Mutation-promoting molecular networks of uncontrolled inflammation

Abstract

More and more studies show that chronic inflammation can lead to tumor formation. The complex interactions of inflammatory cells, stroma and tumor parenchymal cell are closely related to tumor formation. Under the state of chronic inflammatory microenvironment, long-term interaction of inflammatory cells and stromal cells as well as the parenchymal cells makes signaling pathway in parenchyma cells disordered. A series of gene level editor modification, epigenetic changes, and the regulation of transcription and translation changes will happen based on signaling pathway disorder. The changes ultimately lead to cell mutations and phenotypic transformation occurred. Recent findings provide an objective basis for cancer treatment and prevention. However, further discusses at the core of the possible molecular in tumor formation provide a theoretical foundation for future study of the pathogenesis and molecular targeted therapy of cancer. This review summarizes the research in the field of chronic inflammation and cancer in recent years, and analyze the molecules network in the process of the carcinogenic inflammation comprehensively. Beyond that, this review intends to describe possible carcinogenic inflammation core molecular and provides a theoretical basis for future study of the pathogenesis, chemoprevention and molecular targeted therapy of cancer.

Keywords

Chronic inflammatory microenvironment cancer uncontrolled inflammation

Introduction

Inflammation involves a series of dynamic reactions which occur when the body is subjected to physical and chemical injury or infection and the immune system is activated. A variety of inflammatory cells and inflammatory cytokines interact with each other to regulate the balance of pathophysiology in the inflammatory microenvironment. Under normal circumstances, the body’s regulation is restored when pro-inflammatory factors subside and inflammation is resolved. This is known as controllable inflammation, which can resolve infection and injuries, induce apoptosis of damaged cells, avoid the accumulation of damaged cells, and inhibit malignant transformation. If the stimulus persists, the inflammation will develop into a chronic non-controllable state with the infiltration of mononuclear cells.¹ The concept of inflammation mentioned below refers to chronic uncontrolled inflammation.

Epidemiological studies have shown that chronic inflammation leads to a significant increase in the incidence of cancer, particularly tumors of epithelial origin. For example, the incidence of pancreatic cancer following chronic pancreatitis increased by 16-fold, which did not include clinically difficult to detect small foci of inflammation in the pancreas. The incidence of colorectal cancer in patients with inflammatory bowel disease has significantly increased. Liver, stomach, bladder, prostate, and thyroid cancers are also associated with chronic inflammation.^2–6 Studies have shown that various factors leading to uncontrolled inflammation also cause cancer directly. Chronic infection is a predisposing factor for tumors. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection cause liver cancer, human papillomavirus (HPV) infection causes cervical cancer, Epstein–Barr (EB) virus infection causes nasopharyngeal carcinoma and multiple lymphoma, helicobacter pylori (Hp) infections cause gastric carcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma, and Opisthorchis viverrini infection causes cholangiocarcinoma.

Studies have shown that in a chronic inflammatory microenvironment, parenchymal cell signaling pathways are disordered. Followed which, a series of gene-level editor modifications, epigenetic changes, as well as transcription and translation regulation changes lead to cell mutations and phenotypic transformations. It is known that the carcinogenic process is not formed by a single signal, protein, or cytokine but by a complex molecular network consisting of a number of genes, various biological molecules, or metabolic small non-coding RNA molecules. Although the molecular network is extremely complex, there are key nodes in the core area which may involve the interaction of only a few key molecules.

Chronic inflammatory microenvironment

In general, a chronic inflammatory microenvironment includes inflammatory cells (neutrophils, eosinophils, lymphocytes, basophils, and macrophages) and matrix components (stellate cells, fibroblasts, immune cells, endothelial cells, extracellular matrix (ECM), as well as soluble proteins such as cytokines and growth factors) in addition to parenchymal cells. The formation of this microenvironment depends primarily on inflammatory cell activation. Inflammatory cells are activated by inflammatory stimuli such as tissue necrosis, bacterial infection, lipopolysaccharide (LPS), and bioactive lipids. Pro-inflammatory cytokines can be divided into two categories: pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). PAMPs, which are widely present on the surface of pathogens, are mainly recognized by Toll-like receptors (TLRs), scavenger receptors, nucleotide oligomerization domain (NOD)-like receptors (NLRs), RIG-I-like receptors (RLRs), and C-type lectin receptors (CLRs). PAMPs, including HMGB1 and heat shock proteins (HSPs), are mainly released in pathological conditions such as wounds and infection. Inflammatory cells recognize DAMPs via specific receptors such as TLRs. Once the pattern recognition receptors and the corresponding ligands bind, inflammatory cells are activated by downstream signaling pathways, leading to gene and cell phenotype expression changes. Activation of inflammatory cells marked by the nuclear factor-κB (NF-κb) signaling pathway forms a wide variety of inflammatory signaling molecules mediating an inflammatory microenvironment through autocrine or paracrine factors, which promote further release of inflammatory mediators, resulting in the inflammation of cascade.

