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HMGA1 regulates the Plasminogen activation system in the secretome of breast cancer cells.

ABSTRACT: Cancer cells secrete proteins that modify the extracellular environment acting as autocrine and paracrine stimulatory factors and have a relevant role in cancer progression. The HMGA1 oncofetal protein has a prominent role in controlling the expression of an articulated set of genes involved in various aspect of cancer cell transformation. However, little is known about its role in influencing the secretome of cancer cells. Performing an iTRAQ LC-MS/MS screening for the identification of secreted proteins, in an inducible model of HMGA1 silencing in breast cancer cells, we found that HMGA1 has a profound impact on cancer cell secretome. We demonstrated that the pool of HMGA1-linked secreted proteins has pro-migratory and pro-invasive stimulatory roles. From an inspection of the HMGA1-dependent secreted factors it turned out that HMGA1 influences the presence in the extra cellular milieu of key components of the Plasminogen activation system (PLAU, SERPINE1, and PLAUR) that has a prominent role in promoting metastasis, and that HMGA1 has a direct role in regulating the transcription of two of them, i.e. PLAU and SERPINE1. The ability of HMGA1 to regulate the plasminogen activator system may constitute an important mechanism by which HMGA1 promotes cancer progression.

SUBMITTER: Resmini G

PROVIDER: S-EPMC5603555 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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HMGA1 regulates the Plasminogen activation system in the secretome of breast cancer cells.

Resmini Giulia G Rizzo Serena S Franchin Cinzia C Zanin Rossella R Penzo Carlotta C Pegoraro Silvia S Ciani Yari Y Piazza Silvano S Arrigoni Giorgio G Sgarra Riccardo R Manfioletti Guidalberto G

Scientific reports 20170918 1

Cancer cells secrete proteins that modify the extracellular environment acting as autocrine and paracrine stimulatory factors and have a relevant role in cancer progression. The HMGA1 oncofetal protein has a prominent role in controlling the expression of an articulated set of genes involved in various aspect of cancer cell transformation. However, little is known about its role in influencing the secretome of cancer cells. Performing an iTRAQ LC-MS/MS screening for the identification of secrete ...[more]

PMID: 28924209

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Project description:Angiogenin (ANG), a 14-kDa pro-angiogenic secreted protein, has been shown to play a role in cell migration and tumor invasion, which involve proteolytic cleavage of plasminogen to generate plasmin. However, the mechanism by which ANG regulates plasmin formation and cell migration was not known. Our studies here detected elevated levels of secreted and cell surface-bound ANG in highly invasive metastatic breast cancer cells. ANG was also detected at very high levels in the tumor cells in infiltrating ductal carcinomas. By immunofluorescence and immunoprecipitation analysis, ANG was detected at the leading edges of the cell surfaces where it colocalized and interacted with members of the plasminogen activation system (PAS) such as annexin A2 (A2), calpactin (S100-A10) and urokinase plasminogen activator receptor (uPAR). Analysis of lipid raft (LR) and non-lipid raft (NLR) regions of the cell membranes showed the predominance of ANG, A2 and S100-A10 in the LR regions. In contrast, uPAR was detected predominantly in the NLR fractions, suggesting that ANG interacts with uPAR at the junctions of LR and NLR regions. ANG knockdown in T47D and MDA-MB-231 breast cancer cell lines did not affect the cellular expression of A2, S100-A10 and uPAR but decreased cell migration and plasmin formation. Neutralization of ANG with monoclonal antibodies similarly decreased the migration of MDA-MB-231 cells. In the presence of ANG, uPAR was observed to interact with uPA, which is necessary for plasmin formation. Conversely, in the absence of ANG, uPAR did not interact with uPA and FAK and Src kinases were observed to be dephosphorylated. Exogenous addition of recombinant ANG to ANG knocked down MDA-MB-231 cells restored FAK phosphorylation, uPAR interactions with uPA, plasmin formation as well as migration of these cells. Taken together, our results identified a novel role for ANG as a member of the uPAR interactome that facilitates the interaction of uPAR with uPA, leading to plasmin formation and cell migration necessary for tumor invasion and metastasis of breast cancer cells.

Dataset Information

HMGA1 regulates the Plasminogen activation system in the secretome of breast cancer cells.

Publications

HMGA1 regulates the Plasminogen activation system in the secretome of breast cancer cells.

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