic mucosa in addition to the mechanistic association between chronic inflammation and CRC growth and development [24]. The unique cascade of pro-inflammatory and anti-inflammatory molecules involves in chronic inflammation and consequent tissue damage. The equilibrium between these two groups of regulators controls cell death and repair of tissue damage caused due to cell death. Cell death and repair of damage tissue caused due to cell death manages by the equilibrium between these two groups of regulators. Though, many problems in this equilibrium may direct to the development of cancer [25]. Additional factors include cellular mutations also controlling the development of CRC. Various cellular mutations have been characterised as etiologic causes for colon cancer [26]. The DNA repair systems are highly conserved with respect to their central roles in MMR among eukaryotes including human, yeast [27,28] and prokaryotes such as Thermus thermophilus and E. coli (Table 1) [29–32]. The MSH2/MSH6 designates as a MutS homolog, while MLH1/PMS1 considered as homologs of MutL [33]. Study of 16 exons of MSH2 in 34 unrelated HNPCC analogs has showed a heterogeneous array of mutations [34,35]. Four MutS, homologs MSH2, MLH1, MSH6, and PMS2 have been identified as susceptible to hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome in human. Among the mutations associated to HNPCC, MSH2, which encodes a protein of mismatch repair (MMR) pathway is acts an essential role in DNA damage repair while MSH3 and MSH6 seem to alter the

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specificity of this recognition [36]. Hereditary nonpolyposis colorectal cancer (HNPCC) is acquired in an autosomal dominant manner, where only a copy of mutated mismatch repair gene is adequate to develop HNPCC phenotype. Among the mutations linked to HNPCC, MSH2 gene causes approximate 50% of genetic alterations in this disease [37,38]. Though germline mutations in hMSH2 are associated to hereditary HNPCC, mutations causes somatically in this gene are also linked with cases of HNPCC [38]. It is noteworthy that the cellular hMSH2 gene is a homologue of the E. coli gene MutS, which is also responsible for regulating DNA damage repair [39]. Consequently it suggests an additional target for identifying the E. coli association with HNPCC.

4. Possible role of E. coli in host cell cycle modulation Many reports have confirmed the possible role of microbes in colorectal cancer etiology [7,23,40]. The potential of E. coli in the etiology of CRC raised much attention due to escalating data for that connection [15]. It has been confirmed in several studies that E. coli has an adequate efficiency to modulate the cell cycle, therefore raising the possibility for the growth of cancer. Pathogenic strain of E. coli synthesize many virulence factors, including several toxins called cyclomodulins which interrupt the host cell cycle and may act as a potential cell-cycle stimulators for the development of CRC [6]. 4.1. Cytotoxic necrotizing factor E. coli produced cytotoxic necrotizing factor (CNF) is a cyclomodulin which stimulates rho GTP binding protein and ultimately inhibits the process of program cell death. CNF modulates the expression of Bcl-2 key member of apoptotic regulators and mitochondrial homeostasis. It works as a suppressor of apoptosis and stimulator of cell cycle due to the initiation of DNA replication and G1/S transition [41–43]. 4.2. Cycle inhibiting factor Another E. coli toxin, identified as cycle inhibiting factor (Cif), has the capability to induce irreversible arrest of the cell cycle at the G2/M transition [44]. Enteropathogenic (EPEC) and enterohaemorrhagic (EHEC) strains of E. coli are produced Cif [45], induces G2/M arrest by induction of DNA damage independent pathway through supported inhibitory phosphorylation of CDK1 mitosis inducer [44]. Cif also initiates specific changes in the cytoskeleton of actin, directing to its adhering to the host cell membrane and cellular and nuclear enhancement. Nuclear enhancement arises due to repeated DNA replication in the deficiency of nuclear division [46]. The phenomena of endoreduplication amplifies content of cellular DNA, enhances gene copy number and proteins

Please cite this article in press as: Khan S. Potential role of Escherichia coli DNA mismatch repair proteins in colon cancer. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.05.002

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Table 1 Mismatch Repair proteins and their functions in prokaryotes (Escherichia coli, Thermus thermophilus) and eukaryotes (Homo sapiens Saccharomyces cerevisiae). E. coli

T. thermophilus

H. sapiens

S. cerevisiae

Molecular function

Cellular function

MutS

MutS

Mismatch repair

MutL

Complex (Homo/hetrodimer)

Mismatch repair

MutY

MutY

MutS␣ (MSH2/MSH6) MutS␤ (MSH2/MSH3) MutL␣(MLH1/PMS1) MutL␤(MLH1/MLH2) MutL␥(MLH1/MLH3) –

