The Roles of Epigenetic Regulators and Inflammasome in Hepatocellular Carcinoma Tumorigenesis in Patients with Alcoholic Steatohepatitis (ASH) vs Non-Alcoholic Steatohepatitis (NASH)

A B S T R A C T

As the fifth most common cancer and the second leading cause of cancer related deaths worldwide, hepatocellular carcinoma (HCC) is an aggressive tumor type with poor prognosis causing 250,000 to one million deaths annually. Alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) are the two major growing risk factors and both may develop liver fibrosis or even HCC. However, compared with the rate of patients with ASH progressing to HCC annually, it is much lower in NASH patients. The present study is to clarify the protein expression of epigenetic regulators and Inflammasome components in the oncogenesis pathway between ASH and NASH. By using the immunofluorescence method and morphometrically quantitating the fluorescence intensity in liver biopsied specimens from NASH and ASH patients, we studied the protein expression within hepatocytes cytoplasm of candidate epigenetic regulators G9A and LHPP and inflammasome component ASC. Compared with the control group patients, the expression levels of all three proteins were upregulated in the ASH and NASH group of patients (p < 0.001 in all molecules). While compared with the ASH group of patients, only the expression levels of G9a were statistically lower in the NASH group of patients (p < 0.01). The other two molecules, LHPP and ASC did not change. These results are consistent with our previous work that there are significant differences of many molecules including epigenetic modulators and the inflammasome pathway in both NASH and ASH compared to the control group. Thus, we conclude that there are significantly different molecules and pathways involved during the pathogenesis of HCC development in NASH compared to ASH which may shed some light on developing prevention methods and targeted treatments in NASH and ASH patients.

Keywords

Alcoholic Steatohepatitis (ASH),non-Alcoholic Steatohepatitis (NASH),hepatocellular Carcinoma (HCC),tumorigenesis,epigenetic regulators,inflammasome,G9a,LHPP,ASC

Introduction

Hepatocellular carcinoma (HCC) is a very common cancer and the second leading cause of cancer related deaths worldwide which causes 250,000 to one million deaths annually, therefore HCC is a major global healthcare burden and the major risk factors include Hepatitis B (HBV) and hepatitis C (HCV), obesity/metabolic syndrome, and alcoholism [1]. In the last twenty years, the incidence of the non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) increased significantly due to the prevalence of overweight, obesity, and metabolic syndrome. The relationship between NASH and HCC development has been proved by both experimental and epidemic studies. In addition to NAFLD and NASH, Alcoholic liver disease (ALD) and ASH are also becoming the major causes of HCC in the US [2-4]. NASH and ASH specimens have similar histological features, such as fat droplets storage and significant lipid deposition in the hepatocytes. Although both NASH and ASH may progress to fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC), the ratios of progressing are different. NASH progresses to cirrhosis and to HCC in about 7–10% and 0.5% victims, respectively, while ASH progresses to cirrhosis and to HCC in 10–20% patients, annually [5-8].

Although there are many theories including genetic alterations of tumor suppressor genes, oxidative stress, and decreased liver retinoic acid level, the detailed mechanisms underlying tumorigenesis of HCC in NASH and ASH patients are not completely understood [2, 9, 10]. Our previous work found different gene and protein changes in ASH compared with NASH, such as the TLR/NFKB/CXCR4/7, PI3K/AKT/mTORC1 signaling pathways; Ras/RASSF1A/P53 and RUNX3/p53/GSTP1 cross links together in molecular change both in ASH and NASH [11-20]. The present study attempted to identify the role of epigenetic modulator proteins and inflammasome components in ASH and NASH patients. Using liver biopsy specimens from NASH and ASH patients and control groups, we found that the G9a (histone-lysine N-methyltransferase G9a), LHPP (Phospholysine Phosphohistidine Inorganic Pyrophosphate Phosphatase), and ASC (Apoptosis-associated speck-like protein containing a CARD) play important roles in tumorigenesis of HCC for both ASH and NASH groups.

