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Hepatitis B Viral Protein HBx: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Enakshi Sivasudhan.

With 296 million cases estimated worldwide, chronic hepatitis B virus (HBV) infection is the most common risk factor for hepatocellular carcinoma (HCC). HBV-encoded oncogene X protein (HBx), a key multifunctional regulatory protein, drives viral replication and interferes with several cellular signalling pathways that drive virus-associated hepatocarcinogenesis.

  • hepatitis B virus
  • HBx protein
  • hepatocellular carcinoma
  • cancer biology
  • virology
  • cancer hallmarks

1. Introduction

Despite the availability of hepatitis B virus (HBV) vaccines, the worldwide incidence of hepatitis B cases remain to be an estimated 296 million, with over 1.5 million new infections occurring annually [1]. Prolonged chronic inflammation and tissue damage associated with HBV often lead to fibrosis/cirrhosis and eventually hepatocellular carcinoma (HCC), the most common form of liver cancer [2]. According to the latest epidemiological data from Globocan 2020 report, newly diagnosed liver cancer cases account for over 900,000 cancer cases annually (4.7% of all cancers) and there are approximately 830,000 deaths linked to HCC annually [3]. Geographic variations associated with HBV infection show 70–80% hepatitis B surface antigen (HBsAg) seroprevalence in South East Asia and Sub-Saharan Africa, linked to high levels of HBV driven HCC incidence, whereas less than 2% HBsAg seroprevalence is observed in Western Europe, America and Australia with a similar low level of HBV-driven HCC [4].
HBV is a small DNA virus, a prototype of Hepadnaviridae family of viruses, with a 3.2 kilobases circular and partially double stranded genome. During replication, the partially dsDNA genome is gap repaired and transcribed into a full length pre-genomic RNA which is subsequently reverse transcribed by a viral polymerase with RT activity. The genome encodes four overlapping open reading frames (ORF) encoding envelope protein (pre-S1/pre-S2), core protein (pre-C/C), viral polymerase and X protein (HBx) [5]. While the exact molecular mechanisms driving HBV-induced HCC have been poorly defined, it has been speculated that virus-host genome integration, prolonged inflammation aided host immune response and cellular signal transduction pathways altered by the viral regulatory protein HBx could play a crucial role in the progression of liver tumorigenesis [6,7,8][6][7][8].
HBx gene, the smallest ORF of the HBV genome, encodes a 154-amino acid regulatory protein of molecular weight 17 kDa. It is found in all mammalian Hepadnaviruses, termed Orthohepadnaviruses, but interestingly not in avian species which are infected by Avihepadnaviruses. HBx proteins from different species contain conserved regions, helical structures in the amino- and carboxy-terminal as well as a coil-to-coil motif with several regions with known functional domains [9]. Attempts at crystallizing the protein have been proven futile, so no detailed structural information is available. HBx forms homodimers via disulfide bonds and acetylation [10]. It received its name, X protein, due to the lack of sequence homology to any existing protein. Intracellular localization studies based on HBV patient-derived liver biopsies show that HBx predominantly accumulates in the cytoplasm when highly expressed, whereas low expression leads to localization primarily in the nucleus [11,12][11][12].
While the precise functions of HBx are not fully understood, it has been proposed that HBx is multifunctional owing to its negative regulatory/anti-apoptotic N terminal and transactivator C terminal in addition to being the only regulatory protein encoded by the virus. HBx is key to driving HBV viral infection via governing cellular and viral promoters and enhancers, driving promiscuous transactivation, through protein–protein interactions and, without directly binding to DNA [13,14][13][14]. Given its primary localization in the cytoplasm, HBx is able to modulate several signal transduction pathways such as mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), rat sarcoma virus (Ras), rapidly accelerated fibrosarcoma (Raf), janus kinase-signal transducer and activator of transcription (JAK-STAT), focal adhesion kinase (FAK) and kinase C signalling cascades. [15,16][15][16]. Furthermore, HBx has also been implicated in cell cycle regulation, calcium signalling, DNA repair and regulation of apoptosis [17]. The potential role of HBx in hepatocarginogenesis was apparent with the development of HCC in the natural hosts of HBx encoding Orthohepadnaviruses, woodchucks, squirrel monkeys and humans, whereas there is no evidence of liver tumourigenesis for infection with Avihepadnaviruses which lack the HBx protein [18]. In vitro studies have shown that prolonged expression of HBx induces cellular transformation of rodent hepatocytes, while the presence of integrated HBx gene in the chromosomal DNA has been frequently detected in patients diagnosed with HCC [19,20][19][20].

