Immune betrayal function of polyimmunoglobulin receptor pIgR revealed by drugs

The Geng Meiyu and Ding Jian research groups of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences and the Fan Jia research group of Zhongshan Hospital affiliated to Fudan University have made important progress in the research of biomarkers for the malignant transformation of hepatitis-liver cancer and recurrence and metastasis of liver cancer.

Liver cancer is one of the most common malignant tumors that affect human health. Hepatitis is closely related to the occurrence of liver cancer. About three-quarters of liver cancers are associated with hepatitis virus HBV / HCV infection. At present, surgical resection is still the preferred treatment for liver cancer, but the high recurrence rate and metastasis rate after surgery are the bottlenecks that restrict the survival rate of liver cancer patients. In recent years, more and more studies have shown that epithelial mesenchymal transformation (EMT), as an important link to "inflammatory cancer transformation", plays a key role in promoting tumor metastasis, tumor drug resistance and maintenance of tumor stemness.

The polyimmunoglobulin receptor pIgR is a type I transmembrane glycoprotein receptor that mediates the polar transport of polyimmunoglobulin A and polyimmunoglobulin M in cells by sensing the inflammatory microenvironment. All play an important role in immunity.

After years of painstaking research, the research team of Shanghai Institute of Materia Medica discovered for the first time that highly expressed pIgR significantly induces the mesenchymal transformation of hepatoma cells in vivo and in vitro, and promotes the early recurrence and metastasis of liver cancer. The in-depth mechanism discussion showed that pIgR recruited activated Smad complex by using Smad2 as a bridge in early endosomes to induce the occurrence of EMT; the results of functional area analysis showed that Ser682 and Ser734 residues in the intracellular segment of pIgR played a role in EMT transformation The key role is particularly worth noting that the four amino acid residues Tyr677, Tyr743, Ser673 and Ser735, which are closely related to the transport function of pIgR, do not participate in the malignant transformation process of pIgR. In order to explore the correlation between the expression of pIgR and the prognosis of liver cancer, through cooperation with the Fanjia research group of Zhongshan Hospital, it was found that the high expression of pIgR is closely related to the prognosis of liver cancer, especially in HBV-positive liver cancer patients. Further analysis shows that pIgR is an independent predictor of early recurrence and metastasis of liver cancer.

The authoritative academic journal in the field of cancer research, the US National Journal of Cancer Research (J Natl Cancer Inst, impact factor 14.697) published the research results online on October 24. During the same period, Dr. Sendurai A Mani of MD Anderson Cancer Center in the United States reviewed the study on the topic of pIgR: Frenemy of inflammation, EMT, and HCC progression and believed that it was different from the traditional immune defense function of pIgR. Globulin receptor pIgR, as a key mediator of inflammation, promotes the metastasis and transformation of hepatitis to hepatocellular carcinoma by inducing EMT, and may play an important regulatory role in drug resistance of liver cancer and maintenance of liver cancer dryness; Independent predictive markers provide molecular markers and targets for early diagnosis and treatment of liver cancer, and have important guiding significance for avoiding treatment risks; at the same time, pIgR-mediated immunoglobulin transport is different from EMT malignant transformation functional domain, which is specific Sex-targeted pIgR-mediated EMT provides an important intervention strategy. This selective mode of action may be the key to confer anti-tumor recurrence and metastasis and overcome the toxic and side effects caused by non-specific targeted immune transport functions.

This research challenged the limitations of the traditional function of pIgR, laid an important theoretical foundation for redefining the "non-classical function" of the immunoglobulin receptor family, and provided a new research perspective for "inflammatory cancer transformation". The two-sided study of immune defense and immune betrayal of immunoglobulin receptors provides important examples.

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