Mismatch recognition

MutL

MutS␣ (MSH2/MSH6) MutS␤ (MSH2/MSH3) MutL␣(MLH1/PMS1) MutL␤(MLH1/MLH2) MutL␥(MLH1/MLH3) MutYH

Base excision

Mismatch repair

containing growth factors directing to fast growth of cells and maybe cause of cancer [43,47,48]. 4.3. Cytolethal distending toxin Furthermore, cytolethal distending toxin (CDT) is produced by E. coli, which arrests the cell cycle through inflicting of DNA damage [49,50]. CDT is a tripartite complex with the active subunit of CdtB homologous to human DNAse I and CdtA and CdtC [51]. The potential function of CDT in the process of carcinogenic has been identified in a microbial induced hepatocarcinogenesis mouse model. It was examined that Helicobacter hepaticus CDT helped the progress of dysplasia from hepatitis and enhanced proliferation of hepatocytes in this model [52,53]. 4.4. Polyketide synthase Similarly a cyclomodulin polyketide synthase (pks) is also produces by E. coli. The pks island, expressing the colibactin a DNA-damaging toxin, was identified in NC101 strain of E. coli and was also observed in approximate 70% of intestinal E. coli strains in CRC patients. Pks+ E. coli associated with mucosa were detected in a considerably high percentage of CRC and IBD patients [54,55]. The enhanced existence of the E. coli in the colon of IBD patients, and also in those with colon cancer who do not suffer from IBD, recommends that toxins produced by the pks genes have a deleterious effect. This was observed that pks prevented host cell division by inducing cell cycle arrest and enhancing the G2 checkpoint. Pks was also linked with the accumulation of double-strand DNA break (DSBs) and thus has genotoxic activity [18,56]. Recently it has been reported that E. coli infected host cells mismatch repair activity is decreased significantly in colon cancer cell lines and also in CRC patients [57]. The reduced DNA repair activity is directly associated to an acceleration of mutations and is a expected reason for E. coli mediated cancer. Moreover such attributes of cell metabolism in E. coli promoted cancer etiology, this microbes have limited or non-considerable capability for the alteration of N-hydroxy-4-acetyl-aminobiphenyl (N-OH-AABP) to 4-acetylaminobiphenyl [58]. It has been identified that the intestinal microflora have the capability to alter some

carcinogens to non-toxic products in the intestine and therefore decrease the risk of cancer [59]. Though, E. coli is normally exist as a prominent micro organism and can decrease this attribute of the gut microflora during the development of IBD. However many details of evidence suggested carcinogenic activity of E. coli, as an acceptable consent cannot be accomplished on any particular mechanism. The current status requires the more confident data and the identification of more reliable mechanism for the E. coli-CRC relationship.

5. Possible role of the MutS, MutL and MutY gene of E. coli in CRC etiology As per the diverse evidence explained above related to etiology of microbes with CRC, it is fascinating to deduce a possible role of MutS, MutL and MutY along with other DNA repair genes of E. coli in the growth and development of CRC. Specific EPEC strains of E. coli is able to survive in colon cells as a chronic intracellular pathogen and that close connection between the colon cells and bacteria offers a chance for the bacteria to multiply for several generations and for the mature bacterial cells to secrete their contents in cytoplasm of colon cells. Therefore, it can be consider that E. coli reside intracellular will deliver their DNA, MutS, MutL, MutY and other genes products into the host colon cell. A study showed that dimerization of MutS is essential in E. coli but not tetramerization for mismatch repair. But the proposed hypothesis emerges several enigmatic questions. First, can MutS, MutL, MutY and other DNA repair gene products of E. coli transfer from cytoplasm to nucleus of colon cell? Second, do MutS, MutL, MutY and other DNA repair gene products of E. coli interfere with the action of human MMR system protein? Third, due to the considerable homology between MutS, MutL, MutY of E. coli with human MSH2/MSH6, MLH1/PMS1, MUTYH and other DNA repair genes, can horizontal gene transfer (HGT) incidents feasible, that might influence DNA performance? Fourth and last, do epigenetic factors that regulate MutS, MutL, MutY and other DNA repair gene expression also influence MSH2/MSH6, MLH1/PMS1, MUTYH and other genes expression? Even though distant, each of these

Please cite this article in press as: Khan S. Potential role of Escherichia coli DNA mismatch repair proteins in colon cancer. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.05.002