Further evidence has shown that the inflammatory microenvironment matrix components including stellate cells, fibroblasts, myofibroblasts, blood vessels, and the ECM also play important roles in maintaining the inflammatory microenvironment. Parenchymal cells are always present in the chronic inflammatory microenvironment. Similar to the process of development and regeneration interactions between endoderm and mesoderm cells, there are also interactions between epithelial and mesenchymal cells in the chronic inflammatory process, which are highly dynamic interactions and can affect the inflammatory microenvironment. Mesenchymal cells by secreting cytokines may induce the differentiation of epithelial cells. The main source of fibroblast-like cells is stellate cells. Hepatic stellate cells, for example, are activated primarily by autocrine or paracrine cytokines, oxidative stress, and changes in ECM of the microenvironment.^7,8 Activated stellate cells secrete ECM and change into fibroblasts, leading to chronic and irreversible inflammation. Similarly, epithelial cells also have an effect on mesenchymal cells. Vascular endothelial cells migrate to sites of inflammation under the action of chemokines secreted by inflammatory cells and form microvasculature within the area of chronic inflammation due to the action of growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), and transforming growth factor-β (TGF-β) and other factors secreted by fibroblasts, chronic inflammatory cells, and parenchymal cells. Kras in the inflammatory cells can induce the expression of Shh and then activate Gli in stromal cells. Once activated, Gli can bind to the interleukin (IL)-6 promoter to promote its expression. The increase in IL-6 expression in stromal cells in turn induces activation of signal transducer and activator of transcription 3 (STAT3) in parenchymal cells. Thus, the interaction between inflammatory cells and matrix formation takes place in the chronic inflammatory microenvironment. Chronic inflammatory cell infiltration, fibrosis, and angiogenesis often result in the formation of masses in organs and tissues in chronic inflammation.

Signaling pathway disorders in parenchymal cells induced by chronic inflammation

Signaling pathway disorders occur in parenchymal cells due to various inflammatory factors, including the NF-κB⁹ pathway, Janus kinases (JAKs)-STAT pathway,¹⁰ Wnt/β-catenin pathway, RAS-RAF-mitogen-activated protein kinase kinase (MEK)-extracellular signal–regulated protein kinase (ERK) pathway, phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) pathway, and the Hedgehog pathway.

In addition, when oxidative stress occurs, cells which are attacked by reactive oxygen species (ROS) activate phospholipase A2, which results in the hydrolysis of membrane phospholipid, the release of arachidonic acid, and promotion of activator protein 1 (AP-1) expression. ROS can also activate the transcription factor JNKs and then activate the Fos and Jun gene promoter to induce transcription. ROS can also activate NF-κB via IκB kinase. In addition, reactive oxygen/nitrogen species can activate or inhibit many signaling pathways and some signals mediate molecules which then regulate the expression of genes, such as in the nuclear factor E2-related factor 2-cytoplasmic chaperone protein (Nrf2/Keap1) signaling pathway,¹¹ NF-κB signaling pathway,¹² mitogen-activated protein kinases (MAPKs),¹³ protein kinase mTOR,¹⁴ and protein kinase C (PKC).¹⁵

Enhanced cellular proliferation signaling increases the risk of cell mutation. Continued abnormal activation of STAT3 can lead to a variety of diseases such as lung cancer, colon cancer, breast cancer, and prostate cancer.^16,17 Long-term chronic inflammation results in the overexpression of cell growth factors such as EGF, VEGF, and PDGF-B and the corresponding membrane receptors. Cell growth factors, which bind the cognate cell surface receptors, result in receptor tyrosine kinase (e.g. epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR)) carboxyl terminus hyperphosphorylation. A series of reactions then leads to excessive activation of Ras kinase.^18,19 If the Ras protein is activated, the cell will receive a continuous stimulus, which will result in the cell being in a constant state of growth and proliferation which then increases the possibility of cancer.^20,21 In this inflammatory state, Wnt proteins secreted by the cells bind to cell surface receptors FZD and LRP5/6 and activate the Wnt/β-catenin signaling pathway, which regulates target gene transcription such as c-myc, cyclin D1, survivin, gastrin, c-met, VEGF, cyclooxygenase-2 (COX-2), CD44, and matrix metalloproteinases (MMPs).²² Abnormal expression of the wnt pathway has been found in many tumor tissues, such as lung cancer,²³ colorectal cancer,²⁴ breast cancer,²⁵ and malignant melanoma.²⁶

Molecular studies have shown that the Hh signaling pathway can be activated by Ki-ras gene mutation, NF-κB signaling pathway activation, and TGFβ.^27–29 Target genes of the Hedgehog signaling pathway, whose target genes are a growth factors or growth factor receptors frequently including IGF-2, VEGF, and platelet-derived growth factor receptor (PDGFR),³⁰ already have been discovered in the basal cell carcinoma, gastric cancer, colorectal cancer, esophageal cancer, pancreatic cancer, prostate cancer, breast cancer, lung cancer, ovarian cancer, endometrial cancer, and liver cancer tumors.

