Annexin II promotes invasion and migration of human hepatocellular carcinoma cells in vitro via its interaction with HAb18G/CD147

Abstract

HAb18G ⁄ CD147, a member of the immunoglobulin family enriched on the surface of tumor cells, is reported to be correlated with invasion, metastasis, growth, and survival of malignant cells. Here, we found that annexin II, a 36-kDa Ca 2+ -and phospholipid-binding protein and in vivo substrate for tyrosine kinase and PKC, is a new interaction protein of HAb18G ⁄ CD147 in human hepatocellular carcinoma (HCC) cells. In the present study, we explored the unclear role of annxin II in HCC invasion and migration and the interaction effects between HAb18G ⁄ CD147 and annexin II. Our data show that downregulation of annexin II in HCC cells significantly decreased the secretion of MMP, migration ability, and invasive potential, and affected the cytoskeleton rearrangement of tumor cells. The MMP-2 level and invasive potential of HCC cells were regulated by both annexin II and HAb18G ⁄ CD147. Also, interaction effects exist between the two molecules in tumor progression, including MMP-2 production, migration, and invasion. These results suggest that annexin II promotes the invasion and migration of HCC cells in vitro, and annexin II and HAb18G ⁄ CD147 interact with each other in the same signal transduction pathway working as a functional complex in tumor progression. (Cancer Sci 2010; 101: 387-395) I nvasion and migration are two central processes of malignant tumors that usually lead to tumor-associated death. Such migratory and invasive events are regulated by different proteolytic enzymes, including serine protease, cysteine protease, and metalloproteases.(1) These proteolytic enzymes degrade the extracellular matrix (ECM) and basement membrane surrounding blood vessels. During metastasis, cancer cells penetrate through the degraded basement membrane and ECM, become implanted in the underlying tissues, and subsequently form secondary tumors.(2) Among the proteases, MMP are mainly regulated by tumor-stroma interactions via CD147, a highly glycosylated cell surface transmembrane protein belonging to the immunoglobulin superfamily.(3) CD147 was first identified as a factor shed from the surface of tumor cells responsible for stimulating MMP-1 production by fibroblasts. One of the important and most studied functions of CD147 is its role in induction of MMP production via cell interactions -thus the derivation of its other name: extracellular matrix metalloproteinase inducer (EMMPRIN).(4) Accumulating evidence suggests a prominent role for CD147 in mediating interactions both between tumor cells themselves and between tumor cells and 'hijacked' host stromal cells to promote a number of events during cancer progression.(5) Although the detailed mechanisms through which CD147 regulates the phenomenon are not yet known, it is clear that CD147 is a major mediator of malignant cell behavior. Our team previously developed the anti-hepatocellular carcinoma (HCC) mAb HAb18 by using a cell suspension extracted from fresh human HCC tissues to immunize BALB ⁄ c mice and prepare hybridomas.(6-8) Its antigen, HAb18G, was identified ...

Preclinical Pharmacokinetics, Tolerability, and Pharmacodynamics of Metuzumab, a Novel CD147 Human–Mouse Chimeric and Glycoengineered Antibody

“…CD147 stimulates the production of membrane-type matrix metalloproteinases (11,12), promotes cell migration, invasion, and angiogenesis (13)(14)(15)(16), and plays an important role in tumorigenesis. Aberrant expression of CD147 has been observed in various epithelial malignancies (17,18), including hepatocellular carcinoma, lung cancer, breast cancer, and carcinomas of the pancreas, prostate, and bladder.…”

A novel functional site of extracellular matrix metalloproteinase inducer (EMMPRIN) that limits the migration of human uterine cervical carcinoma cells

“…Recent reports have also revealed that the augmented expression of EMMPRIN directly or indirectly stimulates tumor cell migration in vitro (19,20). In addition, the interaction between EMMPRIN and membrane-associated molecules such as caveolin and annexin II on the cell surface has been reported to facilitate human carcinoma cell migration (21,22). However, it is not well understood which extracellular domains of EMMPRIN are requisite for the control of tumor cell migration.…”

WOMEN IN CANCER THEMATIC REVIEW: Ovarian cancer–peritoneal cell interactions promote extracellular matrix processing

“…Annexin A2 increases cancer cell proliferation and cell survival via the ERK1/2 and MAPK pathway (Shiozawa et al 2008) and is a substrate for src kinase and regulates tyrosine 23 phosphorylation of annexin A2 to enhance cancer cell invasion (Zheng et al 2011). Annexin A2 also plays a role in actin cytoskeletal rearrangement and regulates cancer cell migration (Zhao et al 2010).…”