2. Sustaining Proliferative Signalling

According to Hanahan and Weinberg, cancer cells endure proliferative signalling by enabling growth factor expression, stimulating non-malignant cells within the tumour-associated stroma, upregulating receptor protein levels in cancer cells and altering the structures of receptor molecules while activating downstream mitogenic signalling pathways linked to these receptors [22][21]. Conceivably, the most significant function of HBx is its ability to promote cell proliferation in hepatocarcinogenesis. For example, HBx has been proposed to activate stellate cells in fibrosis and elevate expression of transforming-growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) thus promoting cellular transformation [23][22].
HBx-transgenic liver cancer mouse model studying pre-neoplasm showed a five-fold elevated expression of c-myc, a multifunctional transcription factor which promotes cell proliferation, while an In vitro study established a strong correlation between HBx and c-myc which abetted ribosome biogenesis and cellular transformation [24,25][23][24]. Another In vitro study involving HepG2 hepatoma cells, concluded HBx-SMYD3 interaction, guided by the downstream target gene c-myc, promoted cell proliferation [26][25]. Additionally, HBx-transgenic mouse models implicate enhanced expression of fibroblast growth factor-inducible 14 (fn14) in c-myc/TGF-α-driven hepatocarcinogenesis [27][26]. HBx also disrupts cell cycle progression by upregulating p21 and p27, proteins that inhibit cyclin-dependent kinase (CDK) activity, which in turn enhances the ability of mitogen-activated protein kinase (MAPK) signalling to cause proliferation in hepatocytes [28][27]. Similarly, HBx elevates serine/threonine p21 activated kinase 1 (PAK1) and causes cytoskeletal rearrangement in xenograft mouse models [29][28].
With regard to altering mitogenic signalling pathways, HBx promotes cell proliferation via the 5-LOX/FAS mediated positive feedback loop mechanism. In vitro studies in HepG2 and H7402 cells concluded that HBx upregulated the transcription of fatty acid synthase (FAS), known to play a critical role in tumour cell survival and proliferation, mediated by 5-lipoxygenase (5-LOX) through phosphorylated ERK 1/2 [30][29]. Another study also has found that HBx promotes liver cell division by upregulating cyclooxygenase (COX-2) and MERK/ERK kinase 2 (MEKK2), the latter known to regulate several transcription and translation factors [31][30]. COX-2, on the other hand, is highly expressed in HCC, and along with HBx, mediates sequestration of p53 to abolish apoptosis. Incapacitated p53 can induce reactivation of previously suppressed anti-apoptotic proteins such as Mcl-1 thus driving forward an indirect HBx-mediated cell proliferation [32][31]. HBV gene expression and hepatocyte transformation is also driven by Ras-Raf MAPK signalling pathway by HBx-mediated activation of Ras and Src kinase through overriding the pro-apoptotic effects of HBx which will be reviewed in the following sections [33,100][32][33]. Such signalling mechanisms are imperative for successfully stimulating cell cycle and deregulating cell cycle checkpoint controls [101][34].
HBx is also capable of enhancing cytosolic calcium levels leading to elevated mitochondrial calcium uptake which induces HBV replication in vitro [34][35]. HBx may be involved in extracellular matrix remodelling by elevating adhesion protein LASP-1 through PI3K pathway to promote hepatocyte proliferation and invasion [35][36]. It is worth noting that high concentrations of HBx and its subcellular localization, especially in cell systems that lack effective negative growth regulatory pathways and intact tumour suppressors, suggests that cell growth inhibition in such cells is not strictly governed to the extent of that of healthy cells, which could be a key driver of neoplastic transformation [102][37].

3. Evading Growth Suppressors

Neoplastic maladies arise from accumulated genetic and epigenetic changes in proto-oncogenes and tumour suppressor genes with the latter mostly involved in suppression of metastasis, pro-apoptosis and DNA damage repair [103][38]. For instance, mutations arising from the TP53 tumour suppressor gene have been implicated in over half of all human cancers [104][39]. HBx is known to bind to the C terminus of p53 and obstruct numerous crucial cellular processes such as transcriptional binding, DNA sequence-specific binding and apoptosis. More specifically, in human hepatocytes and fibroblasts, HBx partially sequesters p53 in the cytoplasm leading to unfavourable G1 arrest conditions that eventually result in inhibition of apoptosis, typically indicating onset of hepatocarcinogenesis [36,105][40][41]. Interestingly, transient transfection of human pulmonary adenocarcinoma Calu-6 cells has shown that HBx directly interacts with p53 and enables inhibition of p53 response element-directed transactivation [37][42].
Retinoblastoma-associated (Rb) tumour suppressor is another critical gatekeeper of cell cycle progression that is deregulated by HBx. It has been shown that HBx incapacitates inhibition of E2F1 activity, a positive regulator of cell cycle progression, by inactivating Rb gene promoter and thereby tumour suppressor Rb [38][43]. Additionally, HBx increases CDK2 activity, leading to impairment of E2F1–Rb balance, which confers stability to replication initiator protein CDC6 and aids in the HBx-mediated oncogenic sabotage thereafter [39][44].
MicroRNAs (miRNAs), which regulate gene expression through translational repression and degradation of complementary target mRNAs, define tumourigenesis [106][45]. miR-205, a miRNA tumour suppressor is inhibited by HBx via hypermethylation of miR-205 promoter [40][46]. Another vital tumour suppressor miR-520b which targets cyclin D1 and MEKK2 is known to inhibit liver cancer cell proliferation [107][47]. HBx stimulates hepatocarcinogenesis by partnering with survivin by controlling tumor suppressor miR-520b and oncoprotein hepatitis B X-interacting protein (HBXIP), binding protein of HBx [41][48]. Epigenetically, HBx also represses RIZ1, another tumour suppressor of HCC, via methytransferase 1 (DNMT1) governed hypermethylation and suppressed miR-152 [42][49]. Moreover, HBx acts as an epigenetic deregulator by altering transcription of DNMT1 and 3 and thereby suppresses E-cadherin tumour suppressor while hypermethylating p16 via pRb-E2f pathway [43,44][50][51]. Tumour-suppression activity of retinoic acid receptor-beta 2 (RAR-β2) is epigenetically downregulated by HBx via DNMT-driven hypermethylation, instigating upregulation of G1-checkpoint regulators p16, p21 and p27 and eventually E2F1 activation and ensued tumourigenesis [45,108][52][53].