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Figure 1. Schematic representations illustrate the potential role of E. coli MutS, MutL and MutY protein and their products in etiology of CRC through the establishment of intracellular E. coli in colon cells during chronic infection. At homeostasis, normal colonic mucosa colonised by intercellular E. coli in healthy host and prevented from attaching to normal epithelial cells. The colorectal carcinoma mucosa colonised by intracellular E. coli through attachment with epithelial cells in case of CRC. (I) The pathogenic strains of EPEC can disrupt the barrier of epithelial cells, hamper epithelial cell autophagy to support intracellular survival, and up-regulate epithelial cells surface receptors to increase adherence capacity and entry of E. coli in host cells. Furthermore, migration and accumulation of cylomodulin and genotoxin in the host nucleus due to intracellular existence of E. coli. in colon cancer cells. (II) The MMR proteins of E. coli may alter the affectivity of MMR proteins of host cell. (III) The epigenetic regulators of E. coli MutS, MutL and MutY may alter the expression of human MMR protein, which may be possible agents for development of CRC. (IV) Coincidence of horizontal gene transfer may happen with host DNA due to breaking of E. coli DNA and specific sequence homology between MMR genes of E. coli and MMR genes of human, which may eventually potential source for growth and development of CRC.

incidents could direct to an anomalous and defective DNA repair pathway and eventually support the growth of colon cancer (Fig. 1). The defeat in function of MMR protein is suggested as a possible cause of cancer. Altogether, collective presence of host and bacterial DNA MMR proteins can interfere with binding of each other and may be involved in the etiology of colon cancer.

6. Entry of intracellular E. coli effector molecules in host nucleus Several studies have confirmed high prevalence of invasive strains of E. coli such as EIEC, ETEC and LF82 associated with CD patients compared to that for controls, helping in support of putative role of E. coli invasiveness in the pathogenesis of CD [60,61]. The LF82 strain of E. coli isolated from a patient of chronic ileal lesion with CD shown that it is also act as invasive pathogen through OmpC and the sigma(E) regulatory pathway [62]. It invades a broad range of human epithelial cell lines. It is well-studded that EPEC strains of E. coli synthesize diverse types of effector molecules that are capable to altering the cellular DNA repair [63]. The cytosolic localization of E. coli inside to colon cells permits the bacteria to secrete the effector molecules directly into the cytoplasm of

host cells, although these bacterial effector molecules must enter in the cell nucleus of host cell to affect cellular processes. E. coli usually utilises a type three secretion system (T3SS) to transport the effector molecules of bacterial into the cell of eukaryotic host. Although, when bacterial cells are living intracellularly the nuclear localization of the bacterial proteins based on the existence of nuclear localization signals (NLS) on the bacterial proteins [64,65]. NLS are needed for the transfer of proteins from the cytoplasm to nucleus in the active transportation, however <40 kDa molecular weights proteins can transfer to the nucleus by a passive transport system [66,67]. The epigenetic regulators also have a comparable susceptibility for intracellular localization due to efficient relatedness similar to mutY. For instance, replication terminator protein Tus, an epigenetic regulator of E. coli, has both a nuclear export signal (NES) and NLS, which can therefore target the nucleus of host cell. However research in this field is in the very early stages. Among the replication proteins Tus protein is the first protein to illustrated both NES and NLS properties, therefore confirming a possible role in epigenetic targeting to nucleus of the host cell [68]. Although, potential research on epigenetic regulators of bacteria will, surely, discover related host nuclear targeting potential for several proteins of E. coli, perhaps including MutS, MutL and MutY.

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7. In-silico prediction of E. coli MMR proteins host sub cellular localization