Results

The protein expression levels of several candidate molecules in specimens from patients with ASH, NASH, and normal controls were compared. Representative data are shown in (Fig. 1–3). In both NASH and ASH patients, levels of all tested candidate proteins including G9A, LHPP, and ASC (Fig. 1–3) were markedly increased compared with the control group. Although G9A was statistically significant lower in the NASH group specimens compared with the ASH group, LHPP and ASC had no difference (Fig. 1–3).

Discussion and Conclusions

The increasing prevalence of obesity and the metabolic syndrome has become a major health burden worldwide which is leading to an increased number of patients suffering from NASH to cirrhosis and even hepatocellular carcinoma (HCC). NASH is the most rapid growing risk factor in patients receiving liver transplantation due to HCC [21, 22]. The risk to develop HCC in patients drinking alcohol chronically (longer than 10 years and greater than 80 gram/day) is about 5 fold higher compared with the general population [24]. The most common cause of HCC is ALD which leads to around ⅓ of all HCC cases in US and Italy [2, 4]. Both NASH and ASH could progress to fibrosis, cirrhosis and even HCC, but the mechanisms involved remain unclear [23]. Our published data support that different molecules or pathways may be involved in NASH compared with ASH during the tumorigenesis [12, 13]. We showed that the TLR/NFKB/CXCR4/7, PI3K/AKT/mTORC1, and Tec kinase signaling pathways connected with each other during MDB formation both in ASH and NASH [11-20, 24].

Epigenetic modifications of DNA and histones include methylation, acetylation, and phosphorylation. These processes functionally cooperate modulating tumor development and growth, including that of hepatocellular carcinoma (HCC). SUV39H1, the first SET domain-containing histone lysine methyltransferase (HKMT), was reported in 2000. Since then, research on histone methylation has progressed rapidly. In mammals, Euchromatic histone-lysine N-methyltransferase G9a and GLP are also the primary HKMT enzymes for histone H3 dimethylation at lysine-9 (H3K9me2) and exist predominantly as a G9a-GLP heteromeric complex that appears to be a functional H3K9 methyltransferase in vivo. G9a and GLP play critical roles in various biological processes via epigenetic gene regulation [25]. G9A is upregulated in numerous types of cancer including HCC in at least 5 publically available datasets. G9A inhibition may suppress cell proliferation by arresting cells in G1 phase [26]. G9a regulates liver maturation by silencing neural and proinflammatory genes but maintaining/activating cytoprotective and drug-processing genes, in which the G9a/miR-383/PI3K/Akt/Nrf2 (Chop) pathways may play important roles [27]. Adult G9a liver-specific knockout (Liv-KO) mice show marked loss of H3K9me2 proteins in liver without overt liver injury or infiltration of inflammatory cells; while microRNA-383, a negative regulator of the PI3K/Akt pathway, was strongly induced in G9a Liv-KO mice [28]. Knockdown of G9a reduced H3K9me2 levels and impaired both HCC cell growth and sphere formation. Inhibition of G9a by BIX-01294 resulted in both cell growth inhibition and induction of apoptosis in HCC cells. G9a expression levels were significantly positively correlated with H3K9me2 levels in tumor tissues [29]. Overexpression/upregulation of G9a was significantly associated with HCC progression, aggressive clinicopathological features, and poor prognosis. Inactivation of G9a protein remarkably suppressed HCC cell proliferation and metastasis both in vitro and in vivo [30, 31]. Lysine methylation of histone and non-histone substrates by the methyltransferase G9a is mostly associated with transcriptional repression. However, other studies have highlighted G9a’s role as an activator of gene expression through mechanisms that are independent of its methyltransferase activity [32]. Obviously, more detailed studies are needed to clarify the role of G9a in cancers. Our previous work showed that histone methylation factor SUV39H1, acetylation factor HDAC II; DNA methylation factors DNMT1 and DNMT3B were all increased in ASH specimens compared with the control group, and all four factors were much lower in NASH patients when compared with the ASH group. In the present study, the expression of G9a protein was upregulated both in ASH and NASH specimens. The difference in the expression of G9a protein between ASH and NASH groups was statistic significant (Fig. 1) [11, 12].