4. Resisting Cell Death

Programmed cell death by apoptosis, initiated by highly regulated cascades of intrinsic and extrinsic pathways, is another hurdle tumour cells need to circumvent. Series of upstream regulators and downstream effectors of the apoptotic machinery regulate binding of Fas ligand on the cell membrane leading to activation of caspase 8 and caspase 3 and thereby extrinsic pathways, while the mitochondrial release of cytochrome c activates extrinsic pathways, leading to proteolysis that gradually dissembles the cells, eventually consumed by phagocytic neighbouring cells [17,109][17][54].
Intriguingly, HBx-induced apoptosis in HCC plays a contradictory role depending on the cellular conditions and components that HBx interacts with. For instance, pro-apoptotic HBx induces the expression of TRAIL-R2 (DR5), a death receptor that targets TNF µ-related apoptosis inducing ligand (TRAIL) that is known to elicit apoptosis [46][55]. HBx suppresses the E3 ubiquitin ligase activity of A20 via upregulation of miR-125a which prevents inhibition of caspase 8 leading to hepatocyte sensitization to TRAIL-induced apoptosis [47][56]. Conversely, anti-apoptotic HBx elevates the expression of widely known apoptosis inhibitor genes myeloid cell leukemia-1 (Mcl-1) and B cell lymphoma 2 (Bcl-2) which inherently restrains pro-apoptotic Bcl-2-associated X protein (Bax) further inactivating caspase 9 and 3 [48][57]. HBx also modulates apoptotic activities by acting on the mitochondria, caspases and SIRT-related pathways. More precisely, elevated cytoplasmic HBx interacts with apoptosis-inducing factor (AIF) and AIF-homologue mitochondrian-associated inducer of death (AMID) which primarily drives the inhibition of AIF translocation from mitochondrion-to-nucleus [49][58]. The discrepant behaviour of HBx-elicited apoptosis could be partly attributed to HBx mutations, such as C-terminal truncation (trHBx), which are significantly more common in tumour tissues compared to non-tumour tissues [110,111][59][60]. For example, expression of wild type HBx (wtHBx) impaired colony formation in several HCC cell lines while cell growth remained unaltered in cells transfected with trHBx, with some studies even suggesting that C-terminal transactivation might be the primary site of pro-apoptotic function [112][61]. However, it is worth noting that HBx intracellular localization could be another key driver of apoptosis, since wtHBx and trHBx displayed preferential localization in cytoplasm and nucleus, respectively [113,114][62][63].
Autophagy signifies another crucial cell-physiologic response that sequesters protein aggregates and impairs organelles into autophagosomes which fuse with lysosomes, resulting in degradation [50,115][64][65]. HBx is known to incapacitate lysosomal acidification and ensued decrease in lysosomal degradative capacity while simultaneously upregulating autophagy substrate SQSTM1 and lysosomal aspartic protease cathepsin D, which aids in chronic HBV infection followed by liver cancer [50][64]. Similarly, HBx interacts with BECN1 (Beclin 1) and hinders the interaction of BECN1-Bcl-2 complex that inhibits assembly of pre-autophagosomal components [51][66]. Contrariwise, In vitro studies in HepG2 cells suggest the progressive activation of autophagic lysosomal pathway by HBx via the PI3K-Akt-mTOR pathway [52][67]. Such paradoxical behaviour of HBx in driving autophagy of hepatocytes could be attributed to severely stressed cancer cells preferentially undergoing autophagy to achieve reversible dormancy [116][68]. Clarifying such conflicting behaviours of HBx-induced autophagic tumour cells could close a crucial research gap in liver cancer research.

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