8. Possible effects of MMR proteins or its epigenetic regulators in CRC

We were analyzed the MutL, MutS and MutY protein of E. coli (NCBI Accession numbers EDX31583.1; EHF28260.1; EGT70329) for the presence of the nuclear localization signal and eukaryotic cell sub cellular localization through nuclear localization signal (NLS), Balanced Sub Cellular Localization predictor (BaCeILo) mapper and Cell-PLoc in-silico methods [69–71]. The complete protein sequences were used to predict monopartite as well bipartite NLS sequence. According to the literature of cNLS mapper, proteins with cut off value 1–2, 3–5, 7–8, and 8–10 were predicted as localized to the cytoplasm, localized to both nucleus and cytoplasm, partially localized to nucleus, and localized to the nucleus, respectively. In case of multiple NLS sequence in same proteins, the highest cut off value was recorded. The sub cellular localization in other eukaryotic cell compartments was predicted through the Balanced Sub Cellular Localization predictor (BaCeILo) Cell-PLoc. BaCeILo predict cytoplasmic, mitochondrial, nuclear, secretory localization of proteins in plants, animals, and fungi. In addition, Cell-PLoc predict sub cellular localization in eukaryotes, human, plant, Gram-positive bacterial, Gramnegative bacterial and viral proteins through six predictor Euk-mPLoc, Hum-mPLoc, Plant-PLoc, Gpos-PLoc, GnegPLoc and Virus-PLoc, respectively. Hum-mPLoc predicts fourteen sub cellular localization in human such as cytoplasm, nucleus, mitochondria, golgi apparatus, lysosome, centriole, cytoskeleton, endoplasmic reticulum, endosome, extracell, lysosome, microsome, peroxisome, plasma membrane, and synapse. The result of cNLS mapper showed that MutS and (Accession numbers EHF28260.1) MutY (EGT70329) proteins of E. coli can migrate to the host nucleus while MutL protein (EDX31583.1) partially enters to nucleus. Further result of BaCelLo confirmed the entry of MutS and (Accession numbers EHF28260.1) MutY (EGT70329) protein in nucleus except MutL during intracellular infections of E coli. The result of Hum-mPLoc (a tool of Cell-PLoc) reveled that MutL partially migrate to nucleus while MutS and MutY protein enter to golgi apparatus and lysosome, respectively. The little deviation in result may be due to attachment of golgi apparatus to nuclear membrane and little sequences of lysosome in human Hum-mPLoc. However no strict correlation was monitored between cNLS computational prediction tool and BaCeILo and/or Hum-mPLoc. This is partially due to various factors, including that only 27% and 30% of nuclear protein carry by Hum-mPLoc and NLS mapper. This condition offers a chance for competitive interaction of pathogen and host proteins through common sub-cellular substrates, thereby increasing the chances of growth and development of colon cancer. Though, the role of in-silico approach in predicting sub cellular localization with E. coli proteins as the query is questionable and needs to be experimentally validated.

In assessment with human MMR, E. coli MMR proteins are less complicated, which involes MutS and MutL and MutY proteins with their selected function, including correction in mismatches nucleotides during DNA replication and escape proofreading. As the considerable homology between the bacterial MutS, MutL, MutY and other DNA repair genes with human MutS (MSH2/MSH6), MutL (MLH1/PMS1), MUTYH and other genes, the structural and functional analogies between the gene products are about possible. Therefore it can be supposed that if two homologs proteins with identical enzymatic action are exist in the same cell, the relative activity of proteins will be different and both can compete with each other for binding to their substrate. As MutS and MutY are the DNA repair associated proteins, the aberration in DNA repair can lead to development of colon cancer. It has been viewed earlier that the similar enzymes from diverse organisms can be different in their choice of substrate specificity. This fact is clear even for identical enzymes isolated from different bacteria. In the case of the identical enzyme from E. coli and humans, which are distant evolutionary, it is logical to suggest that the existence of both enzymes in the one cell at same instance can interfere actions of each other. This current scenario raises the feasibility that DNA repair can be weakened, permitting the accumulation of mutations that eventually lead to colon cancer. As described in above discussion, E. coli has the capacity to decrease DNA mismatch repair (MMR) in colonic cell lines of host cell and this has also been detected in patients of CRC. This method has been proposed as a potential mechanism for E. coli mediated carcinogenesis [57]. The enteropathogenic strain of E. coli (EPEC) has been demonstrated to produce an effector protein (EspF), which is effectively reducing MMR proteins [63]. The mode of action of effector protein EspF on MMR protein was under the influence on EspF mitochondrial targeting and posttranscriptional. The infection of EPEC also encouraged EspF-independent increase of host reactive oxygen species. However, the function of MutS, MutY and other DNA repair protein in decreasing the DNA repair activity of E. coli infected host cells also needs a specified appraisal. It is significant to note that bacteria posses the capability to transmit epigenetic changes of their eukaryotic host cells and promote pathological alterations through epigenetic re-planning [65]. Epigenetic alterations directing to cancer comprise DNA methylation, histone modification and micro RNA gene silencing [66,67,72]. Thus, on the basis of their sequence homology, MutS, MutY and other DNA repair genes of E. coli and MSH2, MUTYH and other homologous genes of eukaryotes host could share same epigenetic regulators and consequently cause comparable epigenetic changes in the DNA repair machinery of host cells. Micro RNAs are non-coding small RNA molecules interfered in silencing of various genes and translation inhibition including those play crucial role in