Numerous studies have shown that a chronic inflammatory microenvironment can induce parenchymal cell pathway signaling disorders and crosstalk between signaling pathways. On this basis, these events result in a series of editorial modifications at the gene level, regulation at the transcription and translation levels, as well as in epigenetic changes, which can affect gene structure eventually leading to cancer.

Genetic changes caused by signaling pathway disorders in parenchymal cells

Carcinogenesis is a multi-stage and multiple-mutation accumulation process which can be divided into three phases using the molecular switch theory: start-up period, evolution period, and cancerous period. The theory involves some switching genes. Once the switch gene is mutated, cells enter the start-up period which will inevitably progress to cancer. The evolution period refers to cell signaling pathway disorders and crosstalk and other gene mutations which are the start genes. Cells then enter the cancerous period and show malignant behavior such as metastasis and angiogenesis when mutations accumulate to a certain level. It is unknown whether the presence of the switch gene in some cancers does not show significant start-up period features. Although the presence of Ki-ras gene mutation has been found in early pancreatic cancer, studies have shown that Ki-ras gene mutation is also found in normal pancreatic tissue, and Ki-ras mutation alone does not lead to pancreatic cancer. These findings show that the existence of the start-up phase is inconclusive, but the process of evolution is recognized. The main characteristics of evolution are serious cell signaling pathway disorders, resulting in continued accumulation of genetic mutations, which behave as precancerous lesions.

It can be speculated that intracellular signaling pathway disorders may cause genetic mutations through the following mechanisms according to the literature: (1) produce a mutation hotspot and increase the mutation rate by regulating the DNA modification process (methylated bases, deaminated bases, etc.); (2) inhibit base mismatch repair (MMR) system function through epigenetic pathways; (3) influence or are directly involved in DNA replication or repair procedures or directly induce gene mutations by regulating the expression of downstream genes; and (4) other mechanisms.

Regulation of the DNA modification process

Cancer is caused by a genetic defect and epigenetic gene changes. DNA methylation and histone deacetylation are the most common epigenetic events.^31,32 DNA methylation is controlled by DNA methyltransferase (DNMT), a methyl provided by S-adenosylmethionine covalently binding to cytosine on the fifth carbon atom to form 5-methylcytosine. The nucleotide sequence is unchanged after DNA methylation, but gene expression is affected, which could lead to mutations or canceration. There are three DNMTs involved in DNA CpG island methylation: DNMT1, DNMT3a, and DNMT3b. IL-6 can regulate the expression of DNMTI by activating the PI3K/Akt signaling pathway at the messenger RNA (mRNA) level.^33,34 The ERK-MAPK signaling pathway is also involved in the regulation of DNMTI expression.³⁵

Abnormal whole genome hypomethylation which causes activation of oncogenes and CpG island hypermethylation which induces transcriptional inactivation of tumor suppressor genes have become hot issues in cancer research. An overall decline in the genomic methylation level will result in genomic instability, abnormal expression of transposons, abnormal gene expression, malignancy, and oncogenesis.^36–39 Low genomic DNA methylation can also promote loss of heterozygosity (LOH),⁴⁰ which causes harmful gene expression such as activation of oncogenes or the expression of oncogenes or related factors.⁴¹ There is a high concentration of methylated regions around chromosome centromeres; if dense methyl groups are lost, genetic damage and mutations on chromosomes are induced.^42,43 CPG island methylation is closely related to cancer in eukaryotic cell DNA.^44,45 Methylated cytosine is easily deaminated to thymine spontaneously, resulting in an increased mutation rate. It has been shown that CpG is converted to TpG in gene mutations and methylation of cytosine (C) is significantly higher than non-methylated C and increases the probability of the formation of pyrimidine dimers. Studies have found that it is common to find C → T or CC → TT mutations in skin cancer. Histone acetylation–related enzymes include histone acetyl transferases (HATs) and histone deacetylases (HDACs). Hypermethylation of CpG islands and HDAC synergies by specific methylation binding protein (MeCP) induces associated DNA damage repair genes, cell-cycle regulation, and apoptosis genes, and angiogenesis genes are expressed and tumors are induced.^46–48 Abnormal CPG island methylation has gene specificity and tumor specificity, as BRCA1 gene promoter hypermethylation occurs in breast cancer, ovarian cancer, prostate cancer, and uterine cancer cells, whereas hM1H1 MMR gene promoter hypermethylation occurs in colon, stomach, and endometrial cancer cells.

