HRG switches TNFR1-mediated cell survival to apoptosis in Hepatocellular Carcinoma

Abstract

Background: Tumor necrosis factor receptor 1 (TNFR1) signaling plays a pleiotropic role in the development of hepatocellular carcinoma (HCC). The formation of TNFR1-complex I supports cell survival while TNFR1-complex II leads to apoptosis, and the underlying mechanisms of the transformation of these TNFR1 complexes in HCC remain poorly defined. Methods: The interaction protein of TNFR1 was identified by GST pulldown assay, immunoprecipitation and mass spectrometry. In vitro and in vivo assay were performed to explore the biological features and mechanisms underlying the regulation of TNFR1 signals by histidine-rich glycoprotein (HRG). Data from the public databases and HCC samples were utilized to analyze the expression and clinical relevance of HRG. Results: HRG directly interacted with TNFR1 and stabilized TNFR1 protein by decreasing the Lys(K)-48 ubiquitination mediated-degradation. The formation of TNFR1-complex II was prompted by HRG overexpression via upregulating Lys(K)-63 ubiquitination of TNFR1. Besides, overexpression of HRG suppressed expression of pro-survival genes by impairing the activation of NF-κB signaling in the presence of TNFR1. Moreover, downregulation of HRG was a result of feedback inhibition of NF-κB activation in HCC. In line with the pro-apoptotic switch of TNFR1 signaling after HRG induction, overexpression of HRG inhibited cell proliferation and increased apoptosis in HCC. Conclusions: Our findings illustrate a crucial role for HRG in suppressing HCC via inclining TNFR1 to a pro-apoptotic cellular phenotype. Restoring HRG expression in HCC tissues might be a promising pharmacological approach to blocking tumor progression by shifting cellular fate from cell survival to apoptosis.

Regulation of Death Receptor Signaling by S-Palmitoylation and Detergent-Resistant Membrane Micro Domains—Greasing the Gears of Extrinsic Cell Death Induction, Survival, and Inflammation

“…We observed that TNF-R1-mediated apoptosis requires K63-ubiquitination and subsequent internalization of TNF-R1 [ 38 ] ( Figure 2 C). In line, HRG (histidine-rich glycoprotein) interaction with TNF-R1 results in TNF-R1 K63-ubiquitination and apoptosis induction [ 39 ]. HRG has been described to be multiply palmitoylated in murine cells [ 40 ].…”

Bifidobacterium infantis-mediated herpes simplex virus-TK/ganciclovir treatment inhibits cancer metastasis

“…Moreover, HPX, HRG and GIG25 were significantly downregulated in BF-TK/GCV / BF-TK group. Overexpression of HRG (histidine-rich glycoprotein) inhibits cell proliferation and increased apoptosis in hepatocellular carcinoma(Zou et al, 2020). Hemopexin (HPX) promotes invasion and metastasis of the pancreatic cancer and colorectal carcinoma cells(Niu et al, 2021).…”

Ligand-Regulated Expression of TNF Receptors 1 and 2 Determines Receptor-Mediated Functional Responses

“…In contrast, the high expression of TNFR2 was associated with cell proliferation and a decrease in apoptosis, even for tumor cells, which contributed to their escape from immune surveillance [15,16]. Several studies reported that the expression of TNFR1 regulated the activation of the immune control system (including cell proliferation) [17][18][19]. Decreased expressions of TNFR1 and TNFR2 were associated with an increase in sensitivity and a decrease in resistance to infectious diseases [20], and were reported to be a compensatory reaction to prolonged infection accompanied by the shedding of receptors from the surface of the cell membrane, leading to increased levels of soluble TNFR1 [21].…”