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cell proliferation, differentiation and program cell death. Recently, Masotti described that gut microbes have the ability to alter expression of micro RNA thus affecting many biological processes in the host cell of eukaryotes [73]. Gram negative bacterium E. coli within the gut microbes has the potential to alter the expression of micro RNA through it lipopolysaccharide (LPS) content. The LPS of gram negative microbes can promote the over expression of mir-155 although down regulate the expression of mir-125b micro RNAs in macrophages [74]. The inhabitant colonic microbiota is important for the synthesis of short chain fatty acids (SCFA) by the fermentation of indigestible carbohydrates. The secreated SCFAs comprise butyrate which is a inhibitor of enzyme histone deacetylase and can influence DNA methylation and histone modification [75,76]. DNA methylation is identified to alter the expression of many cancer related genes [77]. As the DNA methylation pattern changes from organism to organisms, it may possible that the existence of epigenetic regulators of E. coli can direct to reprogramming as a result alteration in genes expression of host cell including MSH2 MUTYH and other homologue genes. Alteration in DNA methylation pattern is a common molecular modification detected in humans CRC [78]. This idea has previously been explained in epigenetic reprogramming of host genes by intracellular bacteria and viruses [79]. Hence, chronic infection of E. coli may cause a serious condition where chronic inflammation, originated by the infection of E. coli, directs to MutS and/or MutY and other DNA repair proteins mediated cellular alterations in the DNA repair machinery of host cell that regulates the growth of CRC.

9. Opportunity of horizontal gene transfer in progression of CRC Many supports for the association of HGT in CRC progression appears from the illustration of extensive horizontal gene transfer from bacterial intracellular pathogens to their eukaryotic multi-cellular hosts. For example, Wolbachia pipientis an intracellular bacterial endosymbiont, has the capability to transport genes horizontally to their host [80]. The intracellular existence of E. coli in colon cells for the progression of CRC may thus direct to an analogous horizontal gene transfer [24]. Moreover, many microbes, specifically intracellular bacterial pathogens, can affect the metabolism and gene expression of host in order to maintain themselves within the cellular environment of host. Various research studies have been published on the subversion of cellular responses of host through intracellular pathogens [81]. There is a little dilemma regarding to the transfer of genetic material between intracellular E. coli and the cells of eukaryotic host because of many physical barriers, which exist between the host cell and intracellular bacteria. Although, in a comparative genomic report about 40 genes were analyzed that were reliable with lateral gene transfer between

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bacteria and multicellular eukaryotes [80]. During the infection of intracellular bacteria, the DNA of bacterium works as a symbiotic DNA molecule similar to the DNA of chloroplast or mitochondria. It is logical to suggest that these segments of bacterial DNA can influence the host MSH2/MSH6, MLH1/PMS1, MUTYH and other DNA repair genes by HGT. Although, it can be disputed that MSH2/MSH6, MLH1/PMS1, MUTYH and other DNA repair genes mutations are normally bi-allelic while E. coli mediated events direct primarily to mono-allelic mutations. It is significant to note that bi-allelic mutations are approximate ten times fast with comparison to mono allelic mutations in CRC. Therefore, both mono- and bi-allelic mutations have the capability to induced early and late cancers, respectively [82,83].

10. Concluding remarks Colorectal cancer is a leading cause of death and third most commonly diagnosed cancer. The colonization of gut commensal E. coli is tightly managed in normal persons by both host- and pathogen-derived mechanisms. Though, over expression of virulence factor in pathogenic E. coli is often observed in CRC. Recently many research groups examined the potential role of colibactin-producing E. coli in carcinogenic and transcriptional changes in pks-associated genes at the time of progression of colitis-associated CRC [17–19]. Mounting facts suggests a causal association between E. coli infection and CRC and the possible role of pathogenic E. coli for the progression and development of CRC. It was demonstrated that the colonic mucosa of cancer cells contained high numbers of pks+ strain of E. coli compared to non-cancerous colonic mucosa [57]. It has illustrated that EPEC can downregulate the expression of mismatch repair genes in colon epithelial cells. It may be imagined that this altered expression can direct to increased mutation rate. Cuevas-Ramos and colleagues showed that E. coli strains containing the pks island caused DNA damage in human epithelial cells. The gene of pks cluster codes for polyketide synthetases (pks) and non-ribosomal peptide synthetases that synthesize a genotoxin known as Colibactin. Many recent studies have revealed that colibactin is a crucial contributing factor to E. coli-mediated intestinal carcinogenesis [17,18]. Therefore, multiple interaction of different strain of E. coli may increased the carcinogenesis due to chance of recombination in between pks+ and pks− strain, lead to progression of CRC in normal epithelial cells and accelerate the development of CRC in cancer cells. The importance of EPEC interactions with colonic epithelium in causing CRC has been emphasized; however, conclusive scientific efforts in this enigmatic area is still lacking. Various aspects of the proposal summarized above, specifically the intracellular existence of E. coli in cancerous colon cells, the homology between the MutS and MSH2 and MutY and MUTYH genes, possible HGT from the intracellular reside E. coli at the time of colon cancer, and the