Cytidine deaminase (AID) is a demethylase, which changes 5-methyl cytosine (5-mC) into thymine (T) to form a G:T mismatch by deamination. Identification of the G:T mismatched glycosylase initiates the base excision repair (BER) pathway to complete DNA demethylation. AID is highly expressed in many cancers and can induce mutations in multiple genes, including P53, c-Myc, and Bcl-6 gene mutations. Research has shown that during transcription, the induced negative supercoiled form of single-stranded DNA fragment is a substrate of AID-mediated mutagenesis.⁴⁹ A TLR signal and a B-cell surface antigen receptor (BCR) signal can induce AID,⁵⁰ thus increasing the mutation frequency.

Cytosine deaminase APOBEC3B, a type of cytosine deaminase, has activity against a variety of retroviruses and endogenous retroviral elements and results in specific cytosine (C) on the minus-strand DNA which deaminates into uracil (U) in the viral reverse process, and this mutation can thus result in a positive-strand DNA to form a G → A hypermutation.^51,52 This hypermutation generates premature termination codons or highly mutated nonfunctional viral proteins, inhibiting viral replication. APOBEC3B is associated with a wide variety of tumors such as breast cancer,⁵³ chondrosarcoma,⁵⁴ and lung cancer⁵⁵ and can be induced by cytokines such as interferon (IFN), IL-2, and tumor necrosis factor (TNF). It is reasonable to assume that an abnormal increase in APOBEC3B may also be associated with one signaling pathway or a few signaling pathway disorders according to the literature.

Regulation of nucleotide MMR system functions

DNA repair is key to the genetic stability of cells, and a decline in DNA repair capacity leads to increased cancer susceptibility. 8-oxodG, one of the modification products caused by ROS/reactive nitrogen species (RNS) in DNA oxidative damage, can remove the MSH2/MSH6 promoter of proto-oncogenes, downregulate or silence MMR proteins, increase the accumulation of replication errors in the overall genome DNA, and become an initiation factor of cell mutagenesis, teratogenesis, and carcinogenesis.⁵⁶ Intracellular O6-methylguanine-DNA methyltransferase (MGMT) is a direct DNA repair gene and is usually inactivated due to hypermethylation in colorectal cancer, lung cancer, and lymphoma. When MGMT promoter methylation occurs, MGMT decreases and the ability to clear O6-methylguanine is reduced; thus, there is a mismatch with T in DNA replication, which leads to the development of G:C → A:T mutations that cause cancer gene activation and inactivation of tumor suppressor genes (such as p53 and K-ras).⁵⁷

The BER-related genes are hOGG1, MYH, and MTH1. hOGG1 identifies and removes the 8-OHd G:C → A:T transversion in double-stranded DNA caused by active oxygen.^58–60 It was found that increased 8-hydroxy-deoxyguanosine (8-OHdG) can induce changes in hOGGl gene expression.^61,62 Low hOGG1 gene expression causes a reduction or loss of the cellular repair capacity of 8-OHdG, resulting in an abnormally elevated DNA mutation rate. hOGG1 gene defects or abnormal expression are closely related to lung cancer, head and neck cancer, kidney cancer, and skin cancer.^63,64 MYH fast scans sub-strand DNA after DNA replication and excises A mismatched with 8-OHdG in sub-stranded DNA. This leads to G:C → A:T transversion in the replication process if MYH protein is inactivated, resulting in increased G:C → A:T mutations which significantly increase the incidence of colon cancer. The most important related MMR genes are hMLH1 and hMSH2, which result in a common type of mutation such as deletion and methylation, resulting in cell MMR dysfunction and the promotion of tumorigenesis.

MiRNAs

Parenchymal cell signaling pathway disorders affect the expression of downstream genes, including miRNAs, leading to a series of induced effects.⁶⁵ The abnormal expression of miRNAs has been found in a variety of tumor-associated uncontrollable inflammatory conditions and diseases,⁶⁶ such as miR-21-related lung cancer and breast cancer, miRNA-15- and miRNA-16-related chronic lymphocytic leukemia (CLL), and miR-221-/miR-222-related papillary thyroid tumors and malignant glioma. MiRNAs are associated with carcinogenic effects in two main ways: (1) as tumor suppressor factors which inhibit proto-oncogenes and reduce tumor suppressor level and (2) decrease tumor suppressor gene regulation to produce a similar effect in cancer genes. For example, miRNA-15 and miRNA-16 loss or downregulated function related to CLL,⁶⁷ lower miRNA let-7 expression related to lung cancer,⁶⁸ and downregulated miR-143/miR-145 related to colon cancer;⁶⁹ while the upregulation of some miRNAs is related to tumor development, such as miR-221/miR-222 in papillary thyroid tumors⁷⁰ and malignant glioma,⁷¹ miR-21 in breast cancer and lung cancer,⁷² miR-155 in Hodgkin’s lymphoma⁷³ and B-cell lymphoma,⁷⁴ and miR-17-92 in B-cell lymphoma⁷⁵ and small-cell lung cancer.⁷⁶

