HBx-induced S100A9 in NF-κB dependent manner promotes growth and metastasis of hepatocellular carcinoma cells

Abstract

Hepatocellular carcinoma (HCC) is associated with hepatitis B virus (HBV) infection. Myeloid-specific S100 proteins (S100s), namely, S100A8, S100A9 and S100A12, have been recently recognized as newly discovered damage-associated molecular patterns (DAMPs) that are correlated with progression in pathogen of infectious diseases. However, whether S100s are regulated by HBV and involved in HBV-related hepatocarcinogenesis are still unclear. Here, we found that all expression levels of myeloid-specific S100s (S100A8, S100A9 and S10012) were elevated in serum and tissue samples from HCC patients. Expression of S100A9 but not S100A8 and S10012 were also higher in blood serum and tissue samples from HBV-positive HCC patients than that in HBV-negative HCC patients. High levels of intracellular and extracellular S100A9 were also confirmed in HepG2 cells expressing 1.3-fold HBV genome or HBV-encoded X protein (HBx) as well as in a stable HBV-producing cell line HepG2.2.15. HBx was shown to facilitate translocation of NF-κB from the cytoplasm to the nucleus, and NF-κB bound to the promoter of S100A9 to enhance its transcription. Silencing S100A9 expression partially blocked HBx-induced growth and metastasis of HepG2 cells both in vitro and in vivo. Further, serum S100A9 levels were found to correlate with TNM stage, extrahepatic metastasis status and HBV DNA load in HBV-related HCC and also had a better diagnostic value for identifying extrahepatic metastasis. Our these data demonstrate that S100A9 plays a pivotal role in HBx-induced growth and metastasis of HCC and may serve as a potential diagnostic marker for extrahepatic metastasis.

Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid‐induced bone growth impairment

“…The specificity of Ihh and HN antibodies used in this study has previously been validated and well characterized by using with negative control normal IgG isotype (33‐35). Rabbit anri‐proliferating cell nuclear antigen (PCNA) pAb (36) (ab‐18197; Abcam, Cambridge, United Kingdom) was used to assess proliferation in mouse growth plates. The sections were incubated at 4°C overnight.…”

MARCH1 encourages tumour progression of hepatocellular carcinoma via regulation of PI3K‐AKT‐β‐catenin pathways

“…14,17 Briefly, immunostaining analysis was independently performed by two clinical pathologists. The embedded-tissues were cut into 5-μm thick sections placed on adhesion microscope slides (Citoglas, China) and stained with H-E (Novland, China).…”

“…H-E and IHC were done as previously described. 14,17 Briefly, immunostaining analysis was independently performed by two clinical pathologists. Five fields were randomly selected per sample.…”

Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9

“…As a homodimer, A9 potently activates inflammation via Toll-like receptor 4 (TLR4). [18][19][20][21][22][23][24][25][26][27][28][29][30] As a heterocomplex with S100A8 (A8/A9, also known as calprotectin), it is antimicrobial (Figure 1a). [31][32][33][34][35][36][37][38][39][40][41][42][43][44] A9 exacerbates endotoxin-induced shock in mice.…”

“…A9 acts as a Damage-Associated Molecular Pattern (DAMP), activating NF-Band other cytokines through Tolllike receptor 4 (TLR4). [18][19][20][21][22][23][24][25][26][27][28][29][30] The interaction interface(s), affinity, and stoichiometry for the A9/TLR4 interaction are not known. A small region of A9 has been suggested to form part of the A9/TLR4 binding surface, 55 but no mutant of A9 has been identified that substantially compromises its activation of TLR4.…”