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existence of MutS, mutY, MSH2, MUTYH and other related gene products in particular cell offer clues for connecting these threads. Our findings support that EPEC infection could be a cofactor for colorectal carcinogenesis. Advance research will open new doors to understand etiology of CRC and assist us to design strategy for the control of infection of E. coli and CRC. As controlling of an infection is easier than controlling the cancer; thus the role of E. coli MustS, MutY and other DNA repair genes in CRC should be evaluated further.

11. Future perspectives Our existing knowledge regarding to pathogenesis of CRC arises many doubt regarding to possible role of E. coli MutS, MutY and related genes in colon cancer and scientific research in this area is discovering many excellent aspects for the pathogenesis of CRC. An explosion regarding host–pathogen interactions have been observed from past few years. The colonization of common gut commensal E. coli is tightly controlled in healthy individuals by both bacterial and host derived mechanisms. But, excessive representation of E. coli is often observed in disease states such as in IBD and CRC. Various defined microbiota possess distinctive traits of virulence known as alpha bugs including colibactinproducing E. coli have been identified as direct drivers of intestinal carcinogenesis. Many researchers have recently revealed the potential carcinogenic role of colibactin-expressing E. coli in animal models. In brief, advanced research has disclosed an immense deal of information considering the E. coli mechanisms applied to gut pathologies, including CRC and cure or cause cancer, but, various significant issues remain. For instance, do the E. coli cyclomodulins such as CDT and toxins including CNF1 initiate, and contribute to the protumorigenic potential. Another question, do the well defined site specific colonization of E. coli for a cancer be clinically important in treatment, care or detection? One more question is what causes direct to the dysbiotic condition in the inflamed intestine and particularly to the more predominance of E. coli. Final question, do attenuated E. coli be utilized in unharmed and efficiently vaccination as potential therapeutic agents? It should be very imperative to verify whether the activity of colibactin (genotoxic factors), is altered through the gut environment and therapeutic interferences. Colibactin alters many features of host reactions such as cell senescence DSB and transformation. Therefore, we require more research on how the E. coli proteins is assembled, regulated and transported to mediate host responses. This line of questions will continue to explore important insights into mechanisms of pathogenesis. The progressed study of these lines will bring important research still nearer to the mechanisms of pathogenesis of E. coli and prevention, early diagnosis and truly effective treatment of CRC for the betterment of mankind.

Conflict of interest statement The author declares he has no any financial or personal conflict of interest related to this work. Reviewers Professor Christian D. Rolfo, Head of Phase I—Early Clinical TRials Unit, University Hospital Antwerp, Phase I-Early Clinical Trials Unit—Oncology Department, Wilrijkstraat 10, B-2650 Edegem, Antwerpen, Belgium. Professor Hans-Joachim Schmoll, Martin-LutherUniversitat Halle-Wittenberg, Innere Med. IV, ErnstGrube-Strasse 40, D-06120 Halle, Germany. Acknowledgement The author is thankful to Deanship of Scientific Research and Research Center, College of Pharmacy, King Saud University, Saudi Arabia.

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Biography Dr. Shahanavaj Khan is an assistant professor of cancer biology at Nanomedicine & Biotechnology Research Unit, Department of Pharmaceutics, College of Pharmacy, King Saud University, where he worked on development of diagnostic kits for detection of cancer, health informatics and anticancer activity of natural and synthetic drugs with Dr. Abdul Arif Khan. I have contributed over 10 publications including expert review of anticancer therapy, Bioorg. Med. Chem. Lett., J. Biomater. etc. The current research interests in Khan’s group include: (1) Development of diagnostic kit for cancer detection; (2) Development of nanomaterials and evaluation of anticancer activity; and (3) Health informatics.

Please cite this article in press as: Khan S. Potential role of Escherichia coli DNA mismatch repair proteins in colon cancer. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.05.002