Abnormal miRNA expression can directly or indirectly affect the cell signaling pathways in turn. MiR-214 can control the Hedgehog signaling pathway by negative regulator of protein su (fu). MiRNA-146a controls TLRs and cytokine signal transduction by reducing IL-1 receptor-dependent kinase 1 and TNF receptor–associated factor 6 protein levels. MiRNA-61 sustains activation of the Notch pathway, thereby resulting in cell signaling disturbance and crosstalk, leading to other mutations.

DNA oxidative damage

DNA oxidative damage is also an important mechanism of carcinogen-induced cancer because DNA is an important target molecule of radical attacks. Pathways like NF-κB pathway and pro-inflammatory factors like TNF-α, IL-6, and TGF-β can also activate the parenchymal cells to produce excess ROS and RNS,^77–79 which induced DNA damage and genomic instability such as base mismatches, modifications, oxidation, the formation of apurinic/apyrimidinic site, DNA breakage, and increased frequency of mutations. It can be speculated that DNA oxidative damage is caused by the following mechanisms: (1) Hydroxyl radicals can attack DNA molecule ribose carbon positions 3 and 4, causing fracture of the adjacent phosphodiester bond skeleton fracture. DNA strand breaks were constantly repaired; however, enzymes involved in DNA repair are also under attack by free radicals, resulting in mismatches or losses leading to mutations. (2) ROS also oxidized deoxy nucleic acid C-1 and C-4 positions. Oxidation at C-1 position caused the loss of bases in complementary sites then replaced by adenine in the base repair process, while oxidation at C-4 position would causes DNA strand breaks, which caused base deletion, activation of oncogenes and inactivation of tumor suppressor genes (reactive oxygen species causes inactivation of tumor suppressor gene P53 and the activation of proto-oncogene Ras in inflammatory epithelial cells). (3) NO oxidative stress generated can increase DNMT enzyme, causing significantly a large number of cytosine methylation and leading to inactivation of tumor suppressor genes including P16INK4a and E-cadherin. (4) 8-hydroxy-deoxyguanosine (8-oxodG), formed by the oxidation of guanine, is genotoxic and mutagenic,^80,81 making deoxycytidine triphosphate (dCTP) and deoxyadenosine triphosphate (dATP) competitive binding to itself during DNA extended and giving priority to pair with adenine, causing G:C → A:T transversion.^82,83 Areas with oxidative damage parts are prone to fall off the bases leading to breakage of DNA strand,⁸⁴ thus inducing mismatched bases and transcription error infidelity during DNA replication. 8-oxodG accumulation in DNA may stimulate the somatic cell mutation and the occurrence of genetic diseases.^85,86 P53 gene has a G:C → T:A transversion in lung and kidney cancer;⁸⁷ G → T and C → T transversions have been found in colorectal cancer cells and increased 8-OHdG has been observed.⁸⁸

Conclusion

Carcinogenesis is a complex process of multi-stage, multi-gene changes and epigenetic changes. Complex regulatory networks are formed by a large number of cells, matrix components, cytokines, and signaling pathways. It is widely accepted that chronic inflammation causes cancer due to inflammatory microenvironment components in inflammatory cells, stromal cells, and their secretion of inflammatory mediators. Signaling pathways are the main ways through which genes perform various biological functions. Gene expression observed at different stages of the disease contributes to understanding the function of genes that significantly altered. Persistence of the inflammatory microenvironment sustains activation of cell signaling pathways, causing a reduction in epithelial cell apoptosis, sustainable growth, and increased proliferation. At the same time, complex metabolic reactions produce a large number of metabolites that stimulate epithelial cell proliferation and neoplasia and play an important role in tumor development. There are also complex interactions between key signaling pathways, which form a network of mutually activated factors. In addition, signal pathway activation can cause the production of a large number of cytokines, creating a microenvironment conducive for tumor cells to escape immune surveillance. Thus, there is sequential activation of key signaling pathways in the cascade evolution process of inflammation-related canceration. The sequential activation of interacting networks influence each other resulting in a large number of signaling molecules and a microenvironment that promotes tumor development. Therefore, research on inflammation and the development of cancer has significance in clinical diagnosis, treatment, and prognosis.

