Hepatitis B virus X protein and TGF-β: partners in the carcinogenic journey of hepatocellular carcinoma

Abstract

Hepatitis B infection is substantially associated with the development of liver cancer globally, with the prevalence of hepatocellular carcinoma (HCC) cases exceeding 50%. Hepatitis B virus (HBV) encodes the Hepatitis B virus X (HBx) protein, a pleiotropic regulatory protein necessary for the transcription of the HBV covalently closed circular DNA (cccDNA) microchromosome. In previous studies, HBV-associated HCC was revealed to be affected by HBx in multiple signaling pathways, resulting in genetic mutations and epigenetic modifications in proto-oncogenes and tumor suppressor genes. In addition, transforming growth factor-β (TGF-β) has dichotomous potentials at various phases of malignancy as it is a crucial signaling pathway that regulates multiple cellular and physiological processes. In early HCC, TGF-β has a significant antitumor effect, whereas in advanced HCC, it promotes malignant progression. TGF-β interacts with the HBx protein in HCC, regulating the pathogenesis of HCC. This review summarizes the respective and combined functions of HBx and TGB-β in HCC occurrence and development.

Keywords: HBx protein; TGF-β signaling; hepatitis B virus; hepatocellular carcinoma; pro-tumorigenic; tumor suppressor.

Figure 1

HBV genome map. HBV comprises a small, partially ~ dsDNA genome (the inner blue circle), which contains four promoters and two enhancer regions (Enh1/2), in addition to two direct repeats (DR1/2). The four HBV-coded overlapping ORFs: preS/S, precore/C, polymerase, and X, are indicated by the colored arrows. When the virus is replicating, the rcDNA enters the nucleus, it undergoes conversion into cccDNA through the action of host DNA polymerase and repair enzymes, that act as the viral transcription template, showing the primary HBV transcripts (outer black lines), their 5′ initiation sites (black arrowheads), aside with 3′ poly-A tails (AAAA).(This figure is modified from Figure 1 of the article PMID: 35648301) (11).

Figure 2

HBx and its multifunctional roles in hepatocarcinogenesis. HBx interacts with several cellular targets through various mechanisms, including affecting multiple signaling pathways, damaged DNA repair, immune evasion, and epigenetic changes (DNA methylation, histone acetylation, ncRNAs) to accelerate HBV transcription, replication, and malignant progression of HCC.

Figure 3

Canonical and non-canonical TGF-β signaling pathways. Regarding canonical TGF-β signaling pathways (SMAD‐dependent signaling pathways), the TGF-β ligand secreted by extracellular matrix binds to TGFβRII to initiate this pathway; and TGFβRII upon activation, forms a complex with TGFβRI and phosphorylates TGFβRI. Then Smad2/3/4 forms transcription complexes, entering the nucleus besides binding to DNA to regulate the target gene expressions. Smad6/7 are canonical TGF-β pathway inhibitors. Non-canonical Smad pathways (SMAD‐independent signaling pathways) include MAPK, Erk1/2, Rho-like, PI3K/AKT, JNK, p38/MAPK, and Src tyrosine kinase pathways.

Figure 4

TGF-β dichotomous role in HCC development and progression. TGF-β has various tumor-suppressing functions, including G1 and G2 cell cycle arrest, cellular senescence, autophagy, and apoptosis. Conversely, it has the ability to serve as a tumor promoter, inducing cancer cell proliferation, EMT, and immune suppression in HCC.

Figure 5

HBx participated in the conversion of dichotomous effects on HCC in the TGF-β pathway. JNK-activated pSmad2/3L-mediated cell proliferation signal and TβRI-activated pSmad2/3C-mediated cell cycle arrest signal are mutually antagonistic. HBx leads TGF-β signaling in hepatocytes to shift from the TβRI-dependent pSmad3C tumor-suppressive pathway to the JNK-dependent pSmad3L oncogenic pathway during carcinogenic stages.

Figure 6

Multiple mechanisms by which HBx interacts with TGF-β in the non-SAMD pathways to promote HCC. HBx and TGF-β mutually interact through various mechanisms, inducing malignant characteristics in development of HCC, including EMT, anti-apoptosis, proliferation, inflammatory responses, metastasis, invasion, and fibrosis.