Histidine phosphorylation has broader roles in protein and cellular function including cell cycle regulation, phagocytosis, and tumorigenesis. Two mammalian histidine kinases (NME1 and NME2) and two pHis phosphatases (PHPT1 and LHPP) were identified [33]. Global histidine phosphorylation was significantly upregulated in the liver tumors. Proteomic analysis of 12 tumors from an mTOR-driven HCC mouse model revealed that the expression of the putative histidine phosphatase LHPP was downregulated specifically in the tumors, while the NME1 and NME2 were conversely upregulated [34]. Sustained hepatic expression of LHPP in the HCC mouse model reduced tumor burden and prevented the loss of liver function and low expression of LHPP correlated with more advanced tumor and reduced overall survival in HCC patients [34]. Over-expressed LHPP reduced the tumor cell proliferation, migration and invasion possibly via blocking AKT activation and restraining p53 expression levels in cervical cancer cells [35]. So, LHPP is not only a protein histidine phosphatase but also a tumor suppressor. In our present data, the expression of LHPP protein was upregulated both in ASH and NASH specimens and there was no significant difference between ASH and NASH groups (Fig. 2).

Chronic inflammatory microenvironment plays a critical role at different stages of cancer development. The most predominant inflammatory pathways studied in hepatocarcinogenesis include NF-κB and IL-6/STAT3 inflammation signaling pathways [36, 37]. These pathways activate the assembly of the inflammasome and the subsequent secretion of the pro-inflammatory cytokines IL-1β and IL-18 both of which have been implicated in tumour-genesis/progression [38]. Inflammasomes, the potent inducers of interleukin (IL)-1β and IL-18 during inflammation, are the central signaling hubs of the inflammatory response. Apoptosis-associated speck-like protein containing a CARD (ASC) is a key adaptor protein in activation of the inflammasome in case of pathogen infection or stressor attack [39, 40]. At the molecular level, this is accomplished by the sensor-nucleated recruitment and oligomerization of the adapter protein ASC which links activated inflammasome sensors to the effector molecule pro-caspase-1[40]. Inflammasomes are large protein complexes typically consisting of a Nod-like receptor (NLR), the adapter protein ASC, and Caspase-1 [41]. After triggering of inflammasome sensors, ASC assembles into large helical fibrils serving as a supramolecular signaling platform termed the ASC speck. Recruitment of pro-caspase-1 to the inflammasome adapter ASC promotes the autocatalytic activation of caspase-1 and leads to the release of pro-inflammatory cytokines, such as IL-1β [42, 43]. The various inflammasomes and inflammatory cytokines and chemokines play contrasting roles in lung, breast, gastric, liver, colon, and prostate cancers and in glioblastomas [44]. Recently, it was reported that Inflammasomes may also exert anticancer effects by specialized programmed cell death called pyroptosis and immune regulatory functions [45]. Our previous work showed that the inflammasome activity was increased in ASH specimens [46]. In the present study, the expression of ASC protein was upregulated both in ASH and NASH specimens and there was no significant difference between ASH and NASH groups (Fig. 3). It suggests that the chronic inflammatory microenvironment and inflammation modulation are important in both ASH and NASH patients.

In summary, our previous work demonstrated the different expression of proteins which represent different pathways, such as GPCR/PI3K/Akt and TLR4/NF-κB/STAT3 signaling pathways, and Ras/RASSF/Raf and RUNX3/p53/GSTP1 tumor suppress genes. It is consistent with that the risk rates of those progressing to cirrhosis or HCC annually are much lower in the NASH if compared with those in ASH. In present study, we showed that epigenetic modulation and chronic inflammation were involved in the HCC tumorigenesis both in ASH and NASH (Fig. 4). These findings may be very helpful to understand the pathogenesis of HCC and to direct possible preventive and therapeutic pathways. To achieve this goal, more detailed experiments and long term studies are needed

Acknowledgements

This study was funded by NIH/AAA grant # UO-21898-05.

