Upregulation of HYAL1 Expression in Breast Cancer Promoted Tumor Cell Proliferation, Migration, Invasion and Angiogenesis

Faculdade de Medicina, Universidade de São Paulo, Brazil
PLoS ONE (Impact Factor: 3.23). 07/2011; 6(7):e22836. DOI: 10.1371/journal.pone.0022836
Source: PubMed


Hyaluronic acid (HA) is a component of the Extra-cellular matrix (ECM), it is closely correlated with tumor cell growth, proliferation, metastasis and angiogenesis, etc. Hyaluronidase (HAase) is a HA-degrading endoglycosidase, levels of HAase are elevated in many cancers. Hyaluronidase-1 (HYAL1) is the major tumor-derived HAase. We previously demonstrated that HYAL1 were overexpression in human breast cancer. Breast cancer cells with higher HAase expression, exhibited significantly higher invasion ability through matrigel than those cells with lower HAase expression, and knockdown of HYAL1 expression in breast cancer cells resulted in decreased cell growth, adhesion, invasion and angiogenesis. Here, to further elucidate the function of HYAL1 in breast cancer, we investigated the consequences of forcing HYAL1 expression in breast cancer cells by transfection of expression plasmid. Compared with control, HYAL1 up-regulated cells showed increased the HAase activity, and reduced the expression of HA in vitro. Meantime, upregulation of HYAL1 promoted the cell growth, migration, invasion and angiogenesis in vitro. Moreover, in nude mice model, forcing HYAL1 expression induced breast cancer cell xenograft tumor growth and angiogenesis. Interestingly, the HA expression was upregulated by forcing HYAL1 expression in vivo. These findings suggested that HYAL1-HA system is correlated with the malignant behavior of breast cancer.

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    • "HYAL2 expression was significantly increased in all premalignant and malignant melanocytic lesions compared to the benign nevi. In the urothelial carcinoma [47], prostate adenocarcinoma [48] and breast carcinoma [49] HYAL1 has been considered the mostly expressed tumor-derived hyaluronidase. In our specimens, the staining pattern of HYAL1 was not altered in the lesions compared to benign nevi, but the intensity of HYAL1 in melanocytic cells was decreased in superficial and deep melanoma and lymph node metastases compared to in situ melanomas. "
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    ABSTRACT: Background Hyaluronan is an extracellular matrix glycosaminoglycan involved in invasion, proliferation and metastasis of various types of carcinomas. In many cancers, aberrant hyaluronan expression implicates disease progression and metastatic potential. Melanoma is an aggressive skin cancer. The role of hyaluronan in melanoma progression including benign nevi and lymph node metastases has not been investigated earlier, nor the details of its synthesis and degradation. Methods The melanocytic and dysplastic nevi, in situ melanomas, superficially and deeply invasive melanomas and their lymph node metastases were analysed immunohistochemically for the amount of hyaluronan, its cell surface receptor CD44, hyaluronan synthases 1–3 and hyaluronidases 1–2. Results Hyaluronan content of tumoral cells in deeply invasive melanomas and metastatic lesions was clearly reduced compared to superficial melanomas or benign lesions. Furthermore, hyaluronan content in the stromal cells of benign nevi was higher than in the premalignant or malignant tumors. The immunopositivity of hyaluronidase 2 was significantly increased in the premalignant and malignant lesions indicating its specific role in the degradation of hyaluronan during tumor progression. Similarly, the expression of hyaluronan synthases 1–2 and CD44 receptor was decreased in the metastases compared to the primary melanomas. Conclusions These findings suggest that the reciprocal relationship between the degrading and synthesizing enzymes account for the alterations in hyaluronan content during the growth of melanoma. These results provide new information about hyaluronan metabolism in benign, premalignant and malignant melanocytic tumors of the skin.
    BMC Cancer 04/2013; 13(1):181. DOI:10.1186/1471-2407-13-181 · 3.36 Impact Factor
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    • "Two human breast cancer cell lines, MDA-MB-231 and MCF-7, were obtained from the Cell Bank of Chinese Academy of Sciences (Shanghai, China). The breast cancer cells were cultured in medium (MDA-MB-231 cells were in L15 medium, for MCF-7 cells were RPMI-1640) containing 10% fetal bovine serum, 2 mM l-glutamine, 100 U/ml penicillin and 100 µg/ml streptomycin in a humidified incubator at 37°C with 5% CO2 [18], [20], [21]. We have previously reported that one hour of temperin-1CEa incubation exerts cytotoxicity to MDA-MB-231 and MCF-7 cells with IC50 values of 31.78 and 63.26 µM respectively [18]. "
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    ABSTRACT: Temporin-1CEa is an antimicrobial peptide isolated from the skin secretions of the Chinese brown frog (Rana chensinensis). We have previously reported the rapid and broad-spectrum anticancer activity of temporin-1CEa in vitro. However, the detailed mechanisms for temporin-1CEa-induced cancer cell death are still weakly understood. In the present study, the mechanisms of temporin-1CEa-induced rapid cytotoxicity on two human breast cancer cell lines, MDA-MB-231 and MCF-7, were investigated. The MTT assay and the LDH leakage assay indicated that one-hour of incubation with temporin-1CEa led to cytotoxicity in a dose-dependent manner. The morphological observation using electronic microscopes suggested that one-hour exposure of temporin-1CEa resulted in profound morphological changes in both MDA-MB-231 and MCF-7 cells. The membrane-disrupting property of temporin-1CEa was further characterized by induction of cell-surface exposure of phosphatidylserine, elevation of plasma membrane permeability and rapid depolarization of transmembrane potential. Moreover, temporin-1CEa evoked intracellular calcium ion and reactive oxygen species (ROS) elevations as well as collapse of mitochondrial membrane potential (Δφm). In summary, the present study indicates that temporin-1CEa triggers rapid cell death in breast cancer cells. This rapid cytotoxic activity might be mediated by both membrane destruction and intracellular calcium mechanism.
    PLoS ONE 04/2013; 8(4):e60462. DOI:10.1371/journal.pone.0060462 · 3.23 Impact Factor
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    ABSTRACT: The relationship between cancer progression and chronic inflammation is well documented but poorly understood. The innate immune system has long been recognized as the first line of defense against invading pathogens. More recently, endogenous molecules released from tissue matrix (Damage Associated Molecular Patterns [DAMPs]) following tissue injury or periods of active matrix remodeling have also been identified as regulators of innate immunity. DAMPs have been identified as ligands for Toll-like receptors (TLRs), a family of cell-surface proteins which regulate the immune response. TLRs have been identified on resident tissue cells as well as most tumor cells. Therefore, dysregulation of the innate immune response secondary to biochemical and mechanical driven changes in the extracellular matrix of the tumor microenvironment may be a critical component of the chronic inflammation associated with tumor progression. Here we review the role of extracellular matrix (ECM)-derived DAMPS in the activation of TLR4 signaling in the context of tumor progression. We also explore the various types of topographical changes that can lead to ECM-derived DAMPs and their contribution to TLR4 activation.
    01/2013; 9:1-13.
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