Footnotes

Acknowledgements

The authors apologize to their colleagues whose work was not cited for reasons of space limitations.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by the National Natural Science Foundation of China (grant no. 81172312).

References

Mantovani

Allavena

Sica

. Cancer-related inflammation. Nature 2008; 454: 436–444.

Smolle

Zohrer

Bettermann

. Viral hepatitis induces hepatocellular cancer: what can we learn from epidemiology comparing Iran and worldwide findings? Hepat Mon 2012; 12: e7879.

Lamb

Chen

. Role of the helicobacter pylori-induced inflammatory response in the development of gastric cancer. J Cell Biochem 2013; 114: 491–497.

Rubin

Shaker

Levin

. Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer. Front Immunol 2012; 3: 107.

Sfanos

De Marzo

. Prostate cancer and inflammation: the evidence. Histopathology 2012; 60: 199–215.

Liotti

Visciano

Melillo

. Inflammation in thyroid oncogenesis. Am J Cancer Res 2012; 2: 286–297.

Friedman

. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med 1993; 328: 1828–1835.

Friedman

Roll

Boyles

. Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix. J Biol Chem 1989; 264: 10756–10762.

Baud

Karin

. Is NF-κB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov 2009; 8: 33–40.

10.

Pardoll

Jove

. Stats in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9: 798–809.

11.

Sykiotis

Habeos

Samuelson

. The role of the antioxidant and longevity-promoting Nrf2 pathway in metabolic regulation. Curr Opin Clin Nutr Metab Care 2011; 14: 41–48.

12.

Pantano

Reynaert

van der Vliet

. Redox-sensitive kinases of the nuclear factor-kappab signaling pathway. Antioxid Redox Signal 2006; 8: 1791–1806.

13.

McCubrey

Lahair

Franklin

. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid Redox Signal 2006; 8: 1775–1789.

14.

Byun

Kim

. Hydrogen peroxide induces autophagic cell death in C6 glioma cells via BNIP3-mediated suppression of the mTOR pathway. Neurosci Lett 2009; 461: 131–135.

15.

Kanthasamy

Kitazawa

Kanthasamy

. Role of proteolytic activation of protein kinase c delta in oxidative stress-induced apoptosis. Antioxid Redox Signal 2003; 5: 609–620.

16.

Song

Turkson

Karras

. Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene 2003; 22: 4150–4165.

17.

Jove

. The stats of cancer—new molecular targets come of age. Nat Rev Cancer 2004; 4: 97–105.

18.

Sundaram

. RTK/Ras/MAPK signaling. WormBook 2006; 11: 1–19.

19.

Rajalingam

Rudel

. Ras-Raf signaling needs prohibitin. Cell Cycle 2005; 4: 1503–1505.

20.

Crul

de Klerk

Swart

. Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 2002; 20: 2726–2735.

21.

Overmeyer

Maltese

. Death pathways triggered by activated Ras in cancer cells. Front Biosci 2011; 16: 1693–1713.

22.

Tulac

Nayak

Kao

. Identification, characterization, and regulation of the canonical Wnt signaling pathway in human endometrium. J Clin Endocrinol Metab 2003; 88: 3860–3866.

23.

Barg

You

. Wnt signaling in stem cells and non-small-cell lung cancer. Clin Lung Cancer 2005; 7: 54–60.

24.

Oving

Clevers

. Molecular causes of colon cancer. Eur J Clin Invest 2002; 32: 448–457.

25.

Musgrove

. Wnt signalling via the epidermal growth factor receptor: a role in breast cancer? Breast Cancer Res 2004; 6: 65–68.

26.

Maelandsmo

Holm

Nesland

. Reduced beta-catenin expression in the cytoplasm of advanced-stage superficial spreading malignant melanoma. Clin Cancer Res 2003; 9: 3383–3388.

27.

Nolan-Stevaux

Lau

Truitt

. GLI1 is regulated through smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev 2009; 23: 24–36.

28.

Mills

Zhang

Marler

. Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation. J Biol Chem 2013; 288: 11786–11794.

29.

Schumacher

Feng

Aihara

. Helicobacter pylori-induced sonic hedgehog expression is regulated by NFκB pathway activation: the use of a novel in vitro model to study epithelial response to infection. Helicobacter 2015; 20: 19–28.

30.

Xie

. Hedgehog signaling pathway: development of antagonists for cancer therapy. Curr Oncol Rep 2008; 10: 107–113.

31.

Eden

Cedar

. Role of DNA methylation in the regulation of transcription. Curr Opin Genet Dev 1994; 4: 255–259.

32.

Vogelauer

Suka

. Global histone acetylation and deacetylation in yeast. Nature 2000; 408: 495–498.

33.

Hodge

Peng

Cherry

. Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. Cancer Res 2005; 65: 4673–4682.