Disclosure

All authors have no financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Abbreviations

ASH: alcoholic steatohepatitis ALD: alcoholic liver disease NAFLD: non-alcoholic fatty liver disease NASH: non-alcoholic steatohepatitis HCC: hepatocellular carcinoma G9a: histone-lysine N-methyltransferase G9a NME1: Nucleoside diphosphate kinase A, also known as nm23-H1, nometastatic gene 23-H1 NME2: Nucleoside diphosphate kinase B, also known as nm23-H2, nometastatic gene 23-H2 PHPT1: Phosphohistidine Phosphatase 1 LHPP: Phospholysine Phosphohistidine Inorganic Pyrophosphate Phosphatase ASC: Apoptosis-associated speck-like protein containing a CARD SUV39H1: Suppressor Of Variegation 3-9 Homolog 1 RASSF1A: Ras association domain family protein 1A RUNX3: Runt-related transcription factor GSTP1: glutathione S-transferase protein 1 MEK: Mitogen-activated protein kinase kinase GPCR: G protein-coupled receptor PI3K: phosphatidylinositol 3-kinase Akt: also known as PKB, Protein Kinase B TLR4: Toll-like receptor 4 NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells STAT3: signal transducer and activator of transcription 3 FAT10: HLA-F-adjacent transcript 10; FOXO1: forkhead box protein O1 FOXO1: forkhead box protein O1

Article Info

Article Type

Research Article

Publication history

Received: Tue 21, May 2019
Accepted: Mon 29, Jul 2019
Published: Mon 29, Jul 2019

Copyright

© 2023 Yue Jia. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.
DOI: 10.31487/j.COR.2019.03.04

Author Info

Askalu Iyasu Barbara French Brittany Tillman Luan Nguyen Ping Ji Samuel W. French W. French Yue Jia

Corresponding Author

Yue Jia
Harbor-UCLA Medical Center, Department of Pathology, Torrance, CA, 90502 USA

Figures & Tables

Figure 1: Changes of G9A in ASH and NASH specimens. (A) Level of expression of G9A protein upregulated in ASH and NASH compared with normal controls. Expression is measured as fluorescence intensity and displayed as mean +/− standard deviation. Representative images of fluorescence intensity to measure G9A expression in the normal controls (B), ASH (C) and NASH (D) liver specimens. A line is drawn through the image to yield a fluorescence intensity graph; the intensity of the ten highest peaks are measured, excluding nuclear regions which are highlighted by DAPI (not shown). Three areas per slide are measured in this manner including Figure 2 and 3.

Figure 2: Changes of LHPP in ASH and NASH specimens. (A) Level of expression of LHPP protein upregulated in ASH and NASH compared with normal controls. Expression is measured as fluorescence intensity and displayed as mean +/− standard deviation. Representative images of fluorescence intensity to measure LHPP expression in the normal controls (B), ASH (C) and NASH (D) liver specimens.

Figure 3:Changes of ASC in ASH and NASH specimens. (A) Level of expression of ASC protein upregulated in ASH and NASH compared with normal controls. Expression is measured as fluorescence intensity and displayed as mean +/− standard deviation. Representative images of fluorescence intensity to measure ASC expression in the normal controls (B), ASH (C) and NASH (D) liver specimens.

Figure 4: Putative pathway for DNMTs, SUV39H1, HDAC II, G9a, LHPP, and ASC in the HCC tumorigenesis. The similar expression pattern of G9a, LHPP, and ASC proteins suggest similar pathways been involved in ASH and NASH, including certain epigenetic modulators and inflammasome component in HCC tumorigenesis. But other epigenetic modulators such as DNMTs, SUV39H1, HDAC II still have different expression pattern in ASH and NASH specimens which shows the complexity of HCC tumorigenesis from different stressors

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