Hrg, or histidine-rich glycoprotein, binds to various factors and is involved in multiple fundamental biological processes such as blood coagulation, apoptotic cell clearance, and tumor growth [3]. It can regulate the recruitment and activation of neutrophils in the metastatic microenvironment, affecting the formation of neutrophil extracellular traps (NETs) [1]. Additionally, Hrg can influence TNFR1-mediated signaling in hepatocellular carcinoma (HCC), switching cell survival to apoptosis [2].

In liver cancer, hepatocellular carcinoma cells reduce Hrg secretion, promoting neutrophil recruitment and NETs formation, which in turn facilitates lung metastasis. Hrg inhibits this process by binding to FCγR1 on neutrophil membranes, suppressing PI3K and NF-κB activation, reducing IL-8 secretion, and inhibiting IL8-MAPK and NF-κB pathway activation and ROS production [1]. In HCC, Hrg directly interacts with TNFR1, stabilizes TNFR1 protein, promotes the formation of TNFR1-complex II, and suppresses the activation of NF-κB signaling, thereby inhibiting cell proliferation and increasing apoptosis [2].

In conclusion, Hrg plays crucial roles in regulating the metastatic microenvironment in liver cancer and influencing TNFR1-mediated cell fate in HCC. Understanding Hrg's functions through these in-vivo-like studies provides insights into tumor metastasis and HCC progression, potentially leading to new treatment strategies for these diseases.

References:

1. Yin, Yanze, Dai, Huijuan, Sun, Xicheng, Xia, Qiang, He, Kang. . HRG inhibits liver cancer lung metastasis by suppressing neutrophil extracellular trap formation. In Clinical and translational medicine, 13, e1283. doi:10.1002/ctm2.1283. https://pubmed.ncbi.nlm.nih.gov/37254661/

2. Zou, Xuejing, Zhang, Dongyan, Song, Yang, Wu, Dehua, Liu, Li. 2020. HRG switches TNFR1-mediated cell survival to apoptosis in Hepatocellular Carcinoma. In Theranostics, 10, 10434-10447. doi:10.7150/thno.47286. https://pubmed.ncbi.nlm.nih.gov/32929358/

3. Nishibori, Masahiro, Wake, Hidenori, Sakaguchi, Masakiyo. . [The plasma protein HRG is an important factor for preventing sepsis and maintaining homeostatic response]. In Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 159, 107-111. doi:10.1254/fpj.23027. https://pubmed.ncbi.nlm.nih.gov/38432918/