682

BSG

UNLABELLED: epithelial cell-cell contacts maintain normal glandular tissue homeostasis, and their breakage can trigger epithelial-to-mesenchymal transition (EMT), a fundamental step in the development of metastatic cancer. Despite the ability of C-type lectin domains (CTLD) to modulate cell-cell adhesion, it is not known if they modulate epithelial adhesion in EMT and tumor progression. Here, the multi-CTLD mannose receptor, Endo180 (MRC2/uPARAP), was shown using the Kaplan-Meier analysis to be predictive of survival outcome in men with early prostate cancer. A proteomic screen of novel interaction partners with the fourth CTLD (CTLD4) in Endo180 revealed that its complex with CD147 is indispensable for the stability of three-dimensional acini formed by nontransformed prostate epithelial cells (PEC). Mechanistic study using knockdown of Endo180 or CD147, and treatment with an Endo180 mAb targeting CTLD4 (clone 39.10), or a dominant-negative GST-CTLD4 chimeric protein, induced scattering of PECs associated with internalization of Endo180 into endosomes, loss of E-cadherin (CDH1/ECAD), and unzipping of cell-cell junctions. These findings are the first to demonstrate that a CTLD acts as a suppressor and regulatory switch for EMT; thus, positing that stabilization of Endo180-CD147 complex is a viable therapeutic strategy to improve rates of prostate cancer survival. IMPLICATIONS: This study identifies the interaction between CTLD4 in Endo180 and CD147 as an EMT suppressor and indicates that stabilization of this molecular complex improves prostate cancer survival rates.CI - (c)2014 American Association for cancer Research.

Colorectal cancer (CRC) is one of the most common cancers in the world. CD147, a transmembrane protein, has been reported to be correlated with various cancers. In this study, we aimed to investigate the mechanism of CD147 in regulating drug resistance, cell invasion and epithelial-to-mesenchymal transition (EMT) in CRC cells. qRT-PCR and western blotting were used to evaluated the expression of CD147 in 40 CRC cases and 4 cell lines. Increased expression of CD147 at both mRNA and protein levels was found in CRC samples, and the level of CD147 was correlated with lymph node metastasis. CD147 overexpression increased the 5-Fluorouracil (5-FU) resistance, enhanced the invasion and EMT of CRC cells by regulating EMT markers and MMPs. Adverse results were obtained in CD147 knockdown CRC cell line. Further investigation revealed that CD147 activated MAPK/ERK pathway, ERK inhibitor U0126 suppressed the CD147-induced cell invasion, migration and MMP-2, MMP-9 expression. Taken together, our study indicates that CD147 promotes the 5-FU resistance, and MAPK/ERK signaling pathway is involved in CD147-promoted invasion and EMT of CRC cells.

Extracellular matrix metalloproteinase inducer (EMMPRIN) exerts important roles in tumor progression, including angiogenesis, metastasis and therapy resistance. The epithelialmesenchymal transition (EMT), which is induced by hypoxia, is an important process in cancer metastasis. However, the association between hypoxia and EMMPRIN remains to be elucidated in esophageal cancer. The expression of EMMPRIN was determined by western blotting and reverse transcriptionquantitative polymerase chain reaction (RTqPCR), and EMT markers were analyzed by western blotting, RTqPCR and immunofluoresence. The migration and invasion of cells was investigated by Transwell assay. The results indicated that the expression levels of EMMPRIN in esophageal cancer cells were markedly higher compared with those in normal esophageal cells. EMMPRIN was able to promote esophageal cancer cell migration and invasion under both hypoxic or normoxic conditions, as demonstrated by the migration and invasion assay. The expression levels of Ecadherin were reduced, and those of snail family zinc finger 1, fibronectin, alphasmooth muscle actin and fibroblast secretory protein 1 increased in esophageal cancer cells following treatment with human recombinant EMMPRIN under hypoxic conditions. The mRNA expression levels of the EMT markers were similar to those of the protein expression levels. Furthermore, the results demonstrated that EMMPRIN was regulated by hypoxiainducible factor (HIF)1alpha. These data suggested that EMMPRIN promoted metastasis and the EMT in esophageal cancer cells by regulating HIF-1alpha.