Genetic variants in IL-6 and IL-10 genes and susceptibility to hepatocellular carcinoma in HCV infected patients
Introduction
The incidence of HCV and related complications continue to rise globally, and World Health Organization (WHO) reporting an estimated 3% prevalence worldwide [1], [2]. Hepatocellular carcinoma (HCC) is the primary liver malignancy, and the third leading cause of cancer-related deaths worldwide [2]. Chronic HCV infection is associated with variable outcome, ranging from simple hepatic damage, to cirrhosis, and HCC [3]. Most HCV-related HCC cases are found in developing countries [4], and the progression and the development of HCC correlates with HCV infection, predominantly in cirrhosis. Accordingly, routine examination and assessment, including HCV genotype and viral load, will improve the prognosis of HCV infection.
The course of HCV infection is influenced by modifiable and non-modifiable factors, such as duration of infection, gender, alcohol consumption, age, and insulin resistance [5]. Despite the identification of these and related factors, the exact cause underlying most HCV infection cases remain unexplained, suggesting the contribution of other factors, in particular the immune status of the host. A large numbers of single nucleotide polymorphisms (SNPs) in both pro- and anti-inflammatory cytokine genes were previously associated with the outcome of chronic HCV infection [6], including interleukin (IL)-6, a pleiotropic cytokine with a key role in inflammation [7], and innate adaptive immunity [8]. As carcinogenesis is accompanied by a state of low-grade inflammation, a key role for altered IL-6 signalling in human cancers were reported previous reports linking [9], [10], [11].
Recently, IL-6 was shown to drive the differentiation on naïve Th0 cells to the Th17 cell lineage [12], [13]. This expands the role of IL-6, from involvement in innate immunity to its significant contribution to chronic inflammation accompanying disease process. IL-6 is a pleiotropic cytokine expressed by many cell types, and regulates several inflammatory processes, haematopoiesis and immune regulation. Dysregulated IL-6 expression was often seen in cancer, and a role for IL-6 as a prognostic biomarker for breast and prostate cancer was suggested [14]. Elevation in IL-6 serum levels correlated with advanced stages of cancer, and was linked with poor prognosis. The pleiotropy and redundant functions of IL-6 underscores an important signalling axis in oncogenic transformations.
On the other hand, IL-10 is an anti-inflammatory cytokine, which downregulates the synthesis of pro-inflammatory cytokines, including IL-6, and modulates hepatic fibrogenesis [15]. Several study addressed the possible contribution of IL-10 promoter polymorphisms to HCV outcomes. IL-10 plays a key role in the oncogenic and metastatic ability of neoplasms [16], exemplified by the reported increases in IL-10 levels in cancer patients, including those with HCC [17], [18], where it was related to the disease prognosis. Several cell types, including T cells, B cells, monocytes, macrophages, mast cells, granulocytes, dendritic cells and keratinocytes, produce IL-10. Tumor cells and tumor-infiltrating macrophages are also major IL-10 secreting cells [19], [20]. IL-10 exerts immunosuppressive effect on antigen presentation, cell maturation and differentiation, thereby allowing evasion of tumor cells of immune recognition [21]. This indicates that IL-6 and IL-10 drive tumor progression by dampening anti-tumor immunity, and by precipitating by state of inflammation, and escape of apoptotic processes.
The aim of this study was to determine whether specific IL-10 genotypes influence the outcomes of HCV infection in Tunisian patients. The second objective was to examine the possible association of IL-6 promoter polymorphisms with the outcomes of chronic HCV infection.
Section snippets
Study population
Blood samples were collected from 174 Tunisian patients infected with HCV, who were divided into three groups. Group1 (G1) consisted of patients infected with chronic hepatitis C (CHC), and positive for both anti-HCV Ab, and HCV RNA (assessed by RT-PCR). Group 2 (G2) comprised patients infected with cirrhosis (LC), but with no histological evidence of cancer. Lastly, Group 3 (G3) included patients with established HCC, which was confirmed by pathology, computer tomography (CT) imaging, and
Patient characteristics
The general characteristics of the three patient groups included in this study are shown in Fig. 1. There was no significant difference observed between three groups in terms of HCV genotype, and weight. Despite of the lack of association of gender and HCC, it was reported that men are usually more susceptible to HCC than women, partly because of different social habits (alcohol and cigarettes) [25]. Liver transaminase levels, stage of fibrosis, grade of necro-inflammatory activity, and AFP
Discussion
Significant differences were seen among patient groups in terms of age, AST, ALT, AFP, Actitest and Fibrotest stages, with patients in cirrhosis and HCC stage presenting with severe fibrosis, and high necro-inflammatory activity. An interesting finding was the cross-regulation of cytokine expression associated with increased necrosis, consistent with inflammation accompanying liver fibrosis [28], [29], which correlated with elevated IL-6 and IL-17, more than IL-10, levels [29], suggesting that
References (47)
- et al.
