Hepatocellular carcinoma (HCC) is common among chronic hepatitis patients and has long been associated with inflammation caused by hepatitis B (HBV) or C viral infection. The molecular mechanisms behind HCC tumorigenesis and metastasis in patients with chronic hepatitis are unclear. Moreover, recently gained insights have linked inflammation to the aberrant activation of a latent embryonic program—termed the epithelial–mesenchymal transition (EMT)—that endows tumor cells with metastatic competence and resistance to therapy.

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.

Researchers from Dr. GENG Meiyu’s group, Dr. DING Jian’s group at Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Dr. FAN Jia’s laboratory at Liver Cancer Institute, Zhongshan Hospital, Fudan University, have recently identified pIgR as a potential link between hepatitis B virus-derived hepatitis and HCC metastasis, and provided evidence in support of pIgR as a prognostic biomarker for HCC and a potential therapeutic target.

Overexpression of pIgR increased metastasis in an experimental metastasis model in mice and experiments in HCC cell lines showed that increased pIgR expression induces EMT. Mechanistically, pIgR induced the EMT process in vitro and in vivo through activation of Smad signaling. Importantly, high expression of pIgR was inversely associated with disease-free survival and was indicative of poor prognosis in HBV-positive HCC patients. These results identified pIgR as a prognostic biomarker for HCC and a molecular player in hepatitis B infection, chronic liver inflammation, EMT induction, HCC recurrence, and metastatic progression. The discovery of this new role could provide a basis for the study of novel mechanisms underlying inflammation-mediated HCC progression.

This work has recently been published online in the Journal of the National Cancer Institute (October 24, 2011) and significant contribution of the findings were highlighted in an Editorial in the same issue. This study, says Dr. Sendurai A Mani from MD Anderson Cancer Center (Huston, USA), “is the first demonstration of a host immunoglobulin receptor that synergizes with TGF-β/Smad signaling and the inflammatory milieuto engage EMT, thus bestowing metastatic competence upon disseminating HCC cells”. The findings "raise the intriguing possibility that pIgR may also affect stemness”, says Mani. “This is especially important in view of the emerging literature on the roles of EMT and stem cells in HCC progression, heterogeneity, and resistance to therapy”. Another “key finding of this study is that different and separable portions of pIgR are important in mediating its transcytosis functions and the induction of EMT through the recruitment of R-Smads” says Mani. “These results may guide the development of therapies specifically directed toward the inhibition of pIgR-elicited EMT without affecting its roles in transcytosis.”

Article Link: http://jnci.oxfordjournals.org/content/early/2011/10/18/jnci.djr360.full 

Editorial Link: http://jnci.oxfordjournals.org/content/early/2011/10/18/jnci.djr421.full