The role of polymeric immunoglobulin receptor in inflammation-induced tumor metastasis of human hepatocellular carcinoma.
BACKGROUND
Expression of the polymeric immunoglobulin receptor (pIgR), a transporter of polymeric IgA and IgM, is commonly increased in response to viral or bacterial infections, linking innate and adaptive immunity. Abnormal expression of pIgR in cancer was also observed, but its clinical relevance remains uncertain.


METHODS
A human hepatocellular carcinoma (HCC) tissue microarray (n = 254) was used to investigate the association between pIgR expression and early recurrence. An experimental lung metastasis model using severe combined immune-deficient mice was applied to determine the metastatic potential of Madin-Darby canine kidney (n = 5 mice per group) and SMMC-7721 (n = 12 mice per group) cells overexpressing pIgR vs control cells. RNA interference, immunoprecipitation, and immunoblotting were performed to investigate the potential role for pIgR in the induction of epithelial-mesenchymal transition (EMT). In vitro studies (co-immunoprecipitation, immunoblotting, and migration, invasion, and adhesion assays) were used to determine the mechanisms behind pIgR-mediated metastasis. All statistical tests were two-sided.


RESULTS
High expression of pIgR was statistically significantly associated with early recurrence in early-stage HCC and in hepatitis B surface antigen-positive HCC patients (log-rank P = .02). Mice injected with pIgR-overexpressing cells had a statistically significantly higher number of lung metastases compared with respective control cells (Madin-Darby canine kidney cells: pIgR mean = 29.4 metastatic nodules per lung vs control mean = 0.0 metastatic nodules per lung, difference = 29.4 metastatic nodules per lung, 95% confidence interval = 13.0 to 45.8, P = .001; SMMC-7721 cells: pIgR mean = 10.4 metastatic nodules per lung vs control mean = 2.2 metastatic nodules per lung, difference = 8.2 metastatic nodules per lung, 95% confidence interval = 1.0 to 15.5, P = .03). Furthermore, high expression of pIgR was sufficient to induce EMT through activation of Smad signaling.


CONCLUSIONS
pIgR plays a role in the induction of EMT. Our results identify pIgR as a potential link between hepatitis B virus-derived hepatitis and HCC metastasis and provide evidence in support of pIgR as a prognostic biomarker for HCC and a potential therapeutic target.
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, People's Republic of China.
Jing
J
Ai
Qingjuan
Q
Tang
Yanlin
Y
Wu
Yang
Y
Xu
Teng
T
Feng
Ruiyu
R
Zhou
Yi
Y
Chen
Xin
X
Gao
Qingfeng
Q
Zhu
Xihua
X
Yue
Qiuming
Q
Pan
Siyun
S
Xu
Jing
J
Li
Min
M
Huang
Jennifer
J
Daugherty-Holtrop
Yuanzheng
Y
He
H Eric
HE
Xu
Jia
J
Fan
Jian
J
Ding
Meiyu
M
Geng
D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000556:secondary / Q000821:virology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000473:pathology; D019694:Hepatitis B, Chronic / Q000150:complications / Q000276:immunology / Q000473:pathology; D007070:Immunoglobulin A / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology / Q000821:virology; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000601:surgery; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000473:pathology; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D019056:Receptors, Polymeric Immunoglobulin / Q000235:genetics / Q000378:metabolism; D000818:Animals
D007070:Immunoglobulin A; D007075:Immunoglobulin M; D019056:Receptors, Polymeric Immunoglobulin