The pro-and anti-inflammatory properties of the cytokine interleukin-6
Biochim. Biophys. Acta (BBA)-Mol. Cell Res.
(2011) - et al.
IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer
Cancer Cell
(2009) - et al.
The role of IL-6 and STAT3 in inflammation and cancer
Eur. J. Cancer
(2005) - et al.
IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer
Cytokine Growth Factor Rev.
(2011) - et al.
Hormonal-receptor positive breast cancer: IL-6 augments invasion and lymph node metastasis via stimulating cathepsin B expression
J. Adv. Res.
(2016) - et al.
Evaluation of interleukin-6, interleukin-10 and human hepatocyte growth factor as tumor markers for hepatocellular carcinoma
Eur. J. Surg. Oncol.
(2007) - et al.
High tumor necrosis factor-α/interleukin-10 ratio is associated with hepatocellular carcinoma in patients with chronic hepatitis C
Cytokine
(2013) - et al.
Non-Hodgkin’s B cell lymphoma in persons with acquired immunodeficiency syndrome is associated with increased serum levels of IL10, or the IL10 promoter− 592 C/C genotype
Clin. Immunol.
(2003) Is interleukin-10 gene polymorphism a predictive marker in HCV infection?
Cytokine Growth Factor Rev.
(2012)- et al.
IL-6 in autoimmune disease and chronic inflammatory proliferative disease
Cytokine Growth Factor Rev.
(2002)
Risk factors for Hepatitis C virus transmission obscure in nigerian patients
Gastroenterol. Res. Pract.
Epidemiology of liver cancer: an overview
Asian Pac. J. Cancer Prev.
Risk factors for hepatocellular carcinoma in a cohort infected with hepatitis B or C
J. Gastroenterol. Hepatol.
Hepatocellular carcinoma: focus on different aspects of management
ISRN Oncol.
Risk factors for hepatocellular carcinoma
Clin. Liver Dis.
Large-scale candidate gene analysis of spontaneous clearance of hepatitis C virus
J. Infect. Dis.
Cancer-related inflammation
Nature
IL-6: regulator of Treg/Th17 balance
Eur. J. Immunol.
IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis
Proc. Natl. Acad. Sci.
IL-17 and Th17 Cells
Annu. Rev. Immunol.
Interleukin-10 and the interleukin-10 receptor
Annu. Rev. Immunol.
Controversies in surveillance and early diagnosis of hepatocellular carcinoma
Oncology
Interleukin-10 production by human carcinoma cell lines and its relationship to interleukin-6 expression
Int. J. Cancer
Cited by (31)
Immunotherapy for hepatocellular carcinoma
2020, Cancer LettersCitation Excerpt :Neutralizing IL-35 can diminish the development of HCC metastases and increase overall survival (OS) [97]. In patients with advanced HCC, increased IL-10 levels were inversely proportional to OS, similar to the inactivation of LAK and NKs and the upregulation of Tregs [98–100]. Stimulating IL-17 secretion can inhibit the proliferation of HCC cells, and it appears to induce HCC cell apoptosis [98,101,102].
Single nucleotide polymorphism rs1800872 in the promoter region of the IL10 gene is associated with predisposition to chronic hepatitis C in Russian population
2018, Microbes and InfectionCitation Excerpt :It was shown that differential IL10 expression can be mediated by greater affinity of poly (ADP) ribose polymerase 1 in regard to the rs1800872 C versus A allele [20]. The association of this SNP with the severity and outcome of HCV infection has been already shown in some other human populations [21–23]. According to our data, the rs1800872 A/A genotype can be also considered as a genotype “predisposing” to HC in Russian population, since its frequency is significantly increased in HC patients as compared to the control group (Table 2).
Genetic polymorphism between the Sorani and Hawrami kurdish populations and COVID-19 outcome
2023, Molecular Biology ReportsAssociation of IL6 and IL10 gene promotor polymorphisms with susceptibility to acute necrotizing encephalopathy
2023, Frontiers in Neuroscience