Adipocyte-Derived Leptin Promotes PAI-1-Mediated Breast Cancer Metastasis in a STAT3/miR-34a Dependent Manner

Abstract

The crosstalk between cancer cells and adipocytes is critical for breast cancer progression. However, the molecular mechanisms underlying these interactions have not been fully characterized. In the present study, plasminogen activator inhibitor-1 (PAI-1) was found to be a critical effector of the metastatic behavior of breast cancer cells upon adipocyte coculture. Loss-of-function studies indicated that silencing PAI-1 suppressed cancer cell migration. Furthermore, we found that PAI-1 was closely related to the epithelial-mesenchymal transition (EMT) process in breast cancer patients. A loss-of-function study and a mammary orthotopic implantation metastasis model showed that PAI-1 promoted breast cancer metastasis by affecting the EMT process. In addition, we revealed that leptin/OBR mediated the regulation of PAI-1 through the interactions between adipocytes and breast cancer cells. Mechanistically, we elucidated that leptin/OBR further activated STAT3 to promote PAI-1 expression via miR-34a–dependent and miR-34a–independent mechanisms in breast cancer cells. In conclusion, our study suggests that targeting PAI-1 and interfering with its upstream regulators may benefit breast cancer patients.

Cancer‑associated fibroblast‑induced M2‑polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor‑1 pathway

“…Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor encoded by the serpin family E member 1 gene ( 16 ). PAI-1 was found to be upregulated in a variety of different tumors, such as breast ( 17 ), ovarian ( 18 ) and colon cancers ( 19 ), and possess several pro-tumorigenic functions, including supporting proliferation and angiogenesis, inhibiting cell apoptosis and promoting metastasis ( 17 , 18 , 20 ). Along with cancer cells, several other components of the TME, including platelets, macrophages and vascular cells, also secrete PAI-1 ( 16 , 21 ).…”

Breast cancer heterogeneity and its implication in personalized precision therapy

“…After the activation of PI3K/AKT in the breast cancer cells, the expression of IL-6, IL-1β, and tumor necrosis factor-α (TNF-α) in breast cancer cells is increased [ 131 ]. Leptin can also promote plasminogen activator inhibitor-1 expression, which is related to EMT, by activating STAT3 to promote metastasis [ 132 ]. Free fatty acids (FFAs) [ 133 ], monocyte chemoattractant protein-1 (MCP-1) [ 134 ], CC-chemokine ligand 5(CCL5) [ 135 ], and insulin-like growth factor 1 (IGF-1) [ 136 ] secreted by CAAs can induce breast cancer cells to be more invasive or more proliferative.…”

Leptin and Cancer: Updated Functional Roles in Carcinogenesis, Therapeutic Niches, and Developments

“…An orthotopic implantation metastasis model further revealed that plasminogen activator inhibitor-1 (PAI-1) is required for breast cancer metastasis. Mechanistically, the upregulation of PAI-1 expression was elicited by leptin-LEPR-miR-34a axis-mediated STAT3 signaling activation [53]. Leptin also elicits metabolic reprogramming in breast cancer.…”

“…The demonstrations of main biological effects (Table 2) and signaling axes (Figure 4) induced by leptin/leptin receptor in different cancer types were shown. Ovarian Cancer ↑: [41] ↑: [38][39][40]42] ↑: (paclitaxel/docetaxel) [36] Brain Tumor ↑: [45,46] ↑: [47,48] ↑: [45] ↑: (temozolomide) [49] Breast Cancer ↑: [54,58] ↑: [53,55] Liver Cancer ↑: [60,63] ↑: [60,63] ↓: [63] ↓: [65] (rat)…”