34.

Hodge

Cho

Copeland

. IL-6 enhances the nuclear translocation of DNA cytosine-5-methyltransferase 1 (DNMT1) via phosphorylation of the nuclear localization sequence by the Akt kinase. Cancer Genomics Proteomics 2007; 4: 387–398.

35.

Wang

Chen

. Inhibition of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway decreases DNA methylation in colon cancer cells. J Biol Chem 2007; 282: 12249–12259.

36.

Agrawal

Unterberg

Koschmieder

. DNA methylation of tumor suppressor genes in clinical remission predicts the relapse risk in acute myeloid leukemia. Cancer Res 2007; 67: 1370–1377.

37.

Issa

. DNA methylation as a therapeutic target in cancer. Clin Cancer Res 2007; 13: 1634–1637.

38.

Davis

Uthus

. DNA methylation, cancer susceptibility, and nutrient interactions. Exp Biol Med 2004; 229: 988–995.

39.

Feinberg

Tycko

. The history of cancer epigenetics. Nat Rev Cancer 2004; 4: 143–153.

40.

Lengauer

Kinzler

Vogelstein

. DNA methylation and genetic instability in colorectal cancer cells. Proc Natl Acad Sci USA 1997; 94: 2545–2550.

41.

Baylin

Belinsky

Herman

. Aberrant methylation of gene promoters in cancer—concepts, misconcepts, and promise. J Natl Cancer Inst 2000; 92: 1460–1461.

42.

Hernandez

Zhang

. DNA demethylation and pericentromeric rearrangements of chromosome. Mutat Res 1997; 379: 33–41.

43.

Tuck-Muller

Narayan

Tsien

. DNA hypomethylation and unusual chromosome instability in cell lines from ICF syndrome patients. Cytogenet Cell Genet 2000; 89: 121–128.

44.

Tsumura

Hayakawa

Kumaki

. Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases DNMT1, DNMT3a and DNMT3b. Genes Cells 2006; 11: 805–814.

45.

Polanowska

Martin

Garcia-Muse

. A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites. EMBO J 2006; 25: 2178–2188.

46.

Jones

Laird

. Cancer epigenetics comes of age. Nat Genet 1999; 21: 163–167.

47.

Jones

. DNA methylation and cancer. Oncogene 2002; 21: 5358–5360.

48.

Feinberg

. Phenotypic plasticity and the epigenetics of human disease. Nature 2007; 447: 433–440.

49.

Parsa

Ramachandran

Zaheen

. Negative supercoiling creates single-stranded patches of DNA that are substrates for aid-mediated mutagenesis. PLoS Genet 2012; 8: e1002518.

50.

Pone

Zhang

Mai

. BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway. Nat Commun 2012; 3: 767.

51.

Noguchi

Hiraga

Mori

. Dual effect of APOBEC3G on Hepatitis B virus. J Gen Virol 2007; 88: 432–440.

52.

Suspene

Guetard

Henry

. Extensive editing of both Hepatitis B virus DNA strands by APOBEC3 cytidine deaminases in vitro and in vivo. Proc Natl Acad Sci USA 2005; 102: 8321–8326.

53.

Harris

. Molecular mechanism and clinical impact of APOBEC3B-catalyzed mutagenesis in breast cancer. Breast Cancer Res 2015; 17: 8.

54.

Jin

Han

. The role of APOBEC3B in chondrosarcoma. Oncol Rep 2014; 32: 1867–1872.

55.

Sasaki

Suzuki

Tatematsu

. Gene overexpression in non-small-cell lung cancer. Biomed Rep 2014; 2: 392–395.

56.

Yamano

Kagawa

Hanaoka

. Oxidative DNA damage induced by silica in vivo. Environ Res 1995; 69: 102–107.

57.

Jeon

Lee

Shin

. Genetic alterations of APC, K-ras, p53, MSI, and NAGE in Korean colorectal cancer patients. Int J Colorectal Dis 2008; 23: 29–35.

58.

Audebert

Radicella

Dizdaroglu

. Effect of single mutations in the Ogg1 gene found in human tumors on the substrate specificity of the Ogg1 protein. Nucleic Acids Res 2000; 28: 2672–2678.

59.

Chen

. Increased oxidative DNA damage, as assessed by urinary 8-hydroxy-2’-deoxyguanosine concentrations, and serum redox status in persons exposed to mercury. Clin Chem 2005; 51: 759–767.

60.

Stevnsner

Nyaga

de Souza-Pinto

. Mitochondrial repair of 8-oxoguanine is deficient in Cockayne syndrome group B. Oncogene 2002; 21: 8675–8682.

61.

Zhang

Wang

. Chronic occupational exposure to hexavalent chromium causes DNA damage in electroplating workers. BMC Public Health 2011; 11: 224.

