The polymeric immunoglobulin receptor (pIgR) is a mediator of both the adaptive and innate immune systems through the transport of polymeric IgA and IgM in response to inflammation. Previously, Scientists from Shanghai Institute of Materia Medica (SIMM) identified pIgR as a potential link between hepatitis B virus-derived hepatitis and hepatocellular carcinoma (HCC) metastasis, and provided evidence in support of pIgR as a prognostic biomarker for HCC. 

Recently, researchers from the same group describe a previously unrecognized pro-oncogenic function of pIgR in the promotion of cell transformation and proliferation. Mechanistically, pIgR overexpression is associated with Yes activation, which is required for pIgR-induced oncogenic growth. 

Specifically, pIgR activates the Yes-Dap12-Syk-Rac1/CDC42-MEK/ERK cascade in an immunoreceptor tyrosine-based activating motif (ITAM)-dependent manner to promote cell transformation and tumor growth, although pIgR itself does not contain an ITAM sequence. 

Further, cooperation with the scientists from Liver Cancer Institute, Zhongshan Hospital, Fudan University, they found that the combination of pIgR and phosphorylated Yes (p-Yes) levels serves as a prognostic biomarker for hepatitis B surface antigen (HBsAg)-positive and early stage HCC patients. 

Moreover, pharmacological targeting of MEK/ERK or Yes represents a therapeutic option for the subgroup of patients with pIgR/p-Yes-positive HCC based on the data with both cancer cell line-based xenografts and primary patient-derived xenografts. 

This study has important clinical implications and therapeutic significance. Clinical follow-up studies showed a strong correlation between the combination of pIgR expression with p-Yes levels and clinical outcomes in HBsAg-positive patients with HCC and those with early stage HCC. 

The combination of pIgR and p-Yes expression may represent a prospective prognostic biomarker for patients with HCC, particularly those in the early stages of disease or those with HBsAg infection. Moreover, targeting the Yes or MEK/ERK signaling pathways may confer therapeutic benefits to patients with HCC that is positive for pIgR and p-Yes. 

As dasatinib and MEK inhibitors are clinically available, these findings may be readily translated into therapeutic options and rapidly evaluated in clinical trials. Moreover, the finding will help expand new indications for either MEK inhibitors or dasatinib, which are currently limited to B-RAF mutant melanoma or chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), respectively. 

These findings reveal the molecular mechanism by which pIgR promotes cancer malignancy, suggest the clinical potential of targeting this pathway in HCC and provide new insight into the oncogenic role of immunoglobulin receptors. 

This work was supported by the National Program on Key Basic Research Project of China, the National Natural Science Foundation of China, the “Personalized Medicines --Molecular Signature-based Drug Discovery and Development”, Strategic Priority Research Program of the Chinese Academy of Sciences, and the Youth Innovation Promotion Association. 

Full text link: http://onlinelibrary.wiley.com/doi/10.1002/hep.29036/abstract;jsessionid=4D742DC849966740D1D48BB1D15AE757.f02t02 

Figure: Tumor-associated pIgR and Yes Signaling Stratifies Patients with hepatocellular carcinoma with Poor Prognosis (Image by SIMM)

Keywords:

immunoglobulin receptor; pIgR; HCC; ITAM; Yes

Contact:

Prof. GENG Meiyu (mygeng@simm.ac.cn)

(Credit: AI Jing；Editor：PAN Peihua)