Annexin A2 Promotes the Migration and Invasion of Human Hepatocellular Carcinoma Cells In Vitro by Regulating the Shedding of CD147-Harboring Microvesicles from Tumor Cells

Abstract

It has been reported that Annexin A2 (ANXA2) is up-regulated in hepatocellular carcinoma (HCC), but the roles of ANXA2 in the migration and invasion of HCC cells have not been determined. In this study, we found that ANXA2-specific siRNA (si-ANXA2) significantly inhibited the migration and invasion of HCC cells co-cultured with fibroblasts in vitro. In addition, the production of MMP-2 by fibroblasts cultured in supernatant collected from si-ANXA2-transfected HCC cells was notably down-regulated. ANXA2 was also found to be co-localized and co-immunoprecipitated with CD147. Further investigation revealed that the expression of ANXA2 in HCC cells affected the shedding of CD147-harboring membrane microvesicles, acting as a vehicle for CD147 in tumor-stromal interactions and thereby regulating the production of MMP-2 by fibroblasts. Together, these results suggest that ANXA2 enhances the migration and invasion potential of HCC cells in vitro by regulating the trafficking of CD147-harboring membrane microvesicles.

Overexpression of Annexin A2 Receptor Inhibits Neovascularization via the Promotion of Krüppel-Like Transcription Factor 2

“…Although many studies have shown that AX2R is a specific surface receptor for AXNA2, the result we obtained was different [11]. First, the role of AX2R is well known as a receptor for annexin A2 in NV, particularly in tumour diseases [24]. Overexpression of annexin A2, binding and co-localization with S100A10 mediated S100A10 to promote tumour invasion, metastasis, and angiogenesis [25].…”

Up-regulation of annexin A2 expression predicates advanced clinicopathological features and poor prognosis in hepatocellular carcinoma

“…Actually, ANXA2 is found to interact with a variety of binding protein, not only S100A10, and collectively mediate the metastasis of multiple tumors [13]. ANXA2 was further confirmed to enhance migration of HCC cells in vitro via interaction with HAb18G/CD147 [20], pancreatic cancer cells via combining with S100A6 [36], and breast cancer cells via binding to tPA [35] and promote invasion of HCC cells via activation of RhoA-Rac1 pathways and regulation of CD147-harboring microvesicles shedding from tumor cells [21,37]. Conversely, ANXA2 depletion was proved to inhibit invasion [27], delay epidermal growth factor receptor (EGFR) endocytic trafficking via cofilin activation, and enhance EGFR signaling and metastasis formation [38].…”

“…ANXA2 is up-regulated and phosphorylated [16] as the membrane receptor for β2GP I [17] and identified as a discriminative serological candidate in early HCC with a good diagnostic value [18,19]. Furthermore, ANXA2 is found to interact with HAb18G/CD147 [20], promote invasion and migration of HCC cells via the activation of RhoA-Rac1 pathways and regulation of CD147-harboring microvesicles shedding from tumor cells [21], and induce resistance to 5-fluorouracil by regulating β-catenin and cyclin D1 expression [22]. However, the relationship between ANXA2 expression and prognosis of patients with HCC has not been reported so far.…”

RNAi-mediated silencing of Anxa2 inhibits breast cancer cell proliferation by downregulating cyclin D1 in STAT3-dependent pathway

“…Accumulated evidences showed that Anxa2 is a critical regulator in promoting angiogenesis, cancer cell proliferation, cell cycle progression, migration, invasion, and metastasis [5,50,51,59,[61][62][63][64]. Nevertheless, the detailed molecular mechanisms involved in these processes remain elusive.…”

“…The increased expression levels of Anxa2 in cancer tissues are associated with rapid recurrence [21,45], metastasis [32,52], poor response to chemotherapy [6,20], and poor prognosis [32,45]. Importantly, Anxa2 promotes cell adhesion [44], migration [40,44,59,61,62], invasion [51,57,59,61], EMT [63,64], and angiogenesis [26,38], which are crucial for cancer metastasis. In vitro studies demonstrated that Anxa2 downregulation significantly blocks cell cycle progression, cell division, and cell proliferation in cell lines derived from multiple myeloma [2], breast cancer [42,58], and lung cancer [47]; conversely, Anxa2 upregulation promotes cancer cell proliferation [51], these studies presented the implication of Anxa2 in cell cycle progression and cell proliferation.…”