62.

Tong

Chen

. Contribution of HOGG1 Ser³²⁶Cys polymorphism to the development of prostate cancer in smokers: meta-analysis of 2779 cases and 3484 controls. PLoS One 2012; 7: e30309.

63.

Rusin

Markiewicz

Majsterek

. Genetic predeterminations of head and neck cancer. Postepy Hig Med Dosw 2008; 62: 490–501.

64.

Kunisada

Sakumi

Tominaga

. 8-oxoguanine formation induced by chronic UVB exposure makes Ogg1 knockout mice susceptible to skin carcinogenesis. Cancer Res 2005; 65: 6006–6010.

65.

Tili

Michaille

Croce

. MicroRNAs play a central role in molecular dysfunctions linking inflammation with cancer. Immunol Rev 2013; 253: 167–184.

66.

Padgett

Lan

Leung

. Primary biliary cirrhosis is associated with altered hepatic microRNA expression. J Autoimmun 2009; 32: 246–253.

67.

Calin

Dumitru

Shimizu

. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2002; 99: 15524–15529.

68.

Takamizawa

Konishi

Yanagisawa

. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 2004; 64: 3753–3756.

69.

Michael

O’Connor

van Holst Pellekaan

. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 2003; 1: 882–891.

70.

Jazdzewski

. The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci USA 2005; 102: 19075–19080.

71.

Ciafre

Galardi

Mangiola

. Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun 2005; 334: 1351–1358.

72.

Yanaihara

Caplen

Bowman

. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 2006; 9: 189–198.

73.

Kluiver

Poppema

de Jong

. BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J Pathol 2005; 207: 243–249.

74.

Eis

Tam

Sun

. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci USA 2005; 102: 3627–3632.

75.

Ota

Tagawa

Karnan

. Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma. Cancer Res 2004; 64: 3087–3095.

76.

Hayashita

Osada

Tatematsu

. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res 2005; 65: 9628–9632.

77.

Yang

Elner

Bian

. Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells. Exp Eye Res 2007; 85: 462–472.

78.

Sturrock

Cahill

Norman

. Transforming growth factor-β1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2006; 290: L661–L673.

79.

da Silva Krause

Bittencourt

Homem de Bittencourt

Jr . Physiological concentrations of interleukin-6 directly promote insulin secretion, signal transduction, nitric oxide release, and redox status in a clonal pancreatic β-cell line and mouse islets. J Endocrinol 2012; 214: 301–311.

80.

Arashidani

Iwamoto-Tanaka

Muraoka

. Genotoxicity of ribo- and deoxyribonucleosides of 8-hydroxyguanine, 5-hydroxycytosine, and 2-hydroxyadenine: induction of SCE in human lymphocytes and mutagenicity in salmonella typhimurium TA 100. Mutat Res 1998; 403: 223–227.

81.

Cooke

Evans

Dizdaroglu

. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 2003; 17: 1195–1214.

82.

Wang

Abdel-Rahman

. Oxidative DNA damage and its repair in rat spleen following subchronic exposure to aniline. Toxicol Appl Pharmacol 2008; 233: 247–253.

83.

Dantzer

Bjoras

Luna

. Comparative analysis of 8-oxoG:C, 8-oxoG:A, A:C and C:C DNA repair in extracts from wild type or 8-oxog DNA glycosylase deficient mammalian and bacterial cells. DNA Repair 2003; 2: 707–718.

84.

Lai

Chen

. Natural borneol, a monoterpenoid compound, potentiates selenocystine-induced apoptosis in human hepatocellular carcinoma cells by enhancement of cellular uptake and activation of ROS-mediated DNA damage. PLoS One 2013; 8: e63502.

85.

Hori

Satou

Harashima

. Suppression of mutagenesis by 8-hydroxy-2’-deoxyguanosine 5’-triphosphate (7,8-dihydro-8-oxo-2’-deoxyguanosine 5’-triphosphate) by human MTH1, MTH2, and NUDT5. Free Radic Biol Med 2010; 48: 1197–1201.

86.

Karahalil

Girard

Boiteux

. Substrate specificity of the Ogg1 protein of Saccharomyces cerevisiae: excision of guanine lesions produced in DNA by ionizing radiation- or hydrogen peroxide/metal ion-generated free radicals. Nucleic Acids Res 1998; 26: 1228–1233.

87.

Klungland

Bjelland

. Oxidative damage to purines in DNA: role of mammalian Ogg1. DNA Repair 2007; 6: 481–488.

88.

Oliva

Ripoll

Muniz

. Genetic alterations and oxidative metabolism in sporadic colorectal tumors from a Spanish community. Mol Carcinog 1997; 18: 